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Ph.D. thesis

The Relationship between Ischemic Heart Disease

and Diabetes - A population-based

approach

Mette Lykke NorgaardPh.D. thesis ● M

ette Lykke N

orgaard

Faculty of Health Sciences,University of Copenhagen

Gentofte University Hospital, Department of Cardiology

omslag-tryk.indd 1 16-01-2012 08:55:23

Ph.D. thesis

The Relationship between Ischemic Heart Disease and Diabetes

- A population-based approach

Mette Lykke Norgaard

Faculty of Health Sciences, University of Copenhagen Gentofte University Hospital, Department of Cardiology

Academic advisors Professor Professor Christian Torp-Pedersen, M.D, DMSc. Department of Cardiology, Gentofte University Hospital, Denmark Associate Professor Gunnar H. Gislason, M.D, Ph.D. Department of Cardiology, Gentofte University Hospital, Denmark Members of the assessment committee Professor and Chief Physician Jan Skov-Jensen Department of Cardiology, Gentofte University Hospital (Chairman) Chief Physician Peter Rