Cardiovascular diseases and diabetes: causes and cures · focusing on the management of cardiovascular diseases. Its aim is to inform cardiologists and other specialists about the

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Cardiovascular diseases and diabetes: causes and cures

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Number 73 - July 2017

Heart and Metabolism


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Luis Henrique W. Gowdak, MD, PhD, BrazilDerek J. Hausenloy, PhD, UKGary D. Lopaschuk, PhD, CanadaMichael Marber, MB (BS), PhD, UK

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Heart and Metabolism is a journal published three times a year, focusing on the management of cardiovascular diseases. Its aim is to inform cardiologists and other specialists about the newest findings on the role of metabolism in cardiac disease and to explore their potential clinical implications. Each issue includes an editorial, followed by articles on a key topic. Experts in the field explain the metabolic consequences of cardiac disease and the multiple potential targets for phar-macotherapy in ischemic and nonischemic heart disease.

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Contents

EDITORIALDiabetes: getting to the heart of the matter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2G. D. Lopaschuk

ORIGINAL ARTICLESDiabetes: the cost of globalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4P. M. Nilsson, L. Bennet

Better glycemic control and cardiovascular outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9G. D. Lopaschuk

Treating myocardial ischemia in diabetics: drugs, surgery, and stents . . . . . . . . . . . . . . . . . . . . . . . . . . . .13R. Belardinelli

Early detection of left ventricular dysfunction in diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18D. Y. Leung, M. Leung

Clinical benefits of targeting cardiac cells directly with trimetazidine in patients with coronary disease and diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24G. Fragasso, G. Anastasia, G. Monaca, G. Pinto

CASE REPORT Managing chest pain in a diabetic patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29M. C. Scali

REFRESHER CORNERCardiac energy metabolism in diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33K. L. Ho, J. R. Ussher

HOT TOPICSCardiovascular diseases and diabetes: causes and cures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37J. E. Salles

GLOSSARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40G. D. Lopaschuk

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Heart Metab. (2017) 73:2-3Editorial - Gary d. lopaschuk

The prevalence of diabetes worldwide has reached epidemic proportions, with the number of type 2 diabetes mellitus (T2DM)

patients now exceeding 400 million.1 This is a major concern, as T2DM patients are at a much higher risk of developing myocardial ischemia and heart failure than nondiabetic individuals.2 As a result, cardiovas-cular disease is the major cause of death of T2DM patients.2 Although initially considered a “vascular dis-ease” with its associated accelerated atherosclerosis, it is now evident that diabetes also directly affects cardiac cellular mechanisms that can contribute to the incidence and severity of heart failure and isch-emic heart disease. This creates both problems and opportunities when treating the diabetic patient with cardiovascular disease. The main problem is that the physician must not only treat the heart disease, but also control the diabetes. There is opportunity arising from understanding how diabetes directly affects the cellular mechanisms contributing to heart disease, as this has the potential to reveal new targets and approaches in treating cardiovascular disease in the diabetic. The articles in this issue of Heart and Metabolism address the important problem of cardio-vascular disease in the diabetic while addressing both the causes and potential cures for cardiovascular disease in the T2DM patient. The rapid rise in the incidence of T2DM worldwide is especially evident in the South Asian population where T2DM has increased dramatically in places such as India and China. In their article, Peter Nilsson and Louise Bennet highlight how diabetes is a global

concern and the importance of taking a global view in treating diabetes. They also discuss the significant issue of migration and T2DM risk, while emphasiz-ing the importance of public measures to tackle the epidemic in migrant populations at risk for developing diabetes. This includes the promotion of healthy life-styles and improvement of social conditions for these migrant populations. The risk of developing heart failure positively cor-relates with the degree of hyperglycemia in the T2DM patient.3 Although this would imply that lowering blood glucose should decrease cardiovascular risk, this is not always the case. Despite the rapidly expanding list of antihyperglycemic agents used to treat T2DM, many of these agents are not associated with improved cardio-vascular outcomes. However, as reviewed by myself in this issue of Heart and Metabolism, recent large clinical outcome trials have provided evidence that some new-er antihyperglycemic agents can significantly improve cardiovascular outcomes in the T2DM patient. These clinical studies provide encouraging evidence that cer-tain types of glycemic control may be an important approach to lessening the severity of cardiovascular disease in the T2DM patient. Management of heart disease in diabetic pa-tients is complex but should follow the same general principles as for patients without diabetes, which in-cludes controlling ischemic symptoms and reducing ischemic burden. The article by Romualdo Belardinelli nicely describes the indications for medical therapy versus coronary revascularization in diabetic patients with both diabetes and ischemic heart disease. Man-

Diabetes: getting to the heart of the matterGary D. Lopaschuk, PhDMazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada

Correspondence: Dr Gary D. Lopaschuk, 423 Heritage Medical Research Building, University of Alberta, Edmonton, Alberta T6G 2S2, CanadaE-mail: [email protected]

2

agement issues are also evident in diabetic patients presenting with heart failure. Patients with diabetes are at high risk for developing left ventricular dysfunc-tion and heart failure. The article by Dominic Leung and Melissa Leung describes the need for early com-prehensive assessment of cardiac structure and func-tion in diabetics at risk for developing heart disease and the role exercise echocardiography has in this process. Maria Scali also provides an insightful case report as to the need for risk stratification in treat-ing the diabetic with chest pain. A low-cost approach using echocardiography, electrocardiogram changes, and coronary flow reserve provides a versatile ap-proach to treating the diabetic with chest pain. The article by Joao Eduardo Salles provides insights into what the cardiologist needs to know with regard to the new drugs that are now available to control blood glucose in the diabetic, as well as their implications for cardiovascular disease risk. Diabetes results in some dramatic alterations in energy metabolism in the heart. Diabetes can result in unique changes in cardiac function and metabolism, especially at the level of cardiac energy metabolism. The article by Kim Ho and John Ussher provides an update on what is known about the dramatic switch in energy metabolism from glucose to fatty acid me-tabolism and the implications of this on cardiac func-tion in the diabetic. These cardiac metabolic changes seen in the diabetic provide an opportunity to treat

heart disease in the diabetic using approaches that directly target cardiac energy metabolism. The article by Gabriele Fragasso and colleagues describes how using the metabolic modulator trimetazidine could be one such approach. Inhibition of fatty acid oxidation has emerged as a new approach to treating ischemic heart disease and heart failure. This type of approach may be particularly relevant in the diabetic with heart disease due to the metabolic switch in the heart to-ward an excessive use of fatty acids. Cardiovascular disease has now become the number one cause of death worldwide. The rapid global rise in the incidence of T2DM is an important contributor to this grim statistic. Hopefully, this issue of Heart and Metabolism will provide some unique perspectives not only on how the diabetic patient with heart disease should be treated, but also for fu-ture direction in how the diabetic patient should be managed. L

REFERENCES

1. World Health Organization. Global Report on Diabetes, 2016. Available at: http://www.who.int/diabetes/global-report/en/. Published 2016. Accessed December 4, 2016.

2. Seshasai SR, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. Emerging Risk Factors Collaboration. N Engl J Med. 2011;364:829-841.

3. Erqou S, Lee CT, Suffoletto M, et al. Association between gly-cated haemoglobin and the risk of congestive heart failure in diabetes mellitus: systematic review and meta-analysis. Eur J Heart Fail. 2013;15(2):185-193.

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Heart Metab. (2017) 73:2-3 lopaschuk

Diabetes: getting to the heart of the matter

4

The growth of type 2 diabetes (T2DM) as a global public health threat has attracted considerable attention over the last 2 de-

cades. Epidemiological studies have predicted that whereas 422 million subjects were affected by diabetes in 2014, the coming decades will see an astonishing 438 million adults affected by 2030 (www.idf.org). A recent review in The Lancet con-cluded that the burden of diabetes, both in terms of prevalence and number of adults affected, has increased faster in low-income and middle-income countries than in high-income countries.1 The tre-mendous cost of this diabetes epidemic can be counted not only in financial terms as cost of ill-ness, treatment, and disability, but also in terms of the human cost of suffering and a lowered health-related quality of life.

Contributing factors to the diabetes epidemic

The increasing burden of T2DM on a global scale is a reflection of a number of contributing factors with considerable health consequences. First of all, the aging of many populations, with an increasing pro-portion of elderly people, will contribute to the grow-ing number of subjects reaching the age ranges where T2DM becomes more prevalent. Other con-tributing factors include a wider screening effort in health care and a time trend for lowering the plasma glucose threshold for a diagnosis of T2DM. However, the most important factor is probably the detrimen-tal lifestyle changes that are now characteristic of not only Western populations, but also to a substantial proportion of populations in developing countries.2,3 For example, the growing middle class in countries

Diabetes: the cost of globalizationPeter M. Nilsson, MD, PhD; Louise Bennet, MD, PhD

Department of Clinical Sciences, Lund University, Skåne University Hospital, S-20502 Malmö, Sweden

Correspondence: Peter M. Nilsson, MD, PhD, Internal Medicine Research Group, Department of Clinical Sciences, Jan Waldenströms gata 15, 5th floor, Skåne University Hospital, S-20502 Malmö, Sweden

(E-mail: [email protected])

AbstractThe epidemic of type 2 diabetes mellitus (T2DM) on a global scale is a matter of concern, not only from a public health perspective, but also with consideration of societal costs. The increased call on health care resources to treat and monitor T2DM and its complications could put a heavy burden on national health care systems and financing. An important contributing factor for development of T2DM is lifestyle, reflecting increasing affluence and exposure to increased calorie intake in combination with sedentary lifestyle and less human energy expenditure. More detailed glucometabolic studies have been conducted in high-risk migrant populations, eg, from the Middle East. Recently, intervention programs have also been tested to improve lifestyle and reduce the risk of developing T2DM in at-risk individuals. There are many obstacles to success for such programs, which should be tailored not only to the individual in a culture-sensitive way, but also to families and local ethnic communities. L Heart Metab. 2017;73:4-8

Keywords: costs; diabetes; global, lifestyle, migration, obesity

Heart Metab. (2017) 73:4-8OriGinal Article

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Heart Metab. (2017) 73:4-8 nilsson and Bennet

Diabetes and globalization

such as India, China, and some countries in the Mid-dle East is a factor and it is related to increasing af-fluence and a change in diet and calorie-intake com-position. At the same time, increased mechanization of the transport system and working conditions has reduced the amount of physical exercise needed on a daily basis. This is further influenced by a passive lifestyle related to sedentary leisure activities, such as watching television or time spent on the computer, so-called “screen time.” The young generation is es-pecially affected, and this is a reason to worry, as the sedentary young individuals of today risk becoming the patients with T2DM of tomorrow. Another contrib-uting risk factor is smoking, now very prevalent in de-veloping countries even though smoking prevalence rates have decreased in many Western countries. Heavy smoking has been associated with increased insulin resistance, β-cell unresponsiveness to se-creted insulin, chronic inflammation, and impaired glucose metabolism.4 Furthermore, smoking is often combined with an increased intake of alcohol, at least in cultures and countries with no ban on alcohol. This factor could contribute to the damage of pancreatic function and thus act in synergy with heavy smoking to increase the risk of T2DM. Also, smokers tend to have a spontaneously chosen selected diet, including more coffee, alcohol, sucrose, and saturated fat, but less vitamins, vegetables, and fruits, than nonsmok-ers.5 This may be influenced by impaired taste bud function or triggering of brain reward systems due to smoking.

The role of obesity in a global perspective

An interesting aspect is that obesity could be a major contributing factor for T2DM, as it is globally increas-ing, but with different thresholds for diabetes risk. For example, in Asian populations, the risk of type 2 dia-betes starts to increase at a lower body mass index (BMI) than in Western populations,6 and this could also be influenced by the fat distribution; there is a relatively more pronounced tendency for abdominal obesity in subjects of Asian origin. Therefore genetic factors could contribute to differential susceptibility to obesity-induced glucometabolic changes. With globalization, there is an increased flux of people, goods, and work opportunities across bor-ders and regions all around the world. There remain many obstacles to globalization, such as restrictive

regulations, laws, and border controls; nevertheless, political and societal changes in the wake of war, fam-ine, and catastrophes has forced millions of refugees and migrants to cross borders and to move from one country or region to another, often far away. So far, this has influenced lifestyle changes, cultural norms, and health behaviors (and will continue to do so). One typical example is the profound change in lifestyle that migrants from the Middle East region experience as they come to live in Western countries. In addition, these immigrants will also face social problems and adverse living and working conditions, as well as so-cial tensions, prejudice, and even racism, factors that could contribute to social stress, isolation, and diffi-culties in coping with cultural changes during the ac-culturation process. For some migrants with a cultural background where obesity is seen as a sign of wealth and prosperity and, for women, a sign of fertility, the health messages of leanness and calorie restriction in Western societies is sometimes hard to understand and accept. In addition, some religious beliefs could affect eating habits and the timing of food intake (eg, Ramadan), a factor that is associated with adverse changes in glucose metabolism.7

On the other hand, it should not be overlooked that globalization can also encourage healthy eating as free trade can increase the supply of cheap veg-etables, fruits, and seafood. The flux of people visiting other countries could increase exposure to sunshine (vitamin D) and recreation, both of which are health-promoting factors. However, there is also a downside to global trade and traveling, as transportation is en-ergy dependent and contributes to the burden on the environment.

Migration and type 2 diabetes risk

The risk of T2DM in the wake of migration and glo-balization has been studied in certain populations, for example, in people of South Asian origin moving to London in the UK and adapting a Western lifestyle.8 These subjects are known to be at increased risk for developing features of the metabolic syndrome (eg, abdominal obesity, impaired glucose metabolism, and T2DM). One contributing factor besides genetics could be an individual background of impaired fetal growth and the small-for-gestational-age birth phe-notype, as this has been shown to affect the risk of developing T2DM in adult life if combined with un-

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nilsson and Bennet Heart Metab. (2017) 73:4-8Diabetes and globalization

healthy lifestyle.9 Also, diabetes in pregnancy is a growing problem in developing countries,10 with an impact on health in the offspring, thus reinforcing the importance of early life conditions for understanding the global epidemic of T2DM. In Sweden today, 1.6 million out of almost 10 million inhabitants are born abroad with the largest non-European immigrant groups represented by im-migrants from the Middle East, Africa, and Asia (Sta-tistics Sweden, 2016). Extensive epidemiological research on the risk of T2DM in migrants from the Middle East to Sweden has been carried out. Wändell et al has documented that the prevalence of T2DM is at least doubled in migrants from the Middle East, including Turkey and Iraq, as compared with Swed-ish-born subjects.11-13 This phenomenon is especially pronounced in obese Turkish women, as influenced by parity, sedentary lifestyle, and suboptimal dietary habits, even if smoking is not frequent.

The MEDIM study in Iraqi immigrants

In the MEDIM study (the impact of Migration and Ethnicity on Diabetes In Malmö), conducted in the city of Malmö, Sweden, a number of observational, mechanistic, and intervention studies were under-taken to elucidate mechanisms contributing to the increased risk of impaired glucose metabolism and T2DM in adult migrants from Iraq.14-17 The findings from MEDIM, which investigated approximately 1400 Iraqi immigrants and 800 native Swedes via oral glu-cose tolerance testing (OGTT), shows prevalence rates of T2DM of 12% and 6%, respectively. How-ever, the prevalence of T2DM in urban areas in Iraq reaches 19% and is considerably higher than in rural areas (7.5%).18 This higher prevalence in Iraqi cities is thought to be a consequence of a less physically active lifestyle, sedentary work, and higher access to calorie-dense foods than in rural life. Such data could indicate that there is no “true” worsening migration effect (ie, that stress and lifestyle change during mi-gration should increase cardiometabolic disease as is shown in other immigrant groups). One reason for this could be that life in an urban area in Sweden presents a relatively healthy environment compared with urban areas in the Middle East, with access to healthy foods, physical activity opportunities, and public health care, in spite of social adversities. Still, the prevalence of T2DM in Iraqis is twice as high as in

the native Swedish population, and furthermore, the Iraqi immigrants develop T2DM 6 to 7 years earlier than native Swedes. The high T2DM is thus not fully explained by well-known diabetes-related risk factors, such as unhealthy lifestyle, obesity, family history, or socioeconomic vulnerability that clusters in this popu-lation; this indicates that a genetic mechanism may contribute to the increased risk. The Iraqi population displays impaired glucose metabolism with higher glycated hemoglobin (HbA1c) levels and increased insulin resistance, even in the nondiabetic range.19 Further, for the same BMI level, insulin sensitivity is more impaired in the Iraqi immigrant population (Fig-ure 1). One contributing factor to this insulin resis-

tance could be a higher prevalence of nonalcoholic fatty liver disease (NAFLD), which is found to differ in prevalence across ethnicities. Estimation of NAFLD via index scores has shown that the Iraqi population has a higher prevalence, and that NAFLD indices are more strongly associated with insulin resistance in the Iraqi than in the native Swedish population. This indicates that the liver may play a key role in fat and glucose regulation in this population.20

Data from the National Diabetes Register in Swe-den shows that although non-Westernized immigrants diagnosed with T2DM are offered more frequent visits to physicians, their glycemic control is worse, and they develop diabetic microvascular complications faster, than native Swedes.21 Altogether, these data indicate that T2DM in non-Westernized populations progresses faster and is a more complex condition to prevent and manage than T2DM in a native Swedish population.

180 –

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Body mass index>32.5

Insu

lin s

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Born in SwedenBorn in Iraq

Fig. 1 Insulin-sensitivity index (ISI) in relation to body mass index (BMI) in a population of immigrants from Iraq and of native Swedes. Differences in median values of ISI between the two ethnic popula-tions increase with lower BMI and are most obvious in nonobese participants.

Diabetes prevention programs in immigrants

Increased knowledge of mechanisms contributing to the increased diabetes risk in non-European immi-grants is important for the prevention and treatment of diabetes in these populations. A Cochrane review provides evidence that culturally adapted lifestyle in-terventions addressing non-Westernized immigrants with T2DM have beneficial effects on glycemic control in the short term (<24 months), but longer studies are needed.22 In Sweden and Norway, beneficial effects of culturally adapted programs targeting immigrants from Iraq and Pakistan still free from T2DM have shown beneficial effects on cardiometabolic control, indicating that such programs have beneficial preven-tive effects.17,23 The question is how such programs should be organized, since resources addressing preventive actions are not prioritized today. It is highly probable that more proactive primary prevention strategies addressing non-Westernized immigrant populations could save costs spent on dia-betes, but would also contribute to a higher quality of life and health equality.

Summary

In summary, the high cost of globalization for the growing epidemic of T2DM is not only counted in terms of health care, but also in terms of human suf-fering and reduced health-related quality of life. Public health measures to tackle the epidemic should involve both societal changes, such as promotion of healthy lifestyle and improved social conditions for growing populations, and prevention aimed at individuals, families, and local communities.22,24 The technologi-cal changes on a global scale could promote seden-tary lifestyle, but they could also be used to support a healthy lifestyle if consumption of healthy food could be made easier and cheaper. A reduction in smok-ing and alcohol intake could add to the preventive measures of importance not only to counteract the epidemic of T2DM, but also of other chronic disease conditions. Further studies on mechanisms involved to better understand the transition to T2DM in mi-grant populations at risk will be of importance to tailor preventive programs. The time is ripe to offer at-risk populations and individuals access to preventive pro-grams to improve lifestyle and glucose metabolism. Such projects are already underway and should be

expanded in order to increase the evidence base for effective methods. L

REFERENCES

1. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: a pooled analysis of 751 pop-ulation-based studies with 4.4 million participants. Lancet. 2016;387(10027):1513-1530.

2. NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet. 2016;387(10026):1377-1396.

3. Henson J, Dunstan DW, Davies MJ, Yates T. Sedentary behav-iour as a new behavioural target in the prevention and treatment of type 2 diabetes. Diabetes Metab Res Rev. 2016;32(suppl 1):213-220.

4. Pan A, Wang Y, Talaei M, Hu FB, Wu T. Relation of active, pas-sive, and quitting smoking with incident type 2 diabetes: a sys-tematic review and meta-analysis. Lancet Diabetes Endocrinol. 2015;3(12):958-967.

5. Nuttens MC, Romon M, Ruidavets JB, et al. Relationship be-tween smoking and diet: the MONICA-France project. J Intern Med. 1992;231(4):349-356.

6. Chan JC, Malik V, Jia W, et al. Diabetes in Asia: epidemiology, risk factors, and pathophysiology. JAMA. 2009;301(20):2129-2140.

7. Hassan A, Meo SA. Diabetes during Ramadan: underestimated, under-investigated, needs more attention. Eur Rev Med Phar-macol Sci. 2014;18(22):3528-3533.

8. Barnett AH, Dixon AN, Bellary S, et al. Type 2 diabetes and cardiovascular risk in the UK south Asian community. Diabeto-logia. 2006;49(10):2234-2246.

9. Berends LM, Ozanne SE. Early determinants of type-2 diabe-tes. Best Pract Res Clin Endocrinol Metab. 2012;26(5):569-580.

10. Kanguru L, Bezawada N, Hussein J, Bell J. The burden of diabetes mellitus during pregnancy in low- and middle-income countries: a systematic review. Glob Health Action. 2014;7:23987.

11. Wändell PE, Hjörleifsdottir Steiner K, Johansson SE. Diabe-tes mellitus in Turkish immigrants in Sweden. Diabetes Metab. 2003;29(4 pt 1):435-439.

12. Wändell PE, Wajngot A, de Faire U, Hellénius ML. Increased prevalence of diabetes among immigrants from non-European countries in 60-year-old men and women in Sweden. Diabetes Metab. 2007;33(1):30-36.

13. Hjörleifsdottir-Steiner K, Satman I, Sundquist J, Kaya A, Wändell P. Diabetes and impaired glucose tolerance among Turkish immigrants in Sweden. Diabetes Res Clin Pract. 2011;92(1):118-123.

14. Bennet L, Groop L, Lindblad U, Agardh CD, Franks PW. Eth-nicity is an independent risk indicator when estimating diabe-tes risk with FINDRISC scores: a cross sectional study com-paring immigrants from the Middle East and native Swedes. Prim Care Diabetes. 2014;8(3):231-238.

15. Bennet L, Groop L, Franks PW. Ethnic differences in the con-tribution of insulin action and secretion to type 2 diabetes in immigrants from the Middle East compared to native Swedes. Diabetes Res Clin Pract. 2014;105(1):79-87.

16. Bennet L, Stenkula K, Cushman SW, Brismar K. BMI and waist circumference cut-offs for corresponding levels of insulin sen-sitivity in a Middle Eastern immigrant versus a native Swedish population – the MEDIM population based study. BMC Public Health. 2016;16(1):1242.

17. Siddiqui F, Kurbasic A, Lindblad U, Nilsson PM, Bennet L.

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nilsson and Bennet Heart Metab. (2017) 73:4-8Diabetes and globalization

Effects of a culturally adapted lifestyle intervention on cardio-metabolic outcomes: a randomized controlled trial in Iraqi im-migrants to Sweden at high risk for type 2 diabetes. Metabo-lism. 2017;66:1-13.

18. Mansour AA, Al-Maliky AA, Kasem B, Jabar A, Mosbeh KA. Prevalence of diagnosed and undiagnosed diabetes mellitus in adults aged 19 years and older in Basrah, Iraq. Diabetes Metab Syndr Obes. 2014;7:139-144.

19. Bennet L, Lindblad U, Franks PW. A family history of diabetes determines poorer glycaemic control and younger age of dia-betes onset in immigrants from the Middle East compared with native Swedes. Diabetes Metab. 2015;41(1):45-54.

20. Bennet L, Groop L, Franks PW. Country of birth modifies the association of fatty liver index with insulin action in Mid-dle Eastern immigrants to Sweden. Diabetes Res Clin Pract. 2015;110(1):66-74.

21. Rawshani A, Svensson AM, Rosengren A, Zethelius B, Eliasson B, Gudbjörnsdottir S. Impact of ethnicity on progress of gly-

caemic control in 131,935 newly diagnosed patients with type 2 diabetes: a nationwide observational study from the Swedish National Diabetes Register. BMJ Open. 2015;5(6):e007599.

22. Attridge M, Creamer J, Ramsden M, Cannings-John R, Haw-thorne K. Culturally appropriate health education for people in ethnic minority groups with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2014;(9):CD006424.

23. Telle-Hjellset V, Råberg Kjøllesdal MK, Bjørge B, et al. The InnvaDiab-DE-PLAN study: a randomised controlled trial with a culturally adapted education programme improved the risk profile for type 2 diabetes in Pakistani immigrant women. Br J Nutr. 2013;109(3):529-538.

24. Bhopal RS, Douglas A, Wallia S, et al. Effect of a lifestyle in-tervention on weight change in south Asian individuals in the UK at high risk of type 2 diabetes: a family-cluster randomised controlled trial. Lancet Diabetes Endocrinol. 2014;2(3):218-227.


Better glycemic control and cardiovascular outcomes

Gary D. Lopaschuk, PhDMazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada

Correspondence: Dr Gary D. Lopaschuk, 423 Heritage Medical Research Building, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

E-mail: [email protected]

AbstractDiabetics are at high risk of developing cardiovascular disease, which is correlated to the degree of hyperglycemia. However, pharmacological approaches to lowering blood glucose levels in diabetics is not always associated with a decrease in the risk of developing heart failure. In fact, some treat-ments actually increase the risk of cardiovascular disease. For instance, the use of thiazolidinediones (ie, rosiglitazone and pioglitazone) increases the risk of heart failure development in type 2 diabetes mellitus (T2DM) patients. Older antihyperglycemic medications, such as metformin, also seem to have a reduced risk of adverse cardiovascular outcomes compared with sulfonylureas. Newer agents, such as the glucagon-like protein 1 (GLP-1) receptor agonists, the dipeptidyl peptidase-4 (DPP-4) inhibitors, and the α-glucosidase inhibitors, appear to have neutral effects on cardiovascular outcomes. In contrast, recent trials with sodium-glucose cotransporter 2 (SGLT2) inhibitors (ie, empagliflozin) have demon-strated a dramatic decrease in adverse cardiovascular outcomes. As a result, it is clear that care must be taken in choosing the antihyperglycemic agent to be used in T2DM patients, especially if underlying cardiovascular disease is present. L Heart Metab. 2017;73:9-12

Keywords: antihyperglycemic agent; cardiovascular outcome; heart failure; type 2 diabetes mellitus

Introduction

The prevalence of diabetes worldwide has rapidly increased in the last 20 years, with the number of type 2 diabetes mellitus (T2DM) patients

now exceeding 400 million.1 These diabetic patients are at twice the risk of developing cardiovascular disease, which is the most common cause of death in diabetics.2 The risk of developing heart failure in diabetics is also positively correlated to the degree of hyperglycemia.3-6 As a result, this would imply that lowering blood glucose should decrease car-diovascular risk. However, there is uncertainty in this

regard, and lowering glucose levels may not always result in a reduction in the risk of heart failure. It is also becoming clear that the type of pharmacological approach used for lowering blood glucose may have differential effects on cardiovascular risk in the dia-betic. In fact, some antihyperglycemic therapies may actually increase the risk of developing heart failure. As a result, the European Medicines Agency and the US Food and Drug Administration implemented regulations in 2008 calling for adequately powered cardiovascular outcomes trials (CVOTs) to evaluate the efficacy and cardiovascular safety of new antihy-perglycemic agents. Although many of these CVOTs

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are still ongoing, reports from a number of trials are available; in some, antihyperglycemic agents have been reported to increase the risk of developing heart failure; in others, to have neutral effects on heart fail-ure risk or actually lessen heart failure risk. This paper reviews this clinical data.

Blood glucose and heart failure

Poor glycemic control in T2DM is associated with an increased risk of developing heart failure.6,7 This includes poor glycemic control as assessed by in-creased fasting blood glucose, postprandial blood glucose, glycated hemoglobin (HbA1c) levels, and/or measures of insulin resistance in T2DM patients. Trials such as UKPDS (the United Kingdom Pro-spective Diabetes Study) also showed a beneficial effect between lowering blood glucose and decreas-ing heart failure risk in T2DM patients.4 A number of medications have been developed to improve gly-cemic control in T2DM patients, and these include thiazolidinediones (TZDs), insulin analogs, metformin, sulfonylureas, α-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like protein 1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors. However, despite

being effective antihyperglycemic agents, these med-ications have very different effects on heart failure risk in T2DM patients. The reasons for these differences in heart failure risk in T2DM patients taking these medi-cations are not completely clear, although it is clear that it is not related to the degree of glycemic control. However, as the outcomes of more and more CVOTs trials are reported, it is clear that when choosing the type of antihyperglycemic agent to use in T2DM pa-tients, the risk of heart failure development should be carefully considered.

Thiazolidinediones

TZDs are peroxisome proliferator–activated receptor-γ agonists that have insulin-sensitizing actions. Rosigli-tazone and pioglitazone are two agents in this class of medications. However, despite favorable antihy-perglycemic and blood pressure–lowering actions, both of these agents in CVOTs showed increased risk of heart failure in T2DM patients8,9 (Table I). The rea-sons for this increase in heart failure risk are not clear, although plasma volume expansion due to increas-ing renal tubular sodium reabsorption has been pro-posed. The outcomes of these CVOTs suggests that the use of TZDs should be contraindicated in patients at high risk for heart failure.

Metformin

Metformin is an older antihyperglycemic agent that has not been investigated in larger CVOTs. However, UKPDS demonstrated that metformin reduced the rate of adverse cardiovascular outcomes in T2DM patients with heart failure compared with other an-tihyperglycemic agents.4 This included a 20% lower death rate than with other antihyperglycemic agents.

AbbreviationsCVOT: cardiovascular outcomes trial; DPP-4: dipeptidyl peptidase-4; ELIXA: Evaluation of LIXisenatide in Acute coronary syndrome [trial]; EMPA-REG OUTCOME: Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes [trial]; GLP-1: glucagon-like protein 1; SGLT2: sodium-glucose cotransporter 2; T2DM: type 2 diabetes mellitus; UKPDS: United Kingdom Prospective Diabetes Study

lopaschuk Heart Metab. (2017) 73:9-12Better glycemic control and cardiovascular outcomes

Antihyperglycemic agent Heart failure risk Hypoglycemia risk

Thiazolidinediones (rosiglitazone, pioglitazone) Increased Low

Metformin Decreased compared with sulfonylureas Low

Sulfonylureas (tolbutamide, glibenclamide) Increased compared with metformin Higher

GLP-1 receptor agonists (lixisenatide, liraglutide) Neutral Low

DPP-4 inhibitors (saxagliptin, sitagliptin) Increased with saxagliptinNeutral with sitagliptin

Low

α-Glucosidase inhibitors (acarbose) Increased compared with DPP-4 inhibitors Low

SGLT2 inhibitors (empagliflozin) Decreased Low

Table I Classes of antihyperglycemic agents and associated risks of developing heart failure and hypoglycemia in type 2 diabetes mellitus patients.Abbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like protein-1; SGLT2, sodium-glucose cotransporter 2.

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Better glycemic control and cardiovascular outcomes

Although data from CVOTs is missing, this clinical data has resulted in metformin not being contraindi-cated in T2DM patients with heart failure.10

Sulfonylureas

Sulfonylureas, such as tolbutamide and gliben-clamide, are an older class of antihyperglycemic agent and act by increasing insulin release from the β-cells in the pancreas. Like metformin, the sulfo-nylureas have not been investigated in large CV-OTs. However, a review of 72 randomized clinical trials showed that sulfonylureas did not increase all-cause mortality in T2DM patients.11 In contrast, UKPDS did show that sulfonylureas were inferior to metformin in terms of overall survival of T2DM patients.4 Although sulfonylureas are not contra-indicated in T2DM patients with heart failure, it is generally recommended that metformin be prefer-ably used in these patients.

Glucagon-like protein 1 receptor agonists

GLP-1 receptor agonists are injectable antihypergly-cemic agents that mimic the actions of GLP-1, an incretin that stimulates the release of insulin and that lowers glucagon production in T2DM patients. An advantage of these newer antihyperglycemics is that they have a low risk for hypoglycemia. Two repre-sentative GLP-1 agonists are lixisenatide and liraglu-tide. Recently completed CVOTs with these agents did not show any increased risk of heart failure de-velopment. The long-term effects of lixisenatide in CVOTs were examined in the ELIXA trial (Evaluation of LIXisenatide in Acute coronary syndrome), which enrolled 6068 patients. Although lixisenatide did not show any cardiovascular benefit in patients with T2DM and a recent acute coronary syndrome, it also did not show any harm.12 A 3.8-year CVOT was also recently completed with liraglutide, which examined the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in 9340 T2DM patients at high cardiovascular risk.13 A beneficial effect of liraglutide was seen with regard to the primary composite end point (13% vs 14.9% in placebo); a decrease in cardiovascu-lar death was also seen (4.7% vs 6.0% in placebo). This suggests that GLP-1 receptor agonists can be used in heart failure.

Dipeptidyl peptidase-4 inhibitors

DPP-4 inhibitors are oral antihyperglycemic agents that increase incretin levels (GLP-1 and gastric inhibi-tory polypeptide [GIP]) by blocking their degradation by DPP-4; they therefore increase insulin secretion and inhibit glucagon release. Saxagliptin and sita-gliptin are two representative DPP-4 inhibitors. The first major CVOT with DPP-4 inhibitors that was re-ported was with saxagliptin, which examined 16 492 patients with T2DM and a history of cardiovascular disease over a 2.1-year period.14 Although there was no difference in cardiovascular death, myocardial infarction, or stroke seen in the saxagliptin-treated patients, a significant increase in hospitalization for heart failure was observed. In addition, an increased risk for hypoglycemic events was observed. In con-trast, a recently completed CVOT (involving 14 671 patients) that examined sitagliptin in T2DM patients with cardiovascular disease showed that sitagliptin was noninferior to placebo for the primary composite cardiovascular outcomes, and no difference in hospi-talization rates for heart failure was observed.15 As a result, DDP-4 inhibitors have proven cardiovascular safety in T2DM patients, although caution should be used with saxagliptin in heart failure patients.

α-Glucosidase inhibitors

α-Glucosidase inhibitors, which include acarbose, have antihyperglycemic actions by preventing carbo-hydrate digestion in the small intestine. Although a large CVOT has not been performed with acarbose in T2DM patients, a meta-analysis of smaller random-ized clinical trials did not show any differences in heart failure outcomes. However, a recent study comparing add-on therapy with acarbose added to a combined dual therapy with metformin and sulfonylurea showed that the risk of stroke and all-cause mortality was higher with DPP-4 inhibitor add-on therapy.16

Sodium-glucose cotransporter 2 inhibitors

SGLT2 inhibitors are antihyperglycemic agents that act by preventing glucose reabsorption in proximal tubules of the kidney. Three representative SGLT2 inhibitors include empagliflozin, canafligozin, and dapagliflozin. Of these, only empagliflozin has been investigated in a complete and major CVOT, the EM-

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lopaschuk Heart Metab. (2017) 73:9-12Better glycemic control and cardiovascular outcomes

PA-REG OUTCOME trial (Empagliflozin, Cardiovas-cular Outcomes, and Mortality in Type 2 Diabetes).17 Empagliflozin was examined in high-risk patients with diabetes and established cardiovascular disease over a 3-year treatment period. The CVOT reported a dra-matic 35% to 40% relative reduction in cardiovascular death and all-cause mortality in empagliflozin-treated patients. A dramatic decrease in hospitalization for heart failure was also observed. This has generated considerable excitement, although the mechanisms for the beneficial effects of empagliflozin have not been unequivocally determined. Possible mecha-nisms for this benefit include a decrease in diuresis and plasma volume, a decrease in body weight, a decrease in blood pressure, or an increased cardiac efficiency in use of fuel.18-20 Although major CVOTs have yet to be reported for other SGLT2 inhibitors, the dramatic benefit on cardiovascular outcomes with empagliflozin and the low risk for hypoglycemic events has resulted in empagliflozin presently being evaluated for heart failure treatment even in the ab-sence of diabetes.

Summary

Although hyperglycemia is an important contributor to increased cardiovascular risk in diabetics, not all an-tihyperglycemic approaches in T2DM patients have similar effects on heart failure risk. Some pharmaco-logical approaches can actually increase heart failure risk, whereas some have neutral effects. In contrast, some approaches, such as SGLT2 inhibition, may actually significantly decrease the risk of developing heart failure in T2DM. L

REFERENCES

1. World Health Organization. Global Report on Diabetes, 2016. Available at: http://www.who.int/diabetes/global-report/en/. Published 2016. Accessed April 12, 2016.

2. Seshasai SR, Kaptoge S, Thompson A, et al. Diabetes mel-litus, fasting glucose, and risk of cause-specific death. Emerg-ing Risk Factors Collaboration. N Engl J Med. 2011;364:829-841.

3. Erqou S, Lee CT, Suffoletto M, et al. Association between gly-cated haemoglobin and the risk of congestive heart failure in diabetes mellitus: systematic review and meta-analysis. Eur J

Heart Fail. 2013;15(2):185-193.4. UK Prospective Diabetes Study (UKPDS) Group. Effect of

intensive blood-glucose control with metformin on complica-tions in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-865.

5. RR Holman. Post trial monitoring results of the UKPDS sulfo-nylurea plus metformin substudy. EASD Virtual Meeting. Avail-able at: http://www.easdvirtualmeeting.org/resources/6795. Published September 25, 2013. Accessed July 21, 2014.

6. ACCORD Study Group. Long-term effects of intensive glu-cose lowering on cardiovascular outcomes. N Engl J Med. 2011;364:818-828.

7. Leung M, Wong VW, Hudson M, Leung DY. Impact of im-proved glycemic control on cardiac function in type 2 diabetes mellitus. Circ Cardiovasc Imaging. 2016;9(3):e003643.

8. Dormandy JA, Charbonnel B, Eckland DJ, et al; PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PRO-spective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289.

9. Home PD, Pocock SJ, Beck-Nielsen H, et al; RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RE-CORD): a multicentre, randomised, open-label trial. Lancet. 2009;373:2125-2135.

10. Eurich DT, Weir DL, Majumdar SR, et al. Comparative safety and effectiveness of metformin in patients with diabetes mel-litus and heart failure: systematic review of observational stud-ies involving 34,000 patients. Circ Heart Fail. 2013;6:395-402.

11. Hemmingsen B, Schroll JB, Lund SS, et al. Sulphonylurea monotherapy for patients with type 2 diabetes mellitus. Co-chrane Database Syst Rev. 2013;4:CD009008.

12. Pfeffer MA, Claggett B, Diaz R, et al; ELIXA Investigators. Lix-isenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247-2257.

13. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-322.

14. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardio-vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2013;369:1317-1326.

15. Green JB, Bethel MA, Armstrong PW, et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes mellitus. N Engl J Med. 2015;373:232-242.

16. Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality outcomes on alogliptin versus placebo from the EX-AMINE trial. Lancet. 2015;385:2067-2076.

17. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.

18. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39:1108-1114.

19. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energet-ics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME Study? A unifying hypothesis. Diabetes Care. 2016;39:1115-1122.

20. Lopaschuk GD, Verma S. Empagliflozin’s fuel hypothesis: not so soon. Cell Metab. 2016;24:200-202.

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Introduction

Diabetes mellitus is a chronic, progressively worsening disease associated with a variety of complications. Over the last 2 decades, the

decline in heart disease mortality in Western countries has not been paralleled by a similar trend in patients with diabetes mellitus. A reduction in cardiovascular risk factors and improvement in the treatment of heart diseases seem to be less effective in the dia-betic population. Type 2 diabetes mellitus (T2DM) is

an independent risk factor for atherosclerosis and future coronary artery disease. Diabetes mellitus is associated with a higher risk of coronary events and a two-to-fivefold increased risk of death.1 Many patients with T2DM (from 17% to 59%, according to clinical studies) have silent myocardial ischemia on electrocardiography (ECG) stress testing, and a silent acute coronary syndrome occurs in 40% of cases. Management of T2DM should take into account that coronary artery disease is frequently silent for many years in diabetic patients. Thus, primary, as well as

Treating myocardial ischemia in diabetics: drugs, surgery, and stents

Romualdo Belardinelli, MD, FESCCardiovascular Sciences Department, Lancisi Heart Institute, AOR Ancona, Italy

Correspondence: Romualdo Belardinelli, MD, FESC, Cardiologia Riabilitativa Lancisi, AOR, Via Conca 71, 60020 Ancona, Italy


AbstractDiabetes mellitus (T2DM) is a chronic, progressively worsening disease associated with a variety of com-plications. Management of T2DM should take into account that coronary artery disease may be silent for many years in diabetic patients, and so both primary and secondary prevention must be a priority in the treatment of such disease. The management of chronic stable angina in patients with T2DM fol-lows the same principles as those for patients without diabetes mellitus—controlling ischemic symptoms and reducing ischemic burden. To this end, treatment consists of medications combined with lifestyle modifications, the three main interventions being smoking cessation, regular moderate aerobic exercise, and correct nutrition. This article focuses on antianginal/anti-ischemic medications and myocardial revas-cularization procedures. Guidelines suggest use of β-blockers or calcium antagonists as first-line therapy for stable angina in T2DM. Nicorandil, ranolazine, and trimetazidine should be considered when first-line medications cannot be used or are insufficient. On the basis of findings from BARI-2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes), FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal Management of multivessel disease), and recent meta-analyses, coronary artery bypass grafting is considered the preferred coronary revascularization procedure in patients with T2DM and multivessel disease when reduction in clinical events is the main goal of treatment. L Heart Metab. 2017;73:13-17

Keywords: chronic angina; diabetes mellitus; therapeutic strategy


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secondary, prevention must be a priority in the treat-ment of such disease.2

The management of chronic stable angina in pa-tients with T2DM follows the same principles as those for patients without diabetes mellitus, namely, con-trolling ischemic symptoms and reducing ischemic burden.3,4 These objectives are reached by combin-ing medications with lifestyle modifications based on three main interventions: smoking cessation, regular moderate aerobic exercise, and correct nutrition. Here, we focus on antianginal/anti-ischemic medica-tions and myocardial revascularization.

Medications

To date, few specific trials have been published on the efficacy of antianginal agents in the diabetic population, and most information derives from subgroup analyses.

b-Blockers

Ischemic symptoms can be controlled by β-blockers. Large trials have shown that β-blockers are more ef-fective in diabetic patients with myocardial infarction than in nondiabetic patients.5 For instance, in the Göteborg Metoprolol trial, diabetic patients with myo-cardial infarction had a significantly greater relative risk reduction at 3 months than nondiabetic patients (58% vs 36% reduction; P<0.05). This trend was con-firmed at 1-year follow-up.6 β-Blockers are effective in reducing angina pectoris, increasing ischemic thresh-old during exercise, and improving work tolerance by reducing heart rate and double pressure product and myocardial oxygen (O2) consumption at any work rate. β-Blockers are effective in hypertension, which is frequently associated with diabetic patients. They also prevent acute myocardial infarction and sudden death in diabetic patients with no previous myocardial

infarction. These benefits overcome the negative ef-fect of β-blockers on glycemic control and suggest the use of these medications in diabetic patients with stable angina. However, side effects, such as fatigue, depression, bradycardia, and sexual dysfunction may limit their use. Lipophilic agents, such as metoprolol, should be preferred in patients with renal dysfunction.

Calcium antagonists

The three major classes of calcium antagonists (CA) are the dihydropyridines (nifedipine, amlodipine, and felodipine), the phenylalkylamines (verapamil), and the modified benzothiazepines (diltiazem). They improve the balance of O2 supply and demand and dilate blood vessels with a consequent reduction in blood pressure. These effects may explain the increasing use of CA in diabetics, especially those with concomitant hypertension, either as monotherapy or in combina-tion with other agents.7 Although some studies have shown a greater clinical efficacy of β-blockers, there are at present no significant differences in the rate of death or myocardial infarction as compared with CA.8 However, their long-term administration has not been shown to improve survival in post–myocardial infarction patients. CAs are appropriate initial therapy in patients with contraindications to β-blockers or in combination when β-blockade monotherapy is unsuccessful.

Long-acting nitrates

Long-acting nitrates are widely used for preventing angina attacks in patients with stable angina with or without diabetes mellitus. They are potent vessel di-lators, and this effect is predominant in the venous circulation, with subsequent reduction in preload, myocardial wall tension, and O2 demand. This effect depends on the conversion of nitrates to nitric oxide, which activates guanylate cyclase to produce cyclic guanosine monophosphate (cGMP) and smooth muscle relaxation. Nitrate tolerance is less frequent when a daily interval is maintained. The antianginal effect appears to be greater when nitrates are com-bined with CA and/or β-blockers.8

Ranolazine

Ranolazine was recently approved as antianginal medication in stable angina.9 Its efficacy depends on

AbbreviationsBARI 2D: Bypass Angioplasty Revascularization In-vestigation 2 Diabetes [trial]; CA: calcium antagonist; CABG: coronary artery bypass grafting; FREEDOM: Fu-ture REvascularization Evaluation in patients with Di-abetes mellitus: Optimal Management of multivessel disease; OMT: optimal medical therapy; PCI: percuta-neous coronary intervention; T2DM: type 2 diabetes mellitus

Belardinelli Heart Metab. (2017) 73:13-17Medications and myocardial revascularization in diabetes

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Medications and myocardial revascularization in diabetes

two mechanisms, a metabolic effect of inhibition of fatty acid β-oxidation and a reduction in calcium over-load in ischemic myocytes through inhibition of the late inward sodium current.10 A recent trial showed that a dose of 1000 mg twice a day for 8 weeks sig-nificantly reduced the number of weekly angina at-tacks by 13% (P=0.008) and weekly sublingual nitro-glycerin use by 23.5% (P=0.003) as compared with placebo.11 Because of its effect in prolongation of the QT interval, ranolazine is contraindicated in patients with long-QT syndrome or in combination with other QT-prolonging drugs, such as amiodarone, sotalol, and other noncardiovascular active agents.

Ivabradine

Ivabradine decreases heart rate by a selective inhibi-tory effect on funny-current (If ) channels of the sino-atrial node, without any effect on glucose metabolism or adrenergic activity. It has been approved in Europe for the treatment of patients with stable angina with or without diabetes who do not tolerate β-blockers or in those who are inadequately controlled with an optimal dose of a β-blocker.12

Nicorandil

Nicorandil dilates peripheral and coronary vessels through its action as an adenosine triphophate (ATP)-sensitive potassium-channel opener and nitric oxide

donor. As a result, nicorandil reduces preload and afterload and vasodilates coronary arteries. Its anti-ischemic efficacy has been demonstrated in a trial studying 5126 patients with stable angina, with a sig-nificant improvement in outcome owing to a reduc-tion in major coronary events in patients.13 However, in that study, less than 10% of patients had diabetes mellitus.

Trimetazidine

Trimetazidine is a piperazine derivative with antiangi-nal efficacy. Trimetazidine at doses of 20 mg three times a day or 35 mg twice a day improves the isch-emic threshold during exercise and reduces the num-ber of angina attacks and sublingual nitroglycerin use as compared with placebo. This beneficial effect is related to inhibition of β-oxidation requiring five times more O2 than glucose oxidation, which is conse-quently accelerated. This results in a more efficient ATP production by ischemic myocytes and a subse-quent greater contractility, translating into better left ventricular function.14 Trimetazidine has no effect on glucose homeostasis, and its efficacy is predominant in diabetic patients with reduced left ventricular ef-ficiency. In summary, guidelines suggest use of β-blocker or CAs combined as first-line therapy for stable an-gina in T2DM. Nicorandil, ranolazine, trimetazidine, ivabradine, and long-acting nitrates should be con-

Medications Mechanism CV benefits Side effects

β-Blockers ↓ O2 demand↓ Myocardial contractility

↑ Ischemic threshold↓ Angina attacks↑ Work tolerance

Bradycardia↑ Blood glucoseDepressionSexual dysfunction

Calcium antagonists ↓ O2 demand ↑ O2 supply


Bradycardia/tachycardiaLeg edema

Nitrates ↓ O2 demand↑ O2 supply


HeadacheHypotension

Ranolazine Late Na-channel inhibitorsβ-Oxidation inhibition

↓ Angina attacks GI side effectsQT prolongation

Trimetazidine β-Oxidation inhibition ↑ Ischemic threshold↓ Angina attacks↑ Work tolerance

GI side effects

Ivabradine If-channel inhibitors ↑ Ischemic threshold Bradycardia

Nicorandil ATP-channel opening NO donor

↑ Ischemic threshold↓ Angina attacks

Hypotension

Table I Medications to treat stable angina in patients with type 2 diabetes mellitus.Abbreviations: ATP, adenosine triphosphate; CV, cardiovascular; GI, gastrointestinal; Na, sodium; NO, nitric oxide; O2, oxygen

sidered when first-line medications cannot be used or are insufficient. Mechanisms, cardiovascular benefits, and side effects of medications to treat stable angina in patients with T2DM are shown in Table I.

Coronary revascularization

In patients with T2DM and stable angina, the thera-peutic strategy should focus on combining improve-ment in functional capacity and quality of life with re-duction in cardiovascular events and life prolongation. These objectives are obtained with a combination of medications, lifestyle changes, and reduction in re-versible cardiovascular risk factors. Revasculariza-tion approaches should be considered when optimal medical therapy (OMT) alone is insufficient to control symptoms and a patient is at-risk of cardiovascular events due to the severity and extent of coronary ar-tery disease.15,16 Recommendations for percutaneous coronary intervention (PCI; a nonsurgical intervention that may involve stent implantation) or coronary ar-tery bypass grafting (CABG; a surgical intervention) should be based on both the severity and extent of inducible myocardial ischemia, the severity of symp-toms and their control by pharmacological and non-pharmacological tools, and functional deterioration. On the basis of the BARI trial (Bypass Angioplasty Revascularization Investigation) results, patients with T2DM treated with percutaneous transluminal coro-nary angioplasty (PTCA) had a 5-year mortality of 35% vs 19% for those who underwent CABG (P=0.003).17 At 10 years, the superiority of CABG was more evi-dent. On the basis of the findings from BARI 2D (BARI 2 Diabetes), FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Opti-mal Management of multivessel disease), and recent meta-analyses, CABG is considered the preferred coronary revascularization procedure in patients with T2DM and multivessel coronary artery disease when reduction in clinical events is the main goal of treat-ment.18,19 In patients with angina not considered at high risk, survival is similar for surgery, PCI, and OMT. In patients with single-vessel disease in whom revas-cularization is necessary, PCI is preferable to CABG.

Conclusion

The management of chronic stable angina in patients with T2DM follows the same principles as those for

patients without diabetes mellitus, namely, controlling ischemic symptoms and reducing ischemic burden. These objectives are reached through the combina-tion of medications and lifestyle modifications, the three main interventions being smoking cessation, regular moderate aerobic exercise, and correct nu-trition. According to guidelines, a combination of β-blockers and CAs should be considered as first-line therapy for stable angina in T2DM. Nicorandil, ranolazine, trimetazidine, ivabradine, and long-acting nitrates should be considered when first-line medica-tions cannot be used or are insufficient. Revascular-ization approaches should be considered when OMT alone is insufficient to control symptoms and a patient is at-risk of cardiovascular events due to severity and extent of coronary artery disease. Recommendations for PCI or CABG should be based on both the sever-ity and extent of inducible myocardial ischemia, the severity of symptoms and their control by pharmaco-logical and nonpharmacological tools, and functional deterioration. L

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2. Lew WY, DeMaria AN. Diabetes and coronary disease: a need for new therapies for an expanding disease burden. J Am Coll Cardiol. 2013;61:2046-2047.

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nolazine in patients with type 2 diabetes mellitus and chronic stable angina results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). J Am Coll Cardiol. 2013;61:2038-2045.

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16. Park DW, Kim YH, Song HG, et al. Long-term outcome of stents versus bypass surgery in diabetic and nondiabetic pa-tients with multivessel or left main coronary artery disease: a pooled analysis of 5775 individual patient data. Circ Cardio-vasc Interv. 2012;5:467-475.

17. Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary inter-ventions for multivessel disease: a collaborative analysis of in-dividual patient data from ten randomized trials. Lancet. 2009; 373:1190-1197.

18. BARI 2D Study Group; Frye RL, August P, Brooks MM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360:2503-2515.

19. Farkouh ME, Domanski M, Sleeper LA, et al; for the FREEDOM Investigators. Strategies for multivessel revascularization in pa-tients with diabetes. N Engl J Med. 2012;367:2375-2384.

18


Introduction

The prevalence of obesity is skyrocketing in both developing and developed countries. This is accompanied by a corresponding increase in

the prevalence of type 2 diabetes. Patients with type 2 diabetes have a high prevalence of heart failure, both undiagnosed and diagnosed, and left ventricular (LV) dysfunction.1 In these patients, although LV dysfunc-tion and heart failure may be attributed to common comorbidities, such as hypertension, obesity, and

coronary disease, there is evidence for the distinct clinical entity of diabetic cardiomyopathy.2 The spectrum of the disease may range from LV diastolic dysfunction in the early stage3 to systolic dysfunction and overt LV dysfunction and advanced heart failure. The diagnosis of heart failure and LV dysfunction in these patients is often delayed. LV diastolic and systolic dysfunction may be subclinical, and early symptoms of exercise intolerance may be subtle and attributed to lack of physical fitness. Nevertheless, early detection of LV dysfunction in these high-risk

Early detection of left ventricular dysfunction in diabetes

Dominic Y. Leung, MBBS, PhD; Melissa Leung, MBBS, PhDDepartment of Cardiology, Liverpool Hospital, University of New South Wales, Sydney, Australia

Correspondence: Professor Dominic Leung, Department of Cardiology, Liverpool Hospital, Locked Bag, 7103, Liverpool BC, NSW 1871, Australia


AbstractPatients with type 2 diabetes are at risk of developing left ventricular (LV) dysfunction and heart failure. Symptoms associated with LV dysfunction in these patients, especially in the early stages, may be minimal or attributed to other noncardiac factors. LV dysfunction in diabetes is multifactorial, but there is evidence of the specific entity of diabetic cardiomyopathy. Although a direct relationship between glycemic control and LV function has not been firmly established, there is increasing evidence to suggest that poor glyce-mic control is associated with LV dysfunction and that improving glycemic control improves LV function. A high index of suspicion is necessary in managing these patients. Echocardiography is a noninvasive, widely available imaging tool that provides comprehensive assessment of cardiac structure and func-tion. Exercise echocardiography allows detection of coronary disease and assessment of LV diastolic reserve. A multifaceted approach targeting all vascular risk factors in the management of LV dysfunction in these patients is essential. A specific treatment for diabetic cardiomyopathy is still lacking, but optimizing glycemic control and aldosterone antagonism may be beneficial, and trials are currently underway. Early detection of LV dysfunction allows identification of at-risk patients and timely intervention, which could ultimately improve patient outcome in this condition, which is associated with significant morbidity and mortality. L Heart Metab. 2017;73:18-23

Keywords: cardiomyopathy; diabetes; echocardiography

19

Heart Metab. (2017) 73:18-23 leunG and leunG

Left ventricular dysfunction in diabetes

Fig. 1 Evaluation of a 66-year-old man with type 2 diabetes who complained of dyspnea on exertion found left ventricular (LV) hypertrophy, but normal LV ejection fraction. LV global longitudinal strain (GLS) was impaired at -13.2% (Panel A). The patient had grade 1 diastolic dysfunction with a mitral E/A ratio <0.5 at rest (Panel B) and a septal e’ velocity of 6 cm/s (Panel C).Abbreviations: 4-ch, 4-chamber view; ANT_SEPT, anteroseptal; APLAX, apical long axis view; AVC_AUTO, aortic valve closure detected automatically; GLPS_A4C, global longitudinal peak strain, apical 4-chamber view; GLPS_LAX, global longitudinal peak strain, apical long axis view; HR, heart rate; HR_ApLAX, heart rate during acquisition of the apical long axis view; INF, inferior; LAT, lateral; POST, posterior; SEPT, septal.

patients is important; timely, aggressive, multifaceted management is the key to ameliorating the otherwise devastating consequences of diabetic heart disease.

Echocardiography in detection of left ventricular dysfunction

Echocardiography is a versatile, noninvasive, and widely available imaging tool for the assessment of LV structure and function and has been most commonly used in the detection of LV dysfunction. LV ejection fraction is an insensitive marker for early detection of LV dysfunction. Mitral E- and A-wave, and tissue Doppler e’-wave velocities are measures of LV dia-stolic function. An elevated mitral E/e’ velocity ratio is a reliable marker of elevated LV filling pressures, commonly seen in patients with LV dysfunction and heart failure. Echocardiographic strain deformation imaging allows a sensitive, angle-independent, and site-specific assessment of LV systolic function, and assessment of LV global longitudinal strain is superior to ejection fraction in the detection of early diabetic heart disease.4 Moreover, LV global longitudinal strain has incremental prognostic value over ejection frac-tion in a wide range of cardiovascular diseases. Exer-cise echocardiography is a well-accepted, accurate, and noninvasive test for inducible ischemia, allowing detection of coronary artery disease. It also allows as-sessment of LV filling pressures at rest and after ex-ercise.5 As an example, Figure 1 and Figure 2 depict an exercise echocardiographic evaluation of a type 2 diabetes patient with dyspnea on exertion.


The Strong Heart Study demonstrated that heart failure was very prevalent in patients with diabetes despite normal ejection fraction.6 Fang et al found subclinical LV systolic and diastolic dysfunction in a large proportion of patients with type 2 diabetes without ischemia or hypertrophy.7 Compared with age-matched controls, asymptomatic patients with type 2 diabetes had impaired LV longitudinal sys-tolic, as well as diastolic, function.4 In a recent study of 105 patients with poorly controlled type 2 diabe-tes, we found that these patients have impaired LV diastolic and systolic function and elevated LV filling pressures despite normal LV ejection fraction and LV mass.8

The underlying pathophysiological mechanisms of diabetic cardiomyopathy are multifactorial and may include microvascular disease, endothelial dys-function, autonomic dysfunction, hyperglycemia, hyperinsulinemia, insulin resistance and other meta-bolic disturbances, myocardial interstitial fibrosis, and myocardial steatosis.2 Obesity, common in patients with diabetes, may also lead to LV dysfunction. We have demonstrated impaired coronary microvascular function in patients with diabetes in the absence of epicardial coronary stenosis.9 As cardiac extracellu-lar matrix plays an active role in modulating cardiac function, myocardial fibrosis has been suggested as one of the important mechanisms of LV dysfunction in diabetes.2

Although hyperglycemia is the primary metabolic disturbance in diabetes, the relationship between glycemic control and cardiac function is unclear. Some studies have shown poor glycemic control to be associated with abnormal LV relaxation, elevated filling pressures, and impaired systolic contraction.7 Patients who had poorly controlled diabetes in the Strong Heart Study were found to have abnormal LV relaxation.10 In 120 patients with type 2 diabetes, peak systolic strain was independently associated with gly-cated hemoglobin (HbA1c) levels, whereas septal e’ velocities were related more to age and hypertension and not to glycemic control.7 However, a number of other studies have demonstrated no association be-tween glycemic control and ventricular function. The relationship between prevailing glycemic control and LV function may be more complicated and affected by multiple factors, including duration of diabetes, presence and control of other vascular risk factors, medications, body weight, and others that are known to have an impact on LV function.

Impact of improving glycemic control on left ventricular function

A few studies have examined the effect that improved glycemic control has on LV function. von Bibra et al showed that intensive glycemic control with insulin improved LV diastolic, but not systolic, function.11 However, others did not demonstrate improvements, despite better glycemic control.12 Most of these stud-ies examined improved glycemic control over short periods of time, which may not have been sufficient to effect any detectable changes in LV function. We

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leunG and leunG Heart Metab. (2017) 73:18-23Left ventricular dysfunction in diabetes



21

Fig. 2 Evaluation of a 66-year-old man with type 2 diabetes who complained of dyspnea on exertion (see also Fig. 1) found a dilated left atrium (Panel A), with a maximum left atrial volume of 51 mL/m2. On exercise echocardiography, no inducible ischemia was found. Immediately after exercise, the mitral E/A ratio reversed and became >1 (Panel B). The septal e’ velocity decreased to 5 cm/s, leading to a significantly higher E/e’ ratio; this indicates elevated LV filling pressures and limited LV diastolic reserve, explaining the exertional dyspnea.Abbreviations: A2C, apical 2-chamber; A-L, area-length; LAEDV, left atrial end diastolic volume; LAAd, left atrial area; LALd, left atrial longitudinal dimension.

22

recruited 105 patients with suboptimally controlled type 2 diabetes; during a 12-month follow-up peri-od, we optimized treatment aimed to improve their metabolic control. Improved glycemic control led to improvement in LV diastolic and systolic function, and both the magnitude of the improvement and the fi-nal glycemic control affected LV function at follow-up. Worsened glycemic control actually led to further de-terioration of LV systolic function.8 Patients with dia-betes are often overweight and obesity itself is also linked to LV dysfunction. In support of this concept, weight loss has been shown to lead to improved LV function.13 The impact of improving glycemic control on LV function may be mediated through the benefi-cial effects of weight loss on LV function. However, in another study, we demonstrated that both improved glycemic control and weight loss had incremental ad-ditive benefits on LV function.14

Effort intolerance in diabetes

Early stages of LV dysfunction in diabetes may be as-sociated with little or no symptoms. Effort intolerance is usually the first manifestation. Unfortunately, effort intolerance may be attributed to body weight or lack of physical fitness. Coronary artery disease may be another underlying cause. Evaluation of LV function at rest may not be adequate in patients with diabetes. Therefore, examining the response of the left ventricle to exercise may yield further diagnostic information. Diastolic reserve is the ability of LV filling pressures to remain normal with exercise and tachycardia. Im-paired diastolic reserve is seen in the early stages of LV diastolic dysfunction in diabetes. Patients with diabetes have an impaired diastolic reserve, and el-evated LV filling pressures with exercise manifest an exertional dyspnea even without inducible myocardial ischemia.5 Exercise echocardiography, by allowing assessment of LV diastolic reserve, is a useful tool to unmask diastolic and systolic dysfunction to evaluate patients with exertional dyspnea. Improving glycemic control is also associated with an improvement in ex-ercise tolerance in these patients.8

Treatment of left ventricular dysfunction in diabetes

Treatment of LV dysfunction in diabetes requires a multifaceted approach. Early detection of LV dys-function in these patients allows identification of at-

risk patients and early intervention. As these patients often have multiple comorbidities, a comprehensive approach to the management of all vascular risk fac-tors is essential. Aggressive blood pressure lowering, treating hypercholesterolemia to target, and optimiza-tion of body weight are all important parts of manage-ment. Optimization of glycemic control may also lead to improvement in LV systolic and diastolic function and exercise tolerance. A specific therapeutic agent for diabetic cardio-myopathy is still lacking. Aldosterone antagonism, which reduces cardiac extracellular matrix turnover, improves symptoms and outcomes in advanced sys-tolic heart failure and after acute myocardial infarction. Aldosterone antagonism has also been shown to im-prove LV function in dilated and hypertensive cardio-myopathy15 and metabolic syndrome with regression in markers of myocardial fibrosis.16 Trials evaluating the impact of specific aldosterone antagonism on LV systolic and diastolic function in patients with type 2 diabetes are ongoing.17

Conclusions

LV dysfunction and heart failure are prevalent in pa-tients with diabetes. Hypertension, coronary artery disease, and obesity are common comorbidities and may also cause LV dysfunction. Diabetic cardiomy-opathy is considered a distinct entity. LV dysfunc-tion in these patients may be associated with little or no symptoms, with exertional dyspnea a common, though nonspecific, symptom. LV function is linked to glycemic control, and early detection of LV dysfunc-tion is important. Echocardiography, combined with exercise testing, allows comprehensive assessment of LV morphology, systolic and diastolic function at rest and after stress, and exclusion of coronary artery disease. A multifaceted approach targeting all vascu-lar risk factors in the management of LV dysfunction in these patients is essential. A specific treatment for diabetic cardiomyopathy is still lacking, but aldoste-rone antagonists may be beneficial. Timely interven-tion may improve patient outcome for such a con-dition, which is associated with significant morbidity and mortality. L

REFERENCES

1. Boonman-de Winter LJ, Rutten FH, et al. High prevalence of previously unknown heart failure and left ventricular dysfunction

leunG and leunG Heart Metab. (2017) 73:18-23Left ventricular dysfunction in diabetes

in patients with type 2 diabetes. Diabetologia. 2012;55:2154-2162.

2. Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev. 2004;25:543-567.

3. Marwick TH. Diabetic heart disease. Postgrad Med J. 2008;84:188-192.

4. Ng AC, Delgado V, Bertini M, et al. Findings from left ventricular strain and strain rate imaging in asymptomatic patients with type 2 diabetes mellitus. Am J Cardiol. 2009;104:1398-1401.

5. Leung M, Phan V, Whatmough M, Heritier S, Wong VW, Leung DY. Left ventricular diastolic reserve in patients with type 2 dia-betes mellitus. Open Heart. 2015;2:e000214.

6. Devereux RB, Roman MJ, Liu JE, et al. Congestive heart fail-ure despite normal left ventricular systolic function in a popu-lation-based sample: the Strong Heart Study. Am J Cardiol. 2000;86:1090-1096.

7. Fang ZY, Schull-Meade R, Downey M, Prins J, Marwick TH. Determinants of subclinical diabetic heart disease. Diabetolo-gia. 2005;48:394-402.

8. Leung M, Wong VW, Hudson M, Leung DY. Impact of im-proved glycemic control on cardiac function in type 2 diabetes mellitus. Circ Cardiovasc Imaging. 2016;9:e003643.

9. Leung M, Leung DY. Coronary microvascular function in patients with type 2 diabetes mellitus. EuroIntervention. 2016;11:1111-1117.

10. Liu JE, Palmieri V, Roman MJ, et al. The impact of diabetes on left ventricular filling pattern in normotensive and hyper-tensive adults: the Strong Heart Study. J Am Coll Cardiol. 2001;37:1943-1949.

11. von Bibra H, Hansen A, Dounis V, Bystedt T, Malmberg K, Rydén L. Augmented metabolic control improves myocardial diastolic function and perfusion in patients with non-insulin de-pendent diabetes. Heart. 2004;90:1483-1484.

12. Jarnert C, Landstedt-Hallin L, Malmberg K, et al. A random-ized trial of the impact of strict glycaemic control on myocar-dial diastolic function and perfusion reserve: a report from the DADD (Diabetes mellitus And Diastolic Dysfunction) study. Eur J Heart Fail. 2009;11:39-47.

13. Cuspidi C, Rescaldani M, Tadic M, Sala C, Grassi G. Ef-fects of bariatric surgery on cardiac structure and function: a systematic review and meta-analysis. Am J Hypertension. 2013;27:146-156.

14. Leung M, Wong VW, Durmush E, Phan V, Xie M, Leung DY. Cardiac dysfunction in type II diabetes: a bittersweet, weighty problem, or both? Acta Diabetol. 2017;54:91-100.

15. Mottram PM, Haluska B, Leano R, Cowley D, Stowasser M, Marwick TH. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation. 2004;110:558-565.

16. Kosmala W, Przewlocka-Kosmala M, Szczepanik-Osadnik H, et al. A randomized study of the beneficial effects of al-dosterone antagonism on LV function, structure, and fibrosis markers in metabolic syndrome. JACC Cardiovasc Imaging. 2011;4:1239-1249.

17. Leung M, Wong VW, Heritier S, Mihailidou AS, Leung DY. Rationale and design of a randomized trial on the impact of aldosterone antagonism on cardiac structure and function in diabetic cardiomyopathy. Cardiovasc Diabetol. 2013;12:139.



23


Introduction

Type 2 diabetes mellitus is an important predictor of future cardiovascular events, regardless of the presence or absence of coronary disease.1,2

Diabetic patients without overt coronary artery disease

(CAD) have a prognosis similar to nondiabetic patients with CAD, and coronary disease patients with diabe-tes have a cardiovascular death rate double that of nondiabetic patients with CAD.3,4 Glucose-metabolism impairment and the insulin resistance syndrome are, per se, crucial factors in the accelerated development

Clinical benefits of targeting cardiac cells directly with trimetazidine in patients with coronary disease and diabetes

Gabriele Fragasso, MD; Gianluca Anastasia, MS; Giuseppe Monaca, MS; Giuseppe Pinto, MSHeart Failure Clinic, Department of Clinical Cardiology, Ospedale San Raffaele, Milano, Italy

Correspondence: Gabriele Fragasso, MD, Department of Clinical Cardiology, Heart Failure Clinic, Istituto Scientifico San Raffaele, Via Olgettina 60, 20132 Milano, Italy


AbstractPatients with coronary artery disease (CAD) and diabetes have a cardiovascular death rate double that of nondiabetic patients with CAD. Accelerated atherogenesis mediated by altered cellular metabolism is the likely cause of this association. In fact, ischemic metabolic changes, which occur as a conse-quence of the mismatch between blood supply and cardiac metabolic requirements, are heightened by the metabolic changes inherent to diabetes itself. Increased utilization of free fatty acid and the reduced utilization of glucose as a source of energy during stress and ischemia are responsible for the increased susceptibility of the diabetic heart to myocardial ischemia and to a greater decrease in myocardial performance for given amounts of ischemia than observed for nondiabetic hearts. In this context, a therapeutic approach aimed at improving cardiac metabolism through manipulations of the use of metabolic substrates should result in an improvement in myocardial ischemia. Trimetazidine, by acting directly at the cardiac-cell level, partially inhibits fatty acid oxidation, improves global car-diac metabolism, and, as a consequence, increases cardiac resistance to ischemia and reduces the decline of left ventricular function due to chronic underperfusion and repetitive episodes of myocardial ischemia. Therefore, modulation of myocardial metabolism represents a key target in patients with CAD and diabetes. Because of its effect on cardiac metabolism and its well-established beneficial effects on myocardial ischemia and left ventricular function, trimetazidine should be considered an essential treatment for diabetic patients with ischemic heart disease. L Heart Metab. 2017;73:24-28

Keywords: CAD; diabetes; myocardial metabolism; trimetazidine

24

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Heart Metab. (2017) 73:24-28 FraGasso and others Trimetazidine: targeting cardiac-cell metabolism in coronary disease and diabetes

of atherosclerosis and the clinical evolution of the ensuing cardiac diseases. Altered glucose metabolism exerts its detrimental cardiovascular effects at two levels: (i) on vascular wall function and (ii) on regulation of cell energy metabolism.

Direct vascular and muscular effects of deranged glucose metabolism

The direct vascular effects of type 2 diabetes are known to be mediated by endothelial dysfunction.5 Additionally, when the endothelium is damaged, the balance between vasoactive substances—which can either cause vasoconstriction (via endothelin-1 [ET-1] and thromboxane A2) or vasodilation (via nitric oxide and other prostaglandins, such as prostacyclin)—can shift toward a greater production of vasoconstrictor agents, triggering a vicious circle and further promoting atherosclerosis.6 Acute hyperglycemia may itself impair endothelial-derived vasodilation.7 In fact, the inability to increase myocardial blood flow appears independently related to long-term blood glucose control,8 indicating that hyperglycemia itself is of considerable importance for impaired vascular function. Additionally, the impair-ment of insulin action in type 2 diabetes has also been found in both cardiac9 and skeletal muscle.10 Heart and arm skeletal muscle glucose uptake are inversely re-lated to free fatty acid (FFA) levels in the serum and increased FFA flux from adipose tissue to nonadipose tissue,11 resulting from abnormalities in fat metabolism, and participate in and amplify many of the fundamen-tal metabolic derangements that are characteristic of the insulin resistance syndrome and type 2 diabetes.12 Previous findings also suggest that elevated FFA levels not only impair glucose uptake in heart and skeletal muscles but also cause alterations in the metabolism of vascular endothelium, leading to premature cardio-vascular disease.13

Specific effects of glucose derangement on cellular metabolic efficiency

Since glucose is a major energy substrate in the body, its deranged utilization in the diabetic heart may

be particularly deleterious. Increasing FFA oxidation in the heart decreases glucose oxidation, whereas in-creasing glucose oxidation inhibits FFA oxidation. In fact, FFA oxidation is a less efficient source of energy than glucose oxidation (with regard to adenosine tri-phosphate [ATP] produced per oxygen [O2] molecules consumed), and this helps explain why elevated FFA oxidation rates reduce cardiac efficiency.14

Direct effects of ischemia on myocardial metabolism

Apart from diabetes, myocardial ischemia per se re-sults in major cardiac metabolic consequences, ba-sically making ischemia a metabolic problem. The healthy heart derives most of its energy from the FFA pathway, which accounts for approximately two-thirds of energy production (ATP), the other source of energy being derived from glucose oxidation and lactate. In hypoxic conditions, myocardial cells re-spond to mild-to-moderate ischemia by accelerating glucose uptake in order to generate sufficient ATP for the maintenance of ionic gradients and calcium ho-meostasis, as glycolysis requires less O2 per mole of ATP generated than does FFA oxidation. On the other hand, severe ischemia rapidly induces an imbalance between the requirement of cardiac tissue for O2 and coronary blood supply, resulting in functional, meta-bolic, and morphological alteration of the myocardi-um. At a cellular level, glucose uptake is decreased, and conversion to lactate is increased; lactate uptake by the heart is switched to lactate production, and pyruvate is mostly transformed into lactate, thereby increasing cell acidosis and resulting in less ATP pro-duction. These metabolic changes lead to disruption of cell homeostasis, alterations in membrane struc-ture, and ultimately, cell death.14

Therefore, adverse cardiac effects of diabetes are consequent to vascular and muscle metabolic mech-anisms. In these contexts, lowering elevated plasma FFA levels or reducing FFA utilization by the cells could decrease the heart’s reliance on fatty acids.

Metabolic therapeutic approach in coronary diabetic patients: the role of trimetazidine

The possibility of modifying cardiac metabolic sub-strate preferences of the diabetic heart is particularly attractive. Specifically, increasing the rate of glucose

AbbreviationsCAD: coronary artery disease; ET-1: endothelin-1; FFA: free fatty acid

26

FraGasso and others Heart Metab. (2017) 73:24-28Trimetazidine: targeting cardiac-cell metabolism in coronary disease and diabetes

metabolism and, accordingly, reducing FFA oxidation, is a very attractive therapeutical approach. Trimeta-zidine shifts energy production from FFA to glucose oxidation and preserves cellular energy by increasing myocardial high-energy phosphate intracellular levels (Figure 1).15,16 On this basis, several clinical studies

have demonstrated the beneficial effects of trimeta-zidine in patients with CAD,17 and it is currently indi-cated by the European Society of Cardiology for the treatment of angina pectoris.18 Trimetazidine appears particularly effective in the presence of hyperglycemia and hyperinsulinemia,19 which are often observed in insulin-resistance states. For these reasons, trimeta-zidine has been very effective in diabetic patients with CAD and left ventricular dysfunction.20 In a subse-quent study performed in a large cohort of patients with type 2 diabetes mellitus and CAD, trimetazi-dine—by acting directly at the cardiac-cell level—on top of conventional medical treatment decreased the incidence of angina episodes and the ischemic re-sponse in the exercise test with excellent tolerability.21 A subsequent 24-hour ambulatory-electrocardiogra-phy-monitoring study confirmed that in patients with diabetes and chronic stable angina, the addition of trimetazidine to standard medical therapy reduces

the number of episodes of ST-segment depression, the episodes of silent ischemia, and total ischemic burden.22 Finally, since glucose metabolism derangement is the greatest risk factor for restenosis after percutane-ous myocardial revascularization,23 optimal medical management of these patients would appear man-datory. In this context, it was very recently shown that adjunctive therapy with trimetazidine after drug-eluting–stent implantation in elderly multivessel-CAD patients with diabetes can have a beneficial effect on recurrent angina pectoris, as well as on left ventricular function.24 Thus, trimetazidine treatment in coronary diabetic patients undergoing percutaneous interven-tions appears particularly useful.

Specific effects of trimetazidine in the diabetic-ischemic patient

As previously stated, trimetazidine facilitates myocar-dial utilization of glucose instead of FFAs, which in the context of malfunctioning myocardial cells appears to be beneficial. These effects are probably operative on both cardiac and skeletal muscle; therefore, the ef-fects of trimetazidine on glucose metabolism could be dependent on improved cardiac efficiency25 and improved peripheral glucose extraction and utiliza-tion. In fact, trimetazidine has also been shown to re-duce ET-1 release (Figure 2),26,27 which is associated

2.5 –

2.0 –

1.5 –

1.0 –

0.5 –

0.0 –

Placebo TMZ Healthy subjects

PCr/A

TP

P=0.04

Fig. 1 In vivo 31P-magnetic resonance spectroscopy evaluating the effects of 3 months’ therapy with trimetazidine on the left ven-tricular cardiac phosphocreatine-to–adenosine triphosphate (PCr/ATP) ratio in patients with heart failure (a). The histogram shows an important trimetazidine-induced improvement in cellular energy reserve, as evidenced by the significant increase in PCr/ATP com-pared with placebo. As a reference comparison, after trimetazidine, PCr/ATP level is similar to that observed in a control population (b).Abbreviation: PCr/ATP, ratio of phosphocreatine to adenosine triphosphate; TMZ, trimetazidine.Data for placebo and trimetazidine (a) from reference 15: Fragasso et al. Eur Heart J. 2006;27:942-948. © 2006, European Society of Cardiology.Data for healthy subjects (b) from reference 16: Perseghin et al. J Am Coll Cardiol. 2005;46:1085-1092. © 2005, American College of Cardiology Foundation.

Placebo

10

TMZ

ET-1(pg/mL)

F. ET-1 release(pg/100mL/min)

Placebo TMZ

5

15*

0

10

5

15*

0

1.5

-0.5

3.5

-2.5

1.5

-0.5

3.5

*

-2.5

Fig. 2 Endothelin-1 in the basal state (left) and at the end of the euglycemic clamp studies (right) in 15 type 2 diabetic patients with cardiomyopathy after 15 days of trimetazidine (red bars) and after 15 days of placebo (gray bars). When on trimetazidine, endothelin-1 and forearm release of endothelin-1 after hyperin-sulinemic euglycemic clamp are significantly reduced compared with placebo, indicating improved endothelial function. Values are expressed as mean ± standard error. *P<0.05.Abbreviation: ET-1, endothelin-1; F. ET-1 release, forearm release of endo-thelin-1; TMZ, trimetazidine.Adapted from reference 26: Monti et al. Am J Physiol Endocrinol Metab. 2006;290:E54-E59. © 2006, American Physiological Society.

