title sub title SGLT2 Inhibitors – No Longer Just for Those with Diabetes

EXPERT MONOGRAPH ISSUE 46

Introduction

In the past, physicians have adopted a glucocentric approach to the management of diabetes and focused primarily on glycaemic control. Large studies have shown that good glucose control reduces the risk of microvascular disease (retinopathy

and nephropathy). However, the benefits on macrovascular events

(myocardial infarction and stroke) have been less pronounced,1

despite long-term follow up studies showing a small decrease in

major cardiovascular events.2 This is disappointing, as most of the

morbidity and mortality associated with type 2 diabetes is due to

cardiovascular events.3

It has become clear that well-controlled blood pressure and lipids,

particularly with ACEIs or ARBs and statins, reduces the risk of

cardiovascular events and renal dysfunction in patients with type

2 diabetes.

Take Home Messages

į The SGLT2 inhibitors are the only diabetes drugs

that reduce the risk of heart failure

į SGLT2 inhibitors are recommended for patients

with type 2 diabetes where heart failure or

chronic kidney disease predominate

į Recent research indicates that the cardiac

benefits of SGLT2 inhibitors are experienced

even in those patients who do not have diabetes.

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ASSOCIATE PROFESSOR JOHN AMERENA MBBS, PhD, FRACP, FCSANZ

A/Prof John Amerena trained in Melbourne before spending four years in the United States at the University of Michigan. He is now a Cardiologist at Barwon Health, and currently has appointments in the Medical School, Deakin University and the Department of Epidemiology and Preventive Medicine at Monash University. He is the Director of the Geelong Cardiology Research Unit which is currently involved in many phase II-III clinical trials, as well as Director of Cardiac Services at Geelong Private Hospital. While still involved in hypertension, he has also become involved in research in atherothrombosis.

SGLT2 inhibitors are rapidly becoming seen as cardiac drugs in their own right, above and beyond their role in diabetes.

JANUARY 31, 2020

title sub title

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SGLT2 Inhibitors – No Longer Just for Those with Diabetes

A new focus

Now cardiorenal protection is considered as important, if not more important, than glycaemic control.

Until recently, the agents used to control hyperglycaemia in patients with type 2 diabetes have not had any impact on reducing cardiovascular or renal events. Consequently, the results of the more recent studies showing the cardioprotective effect of SGLT2 inhibitors in patients with type 2 diabetes have been met with great enthusiasm.

It is often not appreciated that there is an increased risk of heart failure in patients with type 2 diabetes4. In fact, patients with type 2 diabetes have a 2-3 fold increased risk of developing heart failure, and there is a 60-80% increased risk of cardiomyopathy and cardiovascular death in these patients.5

As well, type 2 diabetes is associated with an increased risk of hospitalisation for heart failure, regardless of whether the patient has heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF).

The impact on heart failure seen with the SGLT2 inhibitors was

not expected.

The incidence of diabetes is increasing as our population ages and as a direct result of this, admissions for heart failure are also increasing. In addition, patients admitted to hospital with heart failure are at high risk of both prolonged stays and readmissions. This represents a significant burden to our health system socially, medically and financially. In recognition of this, there has been an increased focus on the prevention, detection and treatment of heart failure, especially in patients with type 2 diabetes in order to improve the quality and quantity of life of affected individuals, as well as reducing the rate of hospital admissions and costs.

Diabetic drugs and heart failure

Evidence shows that DPP4 inhibitors have no impact in reducing heart failure admissions in patients with type 2 diabetes and cardiovascular disease. In fact, there was an increase in this endpoint in the SAVOR study6 using saxagliptin, and a trend towards an increase in the EXAMINE study7 which involved alogliptin. But there appeared no increased risk of heart failure with sitagliptin as per the TECOS trial.8

The GLP1 agonists have been shown to have no impact on reducing heart failure in the large outcome studies performed with exenatide, liraglutide, semaglutide and dulaglutide.

Following these trials, the impact on heart failure seen with the SGLT2 inhibitors was not expected.

However, the EMPA-Reg study,9 which enrolled patients with type 2 diabetes and established cardiovascular disease, found there was a reduction in the risk of major adverse cardiovascular events, as well as all-cause and cardiovascular mortality among patients treated with empagliflozin compared with placebo.

There was also a significant reduction in heart failure hospitalisations, starting early after treatment initiation and becoming greater over the duration of the study. Of particular interest was the fact this reduction in hospitalisations was seen in patients with and without a diagnosis of heart failure at enrolment.

These results were reproduced in the DECLARE study10 using dapagliflozin, where patients with and without cardiovascular disease at baseline were found to have a decrease in the rate of hospitalisations for heart failure of the same magnitude as that seen in EMPA-Reg. In the CANVAS study11 using canagliflozin (which is not available in Australia), similar reductions were seen in heart failure admissions as in the other studies, raising the possibility that the effects on heart failure are a class effect.

How do SGLT2 inhibitors lower heart failure risk?

In these studies, there was a reduction in BP and weight with active treatment, and only small reductions in HBA1c compared with placebo, as there was more intensive non-SGLT2 therapy in the placebo arms. Although these changes in BP, weight and HBA1c could have contributed to the reduction in heart failure, the effect size was disproportionate to the observed reduction, and it is proposed that there are other mechanisms contributing to the decrease in heart failure with these agents.

There is a natriuretic effect with SGLT2 inhibitors as well as a glycosuric effect, which certainly would be helpful in reducing the risk of heart failure, but it has been postulated that this class of drugs also has effects on glomerulotubular feedback in the kidney, as well as intracellular metabolic effects on the cardiac myocyte. In addition, it is thought the SGLT2 inhibitors provide a better fuel for cardiac function by inducing mild ketosis. These mechanisms are all speculative but are all being actively studied.

Change in guidelines

The results of these studies have been reflected in the recent ADA / EASD 2018 guidelines12 in which SGLT2 inhibitors are recommended for patients with type 2 diabetes where heart failure or chronic kidney disease predominate, if the renal function will permit. These results have also been acknowledged in the 2018 National Heart Foundation heart failure guidelines13 in which SGLT2 inhibitors are recommended in patients with type 2 diabetes and cardiovascular disease to prevent heart failure.

The future

Due to the disconnect between the benefits of SGLT2 inhibition on reducing heart failure and the changes in HBA1c, BP and weight, research is being undertaken looking at whether these benefits can also be seen in patients with HFrEF and HFpEF, both with or without diabetes.

The first of these studies has recently been published. In the DAPA-HF study14, patients with heart failure, with or without diabetes, were studied. There was a significant reduction in the primary endpoint of heart failure admission, urgent heart failure attendance and cardiovascular death with dapagliflozin therapy in both diabetic and non-diabetic patients on top of good guideline based medical therapy for heart failure. The reduction was of the same magnitude as seen in the earlier studies involving patients with type 2 diabetes.

Other studies in this patient population are still underway. If these new results confirm the initial findings, SGLT2 inhibitors will have to be seen as a therapy for heart failure, in addition to their role in treating type 2 diabetes.

Of great interest is the idea that these medications might prove to be effective in patients with HFpEF, independent of their diabetes status, because, currently there are no therapies that have been shown to be beneficial in this common condition.

Prescribing details

At present in Australia SGLT2 inhibitors are eligible for PBS reimbursement, only if the is eGFR> 45 mL/ min. and the HBA1C is > 7.0%. It is important to recognise that these agents have not been approved by the TGA for treatment of heart failure and at present in Australia, can only be prescribed for management of type 2 diabetes with the above restrictions. However it is expected that submissions to the TGA will be forthcoming to extend this indication to include the use of SGLT2 inhibitors as a treatment of heart failure.

If SGLT2 inhibitors are being prescribed, it is essential to educate patients about good genital hygiene to reduce the risk of genital mycotic infection, and to instruct them to temporarily stop treatment in the setting of systemic illness, surgery or procedures where fasting is required (such as angiography or colonoscopy) to avoid euglycaemic diabetic ketoacidosis.

A reduction in the dose of diuretic needs to be considered if patients are on thiazide or loop diuretics (as the SGLT2 inhibitors have a weak diuretic effect). Also down-titration of insulin and oral hypoglycaemic agents needs to be discussed if the HBA1C is already near 7% at treatment initiation. Whether the adverse effects of SGLT2 inhibitors seen in patients with type 2 diabetes will be seen in patients without type 2 diabetes and heart failure is not clear, but it would be expected there would be less mycotic infection and fewer UTIs as there should be no glycosuria in non-diabetic populations.

Conclusion

Hospitalisation for heart failure is common in type 2 diabetes and is associated with considerable morbidity and mortality, as well as representing a significant burden to the health system. The use of SGLT2 inhibitors in appropriate patients has been shown to reduce this adverse outcome in patients with type 2 diabetes, irrespective of whether or not they have established cardiovascular disease. As a result, SGLT2 inhibitors should increasingly be used in these patients.

Recent trials of SGLT2 inhibitors showing a significant reduction in the rate of heart failure in non-diabetic patients are exciting and may well result in this class of agents being thought of as primarily cardiorenal protective medications rather than just an oral hypoglycaemic therapy for patients with type 2 diabetes.

Declaration

A/Prof John Amerena was commissioned by Healthed for this article. The ideas, opinions and information presented are solely those of the author. The author has received honoraria for participation in advisory boards for the companies involved in this area (AstraZeneca, Boehringer Ingelheim/Lilly, and Novo Nordisk). This declaration was updated by the author on 31 January.

References

1. Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009 May 23; 373(9677): 1765-72. DOI: 10.1016/S0140-6736(09)60697-8

2. 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 Oct 9; 359(15): 1577-89. DOI: 10.1056/NEJMoa0806470

3. Rao Kondapally Seshasai S, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011 Mar 3; 364(9): 829-41. DOI: 10.1056/NEJMoa1008862

4. Amaral N, Okonko DO. Metabolic abnormalities of the heart in type II diabetes. Diab Vasc Dis Res. 2015 Jul; 12(4): 239-48. DOI: 10.1177/1479164115580936

5. Cubbon RM, Adams B, Rajwani A, Mercer BN, Patel PA, Gherardi G, et al. Diabetes mellitus is associated with adverse prognosis in chronic heart failure of ischaemic and non-ischaemic aetiology. Diab Vasc Dis Res. 2013 Jul; 10(4): 330-6. DOI: 10.1177/1479164112471064

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SGLT2 Inhibitors – No Longer Just for Those with Diabetes

6. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B. The design and rationale of the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 53 study. Am Heart J. 2011 Nov; 162(5): 818-25.e6. DOI: 10.1016/j.ahj.2011.08.006

7. White WB, Bakris GL, Bergenstal RM, Cannon CP, Cushman WC, Fleck P, et al. EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J. 2011 Oct; 162(4): 620-6.e1. DOI: 10.1016/j.ahj.2011.08.004

8. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015 Jul 16; 373(3): 232-42. DOI: 10.1056/NEJMoa1501352

9. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26; 373(22): 2117-28. DOI: 10.1056/NEJMoa1504720

10. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019 Jan 24; 380(4): 347-57. DOI: 10.1056/NEJMoa1812389

11. Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Erondu N, Shaw W. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018 Sep; 6(9): 691-704. DOI: 10.1016/S2213-8587(18)30141-4

12. Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2018 Dec; 61(12): 2461-98. DOI: 10.1007/s00125-018-4729-5

13. NHFA CSANZ Heart Failure Guidelines Working Group, Atherton JJ, Sindone A, De Pasquale CG, Driscoll A, MacDonald PS, et al. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Guidelines for the Prevention, Detection, and Management of Heart Failure in Australia 2018. Heart Lung Circ. 2018 Oct; 27(10): 1123-208. DOI: 10.1016/j.hlc.2018.06.1042

14. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. Nov 21; 381(21): 1995-2008. DOI: 10.1056/NEJMoa1911303

This monograph was supported by an independent educational grant from AstraZeneca

SGLT2 Inhibitors – No Longer Just for Those with Diabetes

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Editorial TeamMedical Editors: Dr Linda Calabresi, Dr Vivienne Miller Managing Editor: Neil Harris Production Editor: Amanda Bryan Editorial Assistant: Sai Machiraju Executive Editor: Dr Ramesh Manocha