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Heart Metab. (2017) 73:24-28 FraGasso and others Trimetazidine: targeting cardiac-cell metabolism in coronary disease and diabetes

with the severity of myocardial ischemia and dysfunc-tion; its levels correlate with prognosis. Trimetazidine-induced reduction in intracellular acidosis in ischemic myocardium28 could influence not only myocardial function but also endothelial function. By decreasing endothelial damage, trimetazidine may inhibit ET-1 release, which would, in turn, decrease myocardial damage and improve glucose metabolism. A sec-ond possibility is that trimetazidine may inhibit ET-1 release simply by decreasing the effects of chronic myocardial ischemia. Additionally, it has been shown that trimetazidine, in the presence of high levels of triglycerides, may improve both myocardial recovery and ET-1 release after high- and low-flow ischemia.29 Considering the known relation between ET-1 con-centration and glucose metabolism abnormalities, the observed beneficial effects of trimetazidine on glucose metabolism could also be partly attributed to the reduction in ET-1 levels.

Conclusions

Diabetes mellitus is becoming progressively com-mon. Most diabetic patients will develop cardiovas-cular complications, of which CAD is one of the most frequent and insidious. In these patients, ischemic heart disease should be aggressively treated. Drugs directly affecting myocardial cell metabolism could be particularly useful.30 Trimetazidine, by acting directly at the cardiac-cell level, partially inhibits fatty acid oxidation, improves global cardiac metabolism, and as a consequence increases cardiac resistance to ischemia and reduces the decline of left ventricular function due to chronic underperfusion and repetitive episodes of myocardial ischemia. Therefore, modula-tion of myocardial metabolism should be a key target in patients with CAD and diabetes. Because of its ef-fect on cardiac metabolism and its well-established beneficial effects on myocardial ischemia and left ventricular function, trimetazidine should always be considered an essential treatment for diabetic pa-tients with ischemic heart disease. L

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2. Kanters SD, Banga JD, Stolk RP, Algra A. Incidence and de-terminants of mortality and cardiovascular events in diabetes mellitus: a meta-analysis. Vasc Med. 1999;4:67-75.

3. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229-234.

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5. Piatti PM, Monti LD, Galli L, et al. Relationship between endo-thelin-1 concentrations and metabolic alterations typical of the Insulin Resistance Syndrome. Metabolism. 2000;49:748-752.

6. Lüscher TF, Richard V, Tschudi M, Yang ZH, Boulanger C. En-dothelial control of vascular tone in large and small coronary arteries. J Am Coll Cardiol. 1990;15:519-527.

7. Ceriello A, Taboga C, Tonutti L, et al. Evidence for an indepen-dent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment. Circulation. 2002;106:1211-1218.

8. Yokoyama I, Momomura S, Ohtake T, et al. Reduced myocar-dial flow reserve in non insulin-dependent diabetes mellitus. J Am Coll Cardiol. 1997;30:1472-1477.

9. Anderson EJ, Kypson AP, Rodriguez E, Anderson CA, Lehr EJ, Neufer PD. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 dia-betic human heart. J Am Coll Cardiol. 2009;54:1891-1898.

10. Aguer C, McCoin CS, Knotts TA, et al. Acylcarnitines: potential implications for skeletal muscle insulin resistance. FASEB J. 2015;29:336-345.

11. Nuutila P, Knuuti MJ, Raitakari M, et al. Effect of antilipolysis on heart and skeletal muscle glucose uptake in overnight fasted humans. Am J Physiol. 1994;267:E941-E946.

12. Lewis GF, Carpentier A, Adeli K, Giacca A. Disordered fat stor-age and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev. 2002;23:201-229.

13. Steinberg HO, Baron AD. Vascular function, insulin resistance and fatty acids. Diabetologia. 2002;45:623-634.

14. Fillmore N, Mori J, Lopaschuk GD. Mitochondrial fatty acid oxi-dation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy. Br J Pharmacol. 2014;171:2080-2090.

15. Fragasso G, De Cobelli F, Perseghin G, et al. Effects of meta-bolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J. 2006;27:942-948.

16. Perseghin G, Fiorina P, De Coblelli F, et al. Cross-sectional as-sessment of the effect of kidney and kidney-pancreas trans-plantation on resting left ventricular energy metabolism in type 1 diabetic-uremic patients: a phosphorous-31 magnetic reso-nance spectroscopy study. J Am Coll Cardiol. 2005;46:1085-1092.

17. Rosano GM, Vitale C, Fragasso G. Metabolic therapy for pa-tients with diabetes mellitus and coronary artery disease. Am J Cardiol. 2006;98:14J-18J.

18. 2013 ESC guidelines on the management of stable coronary artery disease. The Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34:2949-3003.

19. Fragasso G, Montano C, Perseghin G, et al. The anti-ischemic effect of trimetazidine in patients with postprandial myocar-dial ischemia is unrelated to meal composition. Am Heart J. 2006;151:1238.e1-e8.

20. Fragasso G, Piatti PM, Monti L, et al. Short- and long-term beneficial effects of partial free fatty acid inhibition in diabetic patients with ischemic dilated cardiomyopathy. Am Heart J. 2003;146:e18.

21. Rodríguez Padial L, Maicas Bellido C, Velázquez Martín M, Gil

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FraGasso and others Heart Metab. (2017) 73:24-28Trimetazidine: targeting cardiac-cell metabolism in coronary disease and diabetes

Polo B. A prospective study on trimetazidine effectiveness and tolerability in diabetic patients in association to the previous treatment of their coronary disease. DIETRIC study. Rev Clin Esp. 2005;205(2):57-62.

22. Marazzi G, Wajngarten M, Vitale C, et al. Effect of free fatty acid inhibition on silent and symptomatic myocardial ischemia in diabetic patients with coronary artery disease. Int J Cardiol. 2007;120:79-84.

23. Piatti P, Di Mario C, Monti LD, et al. Association of insulin resis-tance, hyperleptinemia, and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting. Circulation. 2003;108:2074-2081.

24. Xu X, Zhang W, Zhou Y, et al. Effect of trimetazidine on recur-rent angina pectoris and left ventricular structure in elderly mul-tivessel coronary heart disease patients with diabetes mellitus after drug-eluting stent implantation: a single-centre, prospec-tive, randomized, double-blind study at 2-year follow-up. Clin Drug Investig. 2014;34:251-258.

25. Fragasso G, Spoladore R, Cuko A, Palloshi A. Modulation of fatty acids oxidation in heart failure patients by selective phar-macological inhibition of 3-ketoacyl coenzyme-A thiolase. Curr

Clin Pharmacol. 2007;2:190-196.26. Monti LD, Setola E, Fragasso G, et al. Metabolic and endothe-

lial effects of trimetazidine on forearm skeletal muscle in pa-tients with type 2 diabetes and ischemic cardiomyopathy. Am J Physiol Endocrinol Metab. 2006;290:E54-E59.

27. Fragasso G, Piatti PM, Monti L, et al. Acute effects of hepa-rin administration on the ischemic threshold of patients with coronary artery disease: evaluation of the protective role of the metabolic modulator trimetazidine. J Am Coll Cardiol. 2002;39:413-419.

28. Maridonneau-Parini I, Harpey C. Effects of trimetazidine on membrane damage induced by oxygen free radicals in human red cells. Br J Clin Pharmacol. 1985;20:148-151.

29. Monti LD, Allibardi S, Piatti PM, et al. Triglycerides impair postischemic recovery in isolated hearts: roles of endothe-lin-1 and trimetazidine. Am J Physiol Heart Circ Physiol. 2001;281:H1122-H1130.

30. Fragasso G, Salerno A, Spoladore R, Cera M, Montanaro C, Margonato A. Effects of metabolic approach in diabetic patients with coronary artery disease. Curr Pharm Des. 2009;15:857-862.

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Heart Metab. (2017) 73:29-32case report

The risk of myocardial infarction and cardiac death is two- to fourfold higher in diabetic than in nondiabetic patients; the latest European

Society of Cardiology guidelines recommend the use of noninvasive testing for risk stratification of patients with known or suspected coronary artery disease, which should be performed according to clinical needs and clinical judgment and not meant as a general recommendation to be followed in all patients.1,2 Stress echocardiography (stress echo) is certainly an attractive option owing to its widespread availability, low cost, and radiation-free nature, but the problem remains that the negative predictive value

of the test is lower in diabetics than in nondiabetic patients.3 Recent new evidence has emerged that a better negative predictive value can be obtained if we augment regional wall motion analysis with new parameters, such as assessment of left ven-tricular contractile reserve,4 left anterior descending coronary flow reserve,5-7 and/or B-lines during lung ultrasound.8 In particular, coronary flow velocity has long-term prognostic value in diabetics, and a reduc-tion in coronary flow velocity is associated with higher long-term mortality even in patients with normal regional wall motion.9 The case presented here is of a diabetic patient with negative stress echo by wall

Managing chest pain in a diabetic patient

Maria Chiara Scali, MD, PhDCardiovascular Medicine Division, United Hospitals of Valdichiana, Montepulciano, 53045 Siena, Italy.

Correspondence: Maria Chiara Scali, MD, PhD, Cardiothoracic Department, Pisa University, Via Paradisa 2, 56100 Pisa, Italy E-mail: [email protected]

AbstractCoronary artery disease is the leading cause of mortality in patients with diabetes. We present the case of a 61-year-old diabetic male patient with a previous history of percutaneous coronary intervention on the left circumflex coronary artery and who came to our outpatient clinic because of persistence of chest pain and limited exercise tolerance. The patient underwent stress echocardiography (stress echo), which was negative for inducible regional wall motion abnormalities but positive for left anterior descending coronary flow velocity reserve (1.7; normal values are above 2.0). The patient was intolerant to β-blockers and was started on ivabradine 5 mg twice daily plus trimetazidine 20 mg three times a day. After 1 month of therapy, the patient was reevaluated, and we observed a marked improvement in symptoms and a coronary flow velocity reserve of 2.1. With versatile use of stress echo, noninvasive risk stratification in diabetic patients can be obtained efficiently, at low cost, and without cumulative damage from radiation exposure, allowing a comprehensive assessment of wall motion, symptoms, electrocardiogram changes, and coronary flow velocity reserve. The latter was markedly improved by the combination of ivabradine plus trimetazidine. L Heart Metab. 2017;73:29-32

Keywords: B-lines; risk; stress-echo

30

motion criteria but reduced coronary flow reserve that improved after initiation of therapy with ivabradine and trimetazidine.

Case report

We present the case of a 61-year-old diabetic male patient with persistent chest pain and dyspnea after a percutaneous coronary revascularization (3 years earlier) with drug-eluting stent implantation on the proximal left circumflex coronary artery. The patient was referred to the outpatient clinic because of the persistence of symptoms. While under standard anti-ischemic therapy, the patient underwent stress echo (with dipyridamole) testing; the results were negative for wall motion abnormalities, but the chest pain was

reproduced and was associated with a 2-mm ST-segment depression on the anterior leads. After that, the coronary flow velocity reserve on the mid-distal left anterior descending coronary artery (calculated as stress/rest ratio of peak diastolic velocity) was as-sessed, yielding a value of 1.7 (normal values >2.0). Pharmacologic treatment was modified with the intro-duction of ivabradine (5 mg twice daily) plus trimetazi-dine (20 mg thrice daily), and the patient was reevalu-ated after 1 month. Quality of life was substantially ameliorated with the disappearance of chest pain. The stress echo test was repeated, confirming the absence of regional wall motion abnormalities, now without symptom or ST-segment changes and show-ing an increase in the coronary flow velocity reserve from 1.7 to 2.1 (Figure 1).

Rest

Stress

Normal wall motion Normal CFVR after IVA

Rest Stress (CFV=33 cm/s) (CFV =70 cm/s)

Fig. 1 The conceptual approach to dual imaging with vasodilator stress echo (with dipyridamole). The left upper panel shows the schematic representation of a normal epicardial coronary artery perfusing a normally contracting myocardium (square box). In the left lower panel, the standard two-dimensional (2D) stress echo (the end-systolic frames of the 2D short axis view) shows normal wall motion, consistent with the absence of critical coronary stenosis after revascularization. In the right upper panel, the damaged microcirculation (red circles) is sche-matically shown. The patient, on ivabradine, had a coronary flow velocity reserve within normal limits (2.1) during high-dose dipyridamole testing (right lower panels). The right middle panel shows the color Doppler image of coronary flow in the mid-distal left anterior descending artery; the left, the pulsed Doppler tracing at rest; the right, after dipyridamole. The ratio of stress/rest peak diastolic flow velocity is the index of coronary flow velocity reserve. It was 1.7 in a test performed 1 month before, off ivabradine.Abbreviation: CFV, coronary flow velocity; CFVR, coronary flow velocity reserve; cm/s, centimeters per second; IVA, ivabradine.

scali Heart Metab. (2017) 73:29-32Risk stratification in diabetes

31

Heart Metab. (2017) 73:29-32 scali

Risk stratification in diabetes

Discussion

Diabetic patients often pose challenging diagnostic problems. In ischemic diabetic patients, chest pain may be absent or atypical when present. Provoca-tive tests may be required to associate symptoms with objective signs of myocardial ischemia, such as regional wall dysfunction and/or ischemic electrocar-diogram changes. The case we present here was difficult to assess by a standard approach because of the atypicality of symptoms and the absence of transient akynesis during stress. So, we resolved to take advantage of the most recent developments in stress echo imag-ing, where the classical imaging based on regional wall motion analysis has been augmented by assess-ment of coronary flow velocity reserve. Regional wall motion abnormalities are influenced by the epicardial coronary artery stenosis, whereas the coronary artery flow velocity reserve is affected by the coronary mi-crocirculation.

Coronary microvascular dysfunction may be effec-tively targeted by cardiometabolic and hemodynamic agents. Ivabradine has been shown to increase the coronary flow reserve in angina patients—with and without diabetes—in the poststenotic territory, as well as in areas remote from the epicardial coronary stenosis.10 Reported increases in flow velocity re-serve vary from 2.6 to 3.5 (+30%), probably through a combination of effects, including the increase in diastolic perfusion time, improved isovolumic ven-tricular relaxation, a reduction in end-diastolic pres-sure responsible for extravascular resistances, and improved flow through collaterals.11 This approach is not only pathophysiologically appealing, but also expands the potential of risk stratification because in ischemic patients (and especially in diabetics), many cardiac events can occur independently of the coro-nary plaque targeted by the stress-induced approach and are linked to microcirculatory disease. We usually focus solely on coronary stenosis, but the pathophysiological inconsistencies and clinical collateral damage driven by this simplistic approach are well-known.12 Dual-imaging stress echo allows many different variables to be brought into focus.9 The cardiovascular hard-event rate of a diabetic pa-tient with negative stress echo by conventional wall motion criteria is 2%, but with the addition of a normal

response of coronary flow reserve, the hard-event an-nual rate drops off to less than 0.5%. It remains to be clarified with prospective randomized studies wheth-er an improvement in coronary flow velocity reserve achieved with drugs such as ivabradine—and/or trimetazidine, also effective through a different cardio-metabolic effect in patients still symptomatic on stan-dard therapy—modifies the long-term prognosis in diabetic patients. In particular, the role of trimetazidine in diabetics has a strong pathophysiological rationale, as diabetes also affects the microcirculation, which cannot be treated by revascularization and is the pref-erential target of trimetazidine treatment. Such treat-ment may compensate for the deteriorated glucose uptake and utilization in myocardial cells caused by altered insulin levels.13 L

REFERENCES

1. Ryden L, Standl E, Bartnik M, et al; Task Force on Diabetes and Cardiovascular Diseases of the European Society of Car-diology. Guidelines on diabetes, pre-diabetes, and cardiovas-cular diseases: executive summary. Eur Heart J. 2013;28:88-136.

2. Bax JJ, Young LH, Frye RL, et al. Screening for coronary artery disease in patients with diabetes. Diabetes Care. 2007;30:2729-2736.

3. Cortigiani L, Bigi R, Sicari R, et al. Prognostic value of pharma-cological stress echocardiography in diabetic and nondiabetic patients with known or suspected coronary artery disease. J Am Coll Cardiol. 2006;47:605-610.

4. Cortigiani L, Bombardini T, Corbisiero A, et al The additive prognostic value of end-systolic pressure-volume relationship in diabetic patients with negative dobutamine stress echocar-diography by wall motion criteria. Heart. 2009;95:1429-1435.

5. Cortigiani L, Rigo F, Gherardi S, et al. Additional prognostic value of coronary flow reserve in diabetic and nondiabetic pa-tients with negative dipyridamole stress echocardiography by wall motion criteria. J Am Coll Cardiol. 2007;50:1354-1361.

6. Lowenstein JA, Caniggia C, Rousse G, et al. Coronary flow reserve during pharmacologic stress echocardiography with normal contractility adds important prognostic value in diabetic and nondiabetic patients. J Am Soc Echocardiogr. 2014;27:1113-1119.

7. Kawata T, Damon M, Hasegawa R, et al. Prognostic value of coronary flow reserve assessed by transthoracic Doppler echocardiography on long-term outcome in asymptomatic pa-tients with type 2 diabetes without overt coronary artery dis-ease. Cardiovasc Diabetol. 2013;12:121.

8. Scali MC, Cortigiani L, Simionuc A, Gregori D, Marzilli M, Pi-cano E. Exercise-induced B-lines identify worse functional and prognostic stage in heart failure patients with depressed left ventricular function. Eur J Heart Fail. 2017 Feb 15. Epub ahead of print. doi:10.1002/ejhf.776.

9. Cortigiani L, Gherardi S, Faggioni M, et al. Dual-imaging stress echocardiography for prognostic assessment of high-risk as-ymptomatic patients with diabetes mellitus. J Am Soc Echo-cardiogr. 2017;30:149-158.

10. Skalidis EI, Hamilos MI, Chlouverakis G, Zacharis EA, Vardas PE. Ivabradine improves coronary flow reserve in pa-tients with stable coronary artery disease. Atherosclerosis.

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scali Heart Metab. (2017) 73:29-32Risk stratification in diabetes

2011;215(1):160-165. 11. Tagliamonte E, Cirillo T, Rigo F, et al. Ivabradine and bisoprolol

on Doppler-derived coronary flow velocity reserve in patients with stable coronary artery disease: beyond the heart rate. Adv Ther. 2015;32(8):757-767.

12. Marzilli M, Merz CN, Boden WE, et al. Obstructive coronary atherosclerosis and ischemic heart disease: an elusive link! J Am Coll Cardiol. 2012;60:951-956.

13. Dezsi CA. Trimetazidine in practice: review of the clinical and experimental evidences. Am J Ther. 2016;23:e871-e879.

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Heart Metab. (2017) 73:33-36ReFresher Corner

Introduction

As of 2014, it was estimated that there were over 420 million people worldwide living with diabe-tes, of which 90% was accounted for by type 2

diabetes mellitus (T2DM). Despite having a variety of different drug classes to control hyperglycemia in these individuals, the vast majority of diabetics will eventually die from cardiovascular causes such as myocardial infarction and heart failure (HF).1,2 Hence, there has been and continues to be a strong effort within the scientific and medical community to understand the cardiovascular actions of therapies for treating diabetes, in addition to understanding how diabetes itself increases the risk of developing cardiovascular

disease. With regard to the latter, we have now come to appreciate that energy metabolism in the myocardium of an individual with type 1 diabetes mellitus (T1DM) or T2DM is significantly different from that in a healthy individual.2-5 Of particular importance, the healthy heart is a metabolic omnivore with high flexibility that is able to consume a wide variety of substrates according to their availability throughout various physiological states (eg, feeding versus starvation). However, during both T1DM and T2DM, the robust increase in circulating free fatty acids and triglycerides greatly augments fatty acid delivery to the myocardium, making fat the primary fuel choice for the heart’s energy demands, which severely limits its ability to adapt to and use other energy sources (Figure 1). The aims of this

Cardiac energy metabolism in diabetesKim L. Ho1,3,4; John R. Ussher2,3,4

1Department of Pediatrics, University of Alberta, Edmonton, AB Canada; 2Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB Canada;

3Alberta Diabetes Institute, University of Alberta, Edmonton, AB Canada; 4Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB Canada

Correspondence: Dr John R. Ussher, 2-020CKatz Centre for Pharmacy and Health Research, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta,

Edmonton, AB T6G 2E1, Canada E-mail: [email protected]

AbstractDiabetes is a significant risk factor for cardiovascular disease, and ongoing efforts aim to elucidate how diabetes precipitates ventricular dysfunction. Myocardial energy metabolism is intricately regulated because the heart—the most metabolically demanding organ in the body on a per gram basis—must dynamically metabolize a diverse range of fuel sources. However, in type 1 and type 2 diabetes mellitus, increases in myocardial fatty acid oxidation and decreases in myocardial glucose oxidation are observed, and it has been postulated that these metabolic perturbations are key contributors to diabetes-related ventricular dysfunction. With a number of pharmacological tools now available to modulate energy metabolism, targeting the diabetes-induced alterations in myocardial energy metabolism may be a promising strategy to improve ventricular function in diabetic subjects. Such a strategy is widely sup-ported by current evidence in preclinical studies. L Heart Metab. 2017;73:33-36

Keywords: energy metabolism; fatty acid oxidation; glucose oxidation; type 1 diabetes; type 2 diabetes

34

refresher article are to highlight the specific myocardial metabolic alterations observed in patients with T1DM and T2DM, and to describe whether these metabolic alterations can be targeted to improve cardiac function in diabetic subjects.

Myocardial energy metabolism in type 1 diabetes

Because T1DM is often the result of insulin deficiency, many of the alterations in myocardial energy metabo-lism in a T1DM individual can be attributed to deficient myocardial insulin action. In a healthy insulin-sensitive individual, insulin acts to increase glucose uptake in the heart, leading to increases in both glycolysis and glucose oxidation.6 Increases in glucose oxidation lead to a corresponding reduction in fatty acid oxida-tion, a phenomenon first described by Shipp and col-leagues7 in the 1960s, but later given prominence by Philip Randle and colleagues. As such, this reciprocal glucose–fatty acid relationship for oxidative metabolism is commonly referred to as the “Randle Cycle.”8 Insulin also decreases myocardial fatty acid oxidation rates in-directly by inhibiting adipose tissue lipolysis. In addition,

insulin directly inhibits myocardial fatty acid oxidation rates by activating acetyl coenzyme A (CoA) carbox-ylase to increase levels of malonyl CoA, a potent en-dogenous inhibitor of carnitine palmitoyltransferase-1 (CPT-1), which subsequently inhibits mitochondrial fatty acid uptake.3 Therefore, in a T1DM individual, myocar-dial fatty acid oxidation rates are markedly elevated as a result of absent insulin action, whereas glucose oxidation and glycolysis rates are severely diminished. Indeed, studies in rats subjected to experimental T1DM via tail-vein injection of streptozotocin (55 mg/kg) dem-onstrate that fatty acid oxidation accounts for approxi-mately 95% of total oxidative adenosine triphosphate (ATP) production during isolated aerobic working heart perfusion.9 Likewise, the Akita mouse (a mouse model of T1DM due to genetic mutation in the insulin 2 [Ins2] gene) demonstrates no changes in glucose oxidation and significant increases in myocardial fatty acid oxida-tion during isolated aerobic working heart perfusion,10 though the changes in fatty acid oxidation are not nearly as prominent as those seen in the streptozotocin model of T1DM. Similar findings have been recapitulated in humans, in which positron emission tomography (PET) imaging studies in T1DM subjects with 1-11C-glucose and 1-11C-palmitate revealed reductions in myocardial glucose utilization rates and increases in myocardial fatty acid oxidation rates, respectively.11

Myocardial energy metabolism in type 2 diabetes

The myocardial metabolic alterations reported in animal models of obesity and/or T2DM, or in T2DM patients are similar to those observed in a T1DM individual. In mice subjected to chronic high-fat feeding (60% kcal from lard) for 12 weeks to induce experimental obe-sity, marked reductions in glucose oxidation rates are observed, whereas fatty acid oxidation rates remain largely unaffected.12 Of interest, severe insulin resis-tance is observed in this model with regard to insulin’s ability to promote glucose oxidation, such that in the presence of insulin, the vast majority of oxidative en-ergy metabolism is met through the oxidation of fatty acids.12 In genetic mouse models of T2DM, including both leptin-deficient ob/ob and leptin receptor–de-ficient db/db mice, marked increases in myocardial fatty acid oxidation and corresponding decreases in glucose oxidation rates are observed during isolated aerobic working heart perfusions.13 These changes in myocardial energy metabolism are associated with sig-

AbbreviationsATP: adenosine triphosphate; CoA: coenzyme A; CPT-1: carnitine palmitoyltransferase-1; DCA: dichloroacetate; HF: heart failure; MRI: magnetic resonance imaging; PDH: pyruvate dehydrogenase; PET: positron emission tomography; T1DM: type 1 diabetes mellitus; T2DM: type 2 diabetes mellitus

ho and ussher Heart Metab. (2017) 73:33-36Cardiac energy metabolism in diabetes

Fatty acid oxidationOxygen consumption

Glucose oxidationCardiac ef�ciency

Fig. 1 Alterations in myocardial energy metabolism in the diabetic heart. The figure illustrates the prominent metabolic perturbations that take place in the heart during diabetes, which are character-ized by an increase in fatty acid oxidation rates and subsequent decrease in glucose oxidation rates. These changes in oxidative metabolism are associated with an increase in myocardial oxygen consumption, which contributes to a reduction in cardiac efficiency.

35

Heart Metab. (2017) 73:33-36 ho and ussher Cardiac energy metabolism in diabetes

nificant increases in myocardial oxygen consumption rates, but are not matched by an equivalent increase in cardiac work/power, such that the efficiency of con-tractile function is reduced in both ob/ob and db/db mice.13 These observations have been recapitulated in a human cohort study of obese women from Petersen and colleagues, whereby PET imaging studies revealed marked increases in fatty acid oxidation rates in obese women, which strongly correlated with the degree of glucose intolerance.14 Moreover, increasing obesity is inversely associated with cardiac efficiency in these women.14 Additional PET imaging studies have record-ed similar observations, as Rijzewijk and colleagues demonstrated an elevation in myocardial fatty acid oxi-dation rates and a decline in myocardial glucose uptake in T2DM patients with diastolic dysfunction.15

Myocardial energy metabolism alterations in diabetic subjects with heart failure

An important potential confounding factor when as-sessing the impact of diabetes on myocardial energy metabolism is the comorbidity of HF. Diabetes is a major risk factor for HF, and it is estimated that 30% to 40% of HF patients have some form of diabetes.16 Because HF is associated with its own distinct myo-cardial metabolic phenotype, most notably a reduc-tion in fatty acid oxidation rates that appears to cor-relate with the severity of the decline in ventricular function,3,5 careful consideration needs to be taken with interpretation of myocardial energy metabolism profiles in comorbid diabetic/HF individuals.

Optimizing myocardial energy metabolism to improve cardiac function in diabetes

A key question arising from the myocardial metabolic aberrations in diabetic subjects is whether they can be targeted to improve cardiac function in these in-dividuals. Of particular relevance, a number of stud-ies in animal models of obesity and/or diabetes have demonstrated that pharmacological activation of glu-cose oxidation often improves both cardiac function and contractile efficiency of the heart.2,3 For example, isolated working hearts from rats treated with strepto-zotocin to induce T1DM demonstrate a marked reduc-tion in cardiac function during aerobic perfusion, which is negated by the inclusion of 0.5 mM dichloroacetate (DCA) in the perfusate.17 DCA is a pharmacological in-

hibitor of pyruvate dehydrogenase (PDH) kinase, and thereby increases glucose oxidation by preventing phosphorylation-induced inhibition of PDH, the rate-limiting enzyme of glucose oxidation.18 Likewise, DCA supplementation in the drinking water (final concentra-tion of 1 mM) has also been shown to increase myo-cardial glucose oxidation rates via a novel 13C hyperpo-larized magnetic resonance imaging (MRI) method in a rat model of experimental T2DM (long-term high-fat feeding plus a single low-dose streptozotocin injec-tion), ultimately resulting in an abrogation of diastolic dysfunction.19 Of interest, inhibiting fatty acid oxidation rates in animal models of experimental obesity/insulin resistance also has beneficial actions on the myocar-dium. Indeed, mice with a deficiency for malonyl CoA decarboxylase, which decreases fatty acid oxidation rates due to elevating levels of malonyl CoA and sub-sequent inhibition of CPT-1, demonstrate increases in cardiac efficiency, as well as a marked improvement in insulin-stimulated glucose oxidation rates.12 In addi-tion, the antianginal agent trimetazidine, which reduces myocardial fatty acid oxidation rates by inhibiting the β-oxidation enzyme, 3-ketoacyl-CoA thiolase, can attenuate diastolic dysfunction in middle-aged mice subjected to experimental obesity/insulin resistance.20 Similarly, trimetazidine treatment for 6 months in T2DM subjects with idiopathic cardiomyopathy improves both diastolic function and systolic function.21 As mentioned in the previous section, myocardial fatty acid oxidation rates are often impaired in indi-viduals with HF3,5; thus, it may be anticipated that in-hibiting myocardial fatty acid oxidation in a comorbid diabetic/HF subject would be undesirable. Neverthe-less, treatment with trimetazidine for 3 months has been shown to reduce myocardial fatty acid oxida-tion rates and improve ventricular function in systolic HF patients with idiopathic dilated cardiomyopathy.22 Moreover, treatment of optimally medicated chronic HF patients for 8 weeks with perhexiline, a fatty acid oxidation inhibitor that directly antagonizes CPT-1, also leads to significant improvements in ventricular function.23 Therefore, inhibition of myocardial fatty acid oxidation rates may still be potentially beneficial even in a comorbid diabetic/HF subject.

Summary

It has been strongly established that both T1DM and T2DM lead to significant alterations in myocardial en-

36

ho and ussher Heart Metab. (2017) 73:33-36Cardiac energy metabolism in diabetes

ergy metabolism, most notably an elevation in fatty acid oxidation rates and a reduction in glucose oxi-dation rates (Figure 1), as determined in preclinical studies. Elevations in myocardial fatty acid oxidation have also been seen in human subjects with T1DM or T2DM, but because methodologies to assess glu-cose oxidation in vivo are limited, confirmation that glucose oxidation rates are reduced in diabetic pa-tients is lacking. However, the development of the novel 13C hyperpolarized MRI method to quantify glucose oxidation in vivo has recently been success-fully applied to human subjects,24 suggesting that we may soon have confirmation of reduced myocardial glucose oxidation rates in diabetic subjects. Current evidence from preclinical studies supports the notion that normalizing diabetes-induced alterations in myo-cardial energy metabolism may be a novel approach to attenuate diabetes-induced ventricular dysfunc-tion. Though human data is lacking, this is a promis-ing area that requires further investigation. L

REFERENCES

1. Ussher JR, Sutendra G, Jaswal JS. The impact of current and novel anti-diabetic therapies on cardiovascular risk. Future Cardiol. 2012;8:895-912.

2. Zlobine I, Gopal K, Ussher JR. Lipotoxicity in obesity and diabetes-related cardiac dysfunction. Biochim Biophys Acta. 2016;1860:1555-1568.

3. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90:207-258.

4. Ussher JR. The role of cardiac lipotoxicity in the pathogen-esis of diabetic cardiomyopathy. Expert Rev Cardiovasc Ther. 2014;12:345-358.

5. Ussher JR, Elmariah S, Gerszten RE, Dyck JR. The Emerging role of metabolomics in the diagnosis and prognosis of cardio-vascular disease. J Am Coll Cardiol. 2016;68:2850-2870.

6. Brownsey RW, Boone AN, Allard MF. Actions of insulin on the mammalian heart: metabolism, pathology and biochemical mechanisms. Cardiovasc Res. 1997;34:3-24.

7. Shipp JC, Opie LH, Challoner D. Fatty acid and glucose me-tabolism in the perfused heart. Nature. 1961;189:1018-1019.

8. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glu-cose fatty-acid cycle. Its role in insulin sensitivity and the meta-bolic disturbances of diabetes mellitus. Lancet. 1963;1:785-789.

9. Sakamoto J, Barr RL, Kavanagh KM, Lopaschuk GD. Con-tribution of malonyl-CoA decarboxylase to the high fatty acid

oxidation rates seen in the diabetic heart. Am J Physiol Heart Circ Physiol. 2000;278:H1196-H1204.

10. Basu R, Oudit GY, Wang X, et al. Type 1 diabetic cardiomyopa-thy in the Akita (Ins2WT/C96Y) mouse model is characterized by lipotoxicity and diastolic dysfunction with preserved systolic function. Am J Physiol Heart Circ Physiol. 2009;297:H2096-H2108.

11. Herrero P, Peterson LR, McGill JB, et al. Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus. J Am Coll Cardiol. 2006;47:598-604.

12. Ussher JR, Koves TR, Jaswal JS, et al. Insulin-stimulated car-diac glucose oxidation is increased in high-fat diet-induced obese mice lacking malonyl CoA decarboxylase. Diabetes. 2009;58:1766-1775.

13. Buchanan J, Mazumder PK, Hu P, et al. Reduced cardiac ef-ficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology. 2005;146:5341-5349.

14. Peterson LR, Herrero P, Schechtman KB, et al. Effect of obe-sity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation. 2004;109:2191-2196.

15. Rijzewijk LJ, van der Meer RW, Lamb HJ, et al. Altered myo-cardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic reso-nance imaging. J Am Coll Cardiol. 2009;54:1524-1532.

16. Dei Cas A, Fonarow GC, Gheorghiade M, Butler J. Concomi-tant diabetes mellitus and heart failure. Curr Probl Cardiol. 2015;40:7-43.

17. Nicholl TA, Lopaschuk GD, McNeill JH. Effects of free fatty ac-ids and dichloroacetate on isolated working diabetic rat heart. Am J Physiol. 1991;261:H1053-H1059.

18. Ussher JR, Wang W, Gandhi M, et al. Stimulation of glucose oxidation protects against acute myocardial infarction and re-perfusion injury. Cardiovasc Res. 2012;94:359-369.

19. Le Page LM, Rider OJ, Lewis AJ, et al. Increasing pyruvate dehydrogenase flux as a treatment for diabetic cardiomyopa-thy: a combined 13C hyperpolarized magnetic resonance and echocardiography study. Diabetes. 2015;64:2735-2743.

20. Ussher JR, Fillmore N, Keung W, et al. Trimetazidine therapy prevents obesity-induced cardiomyopathy in mice. Can J Car-diol. 2014;30:940-944.

21. Zhao P, Zhang J, Yin XG, et al. The effect of trimetazidine on cardiac function in diabetic patients with idiopathic dilated car-diomyopathy. Life Sci. 2013;92:633-638.

22. Tuunanen H, Engblom E, Naum A, et al. Trimetazidine, a meta-bolic modulator, has cardiac and extracardiac benefits in id-iopathic dilated cardiomyopathy. Circulation. 2008;118:1250-1258.

23. Lee L, Campbell R, Scheuermann-Freestone M, et al. Meta-bolic modulation with perhexiline in chronic heart failure: a ran-domized, controlled trial of short-term use of a novel treatment. Circulation. 2005;112:3280-3288.

24. Cunningham CH, Lau JY, Chen AP, et al. Hyperpolarized 13C metabolic MRI of the human heart: initial experience. Circ Res. 2016;119:1177-1182.

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Heart Metab. (2017) 73:37-39Hot Topics

Type 2 diabetes (T2DM) is related to an increased cardiovascular risk, and the main reason for this is thought to be insulin resistance, which

is clinically represented by metabolic syndrome. Metabolic syndrome manifests as an association of symptoms and signs, such as hypertension with blood pressure over 130/85 mm Hg, triacylglycerols higher than 150 mg/dL, high-density lipoprotein levels under 40 mg/dL for men and under 50 mg/dL for women, fasting blood glucose greater than 100 mg/dL, or established T2DM and an abdominal cir-cumference greater than 94 cm for men and greater than 80 cm for women. Of those five signs, the presence of two or more determines a diagnosis of metabolic syndrome.1 Recently, studies have shown an increased incidence of cardiovascular disease in patients with metabolic syndrome, and added to this, the association of altered blood glucose levels may

lead to a further increase in cardiovascular risk.1 More than half of the patients with T2DM are considered obese and to have metabolic syndrome.1

Hyperglycemia observed both in diabetes type 1 and 2 already increases the cardiovascular risk due to endothelial lesions. Recently, Ceriello et al pub-lished possible reasons for why patients with unsat-isfactory glycemic control over a long period of time do not benefit from better metabolic control.2 These authors believe that oxidized advanced glycated end products (AGEs) would form as a result of an increase in mitochondrial reactive oxygen species, or ROS. This could modify proteins of the respiratory chain that are encoded by mitochondrial deoxyribo-nucleic acid (DNA), which—after this damage—lead to persistent formation of ROS independently of hyperglycemia; ROS represent the main factor re-sponsible for AGE formation.2 It is known that the

Cardiovascular diseases and diabetes: causes and cures

Joao E. Salles, MD, PhD Santa Casa de São Paulo Hospital, Internal Medicine Department, Endocrinology Unit, São Paulo, Brazil

Correspondence: Rua Padre João Manoel, 222 cj 77 CEP 01411001, São Paulo, Brazil E-mail: [email protected]

AbstractThe relationship between type 2 diabetes and an increased cardiovascular risk involves insulin resistance, which is clinically represented by the metabolic syndrome. Hyperglycemia in diabetes—both types 1 and 2—increases cardiovascular risk due to endothelial lesions. Control of all risk factors, including lip-ids, hypertension, and blood glucose are important to decrease the risk of cardiovascular disease. With particular regard to blood glucose, the UKPDS study (United Kingdom Prospective Diabetes Study) showed that early intensive glycemic control was essential in the reduction in cardiovascular disease. A decrease in mortality observed with glucagon-like peptide-1 (GLP-1) analog use is probably due to a reduction in body weight; findings for empagliflozin still remain unclear. L Heart Metab. 2017;73:37-39

Keywords:

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presence of ROS is the triggering factor behind de-velopment of diabetes complications, both macro and micro, due to endothelial injury.2

However, in an approximately 23-year retrospec-tive comparison of patients with type 1 diabetes mel-litus (T1DM) and T2DM, diagnosed at the same age (15 and 30 years old), patients with T2DM presented with a higher incidence of macro and microvascular disease and had a higher mortality.3 Regarding cardiovascular coronary dysfunction, Bonamichi et al revealed through intravascular ul-trasound that hyperglycemia plays an important role in the development of atherosclerotic disease in pa-tients with metabolic syndrome and may lead to a worsening of the pathology.4

The control of all risk factors, including lipids, hy-pertension, and blood glucose, plays an important role in decreasing cardiovascular disease risk. Par-ticularly with blood glucose, the UKPDS study (United Kingdom Prospective Diabetes Study) was effective in demonstrating that early intensive glycemic control is essential to reduce cardiovascular disease.5 The results of UKPDS 80, a trial that evaluated the same UKPDS outcomes published in 1998, demonstrated that the patients that benefited most in terms of pre-vention of heart attack and all-cause mortality were the patients in the intensive treatment group.5

Cardiovascular safety of hypoglycemic medications

Cardiovascular safety studies performed with hypo-glycemic medications for T2DM were and are impor-tant, not just to evaluate the primary outcomes re-lated to cardiovascular disease, but also to establish and evaluate possible side effects, as well as benefits, of those medications. With regard to dipeptidyl peptidase-4 (DPP-4) inhibitors, the studies that have been thus far pub-lished, such as SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with dia-betes mellitus – Thrombolysis In Myocardial Infarc-tion),6 EXAMINE (Examination of Cardiovascular Out-comes with Alogliptin Versus Standard of Care),7 and TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin),8 have demonstrated cardiovascular safety. However, they have not shown significant de-creases in the complications related to T2DM. The ADVANCE study (Action in Diabetes and Vas-cular disease: PreterAx and DiamicroN MR Controlled

Evaluation) also demonstrated cardiovascular safety with gliclazide use in patients with T2DM and estab-lished cardiovascular disease.9 The results are im-portant for the differentiation of gliclazide from other medications in terms of cardiovascular safety.9

After the ADVANCE study, patients were followed-up for approximately 6 years in the ADVANCE-ON (ADVANCE Observational) trial. Glycated hemoglobin in both ADVANCE and ADVANCE-ON studies was established to be an average of 7.4%, suggesting methodological importance, leading us to conclude that the intensive glucose control at baseline was the main difference.9 Recently, results of cardiovascular outcomes trials (CVOTs) were published for two classes of medica-tions. Cardiovascular safety of GLP-1 analogs was shown, with a decrease in mortality in the LEADER trial (Liraglutide Effect and Action in Diabetes: Evalu-ation of cardiovascular outcome Results)10 and a de-crease in major adverse cardiac events (MACE) in the SUSTAIN trial (Trial to Evaluate Outcomes with Sema-glutide in Subjects with Type 2 Diabetes).11 Sodium-glucose cotransporter-2 (SGLT2) inhibitors were shown to reduce mortality and MACE in the EMPA-REG OUTCOME trial (Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) with empa-gliflozin, though there was no reduction in cardiovas-cular events.12

We conclude that treatment for cardiovascular disease in patients with T2DM should be sought from the first day of diabetes diagnosis, with intensive gly-cemic control, lipid control through use of statins, and hypertension control. The decrease in mortality observed with GLP-1 analogs is probably due to a reduction in body weight, whereas the findings of the empaglifozin study remain unclear. L

REFERENCES

1. Alberti KG, Zimmet P, Shaw J; IDF Epidemiology Task Force Consensus Group. The metabolic syndrome--a new world-wide definition. Lancet. 2005;366(9491):1059-1062.

2. Ceriello A, Ihnat MA, Thorpe JE. Clinical review 2: The “meta-bolic memory”: is more than just tight glucose control nec-essary to prevent diabetic complications? J Clin Endocrinol Metab. 2009;94(2):410- 415.

3. Constantino MI, Molyneaux L, Limacher-Gisler F, et al. Long-term complications and mortality in young-onset diabetes: type 2 diabetes is more hazardous and lethal than type 1 dia-betes. Diabetes Care. 2013;36(12):3863-3869.

4. Bonamichi BD, Parente EB, Campos AC, Cury NA, Salles JE. Hyperglycemia effect on coronary disease in patients with met-abolic syndrome evaluated by intracoronary ultrasonography.

salles Heart Metab. (2017) 73:37-39Cardiovascular diseases and diabetes: causes and cures

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Heart Metab. (2017) 73:37-39 salles Cardiovascular diseases and diabetes: causes and cures

PloS One. 2017;12(2): e0171733.5. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-

year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-1589.

6. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardio-vascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326.

7. White WB, Cannon CP, Heller SR, et al; EXAMINE Investiga-tors. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-1335.

8. Green JB, Bethel MA, Armstrong PW, et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232-242.

9. Zoungas S, Chalmers J, Neal B, Billot L, et al; ADVANCE-ON Collaborative Group. Follow-up of blood-pressure low-ering and glucose control in type 2 diabetes. N Engl J Med. 2014;371(15):1392-1406.

10. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P; LEAD-ER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.

11. Marso SP, Bain SC, Consoli A, Eliaschewitz FG; SUSTAIN-6 In-vestigators. Semaglutide and cardiovascular outcomes in pa-tients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844.

12. Zinman B, Wanner C, Lachin JM; EMPA-REG OUTCOME Inves-tigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.

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Heart Metab. (2017) 73:40-41Glossary Gary d. lopaschuk

α-Cellα-Cells are endocrine cells localized within islets of the pancreas, where they secrete the peptide hor-mone glucagon during times of prolonged fasting/starvation in order to stimulate hepatic glucose pro-duction for maintaining normoglycemia. The α-cell makes up approximately 20% of the pancreatic islet-cell population in humans.

Body mass indexBody mass index (BMI) is a formula for measuring an individual’s relative weight based on their mass and height and is calculated by the formula BMI = mass in kilogram/(height in meters)2. A healthy BMI is gen-erally considered to be in the range of 18.5 to 24.9, whereas those with BMIs in the 25 to 29.9 range are classified as being overweight, and those with BMIs >30 are classified as obese. Although BMI is fre-quently used to assess general body mass in patient populations, the BMI does not take into account age, sex, or muscle mass, and it can result in large BMI scores for people that actually have very low body fat percentages, such as body builders.

Carnitine palmitoyl transferase-1Carnitine palmitoyl transferase-1 (CPT-1) is the rate-limiting enzyme involved in the uptake of fatty acids in the mitochondria. It converts fatty acyl–coenzyme A to fatty acylcarnitine, which is then transported into the mitochondria where it is further metabo-lized. CPT-1 is a highly regulated enzyme that pre-vents excess fatty acid from being taken up into the mitochondria.

Endothelin-1Endothelin-1 is a small peptide produced in a variety of tissues, including endothelial and vascular smooth muscle cells. It acts as a modulator of vasomotor tone, cell proliferation, and hormone production. It is a potent vasoconstrictor.

Glycated hemoglobinGlycated hemoglobin (HbA1c) forms from the nonen-zymatic coupling of glucose to the major component of adult hemoglobin (ie, HbA α2β2). Glucose, via a complex series of reactions, is coupled to specific valine residues of HbA β chains. HbA1c levels at a threshold of 6.5% can be used as a diagnostic test indicative of diabetes. HbA1c levels are reflective of av-

erage glycemic control over a period of 2 to 3 months before testing/analysis.

GlycolysisGlycolysis is the series of biochemical reactions oc-curring in the cytosolic compartment that converts a glucose molecule into two molecules of pyruvate. In the presence of oxygen (ie, the aerobic setting), pyru-vate is transported into the mitochondria and under-goes oxidative decarboxylation, yielding acetyl-CoA. In the absence of oxygen (ie, the anaerobic setting), pyruvate is reduced to lactate by the enzyme lactate dehydrogenase, which generates the nicotinamide adenine dinucleotide (NAD+) required to maintain flux through glycolysis.

IncretinIncretin refers to gastrointestinal peptide hormones released by enteroendocrine cells of the intestinal mucosa in response to the ingestion of food (or oral glucose load). The two major incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent in-sulinotropic polypeptide (GIP). Incretins enhance glucose-stimulated insulin secretion and, thus, are important regulators of glucose homeostasis. In ad-dition, a variety of extraglycemic effects of incretins have been documented, including a slowing of gas-tric emptying, promotion of satiety, and reductions in food intake.

InsulinInsulin is a pancreatic peptide hormone secreted from β-cells of the islets of Langerhans in the post-absorptive state. Its major metabolic effects are ana-bolic in nature, exemplified by the ability of insulin to do the following: increase glucose and amino acid uptake, as well as glycogen and protein synthesis, in muscle; increase glucose uptake and triacylglycerol synthesis in adipose tissue; and increase glucose uptake, glycogen, and triacylglycerol synthesis in the liver.

LeptinLeptin is a peptide hormone synthesized by adipo-cytes and plays a key role in the regulation of appetite and energy expenditure. This can occur through di-rect actions of leptin on the hypothalamus or on pe-ripheral lipid and glucose metabolism.

Glossary Gary d. lopaschuk

Thromboxane A2

Thromboxane A2 is a product of the cyclooxygenase pathway of arachidonic acid metabolism. In that pathway, cyclooxygenase catalyzes the production of prostaglandin H2 (PGH2) from arachidonic acids; PGH2 can then be used in the formation of a number of different eicosanoid products, including prosta-glandins. Metabolism of PGH2 by thromboxane syn-thase, which is abundant in lung and platelets, results in the production of thromboxane A2. Thromboxane A2 has a variety of biological effects, including vaso-constriction and promotion of platelet aggregation.

Heart Metab. (2017) 73:40-41

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Cardiovascular diseases and diabetes: causes and cures · focusing on the management of cardiovascular diseases. Its aim is to inform cardiologists and other specialists about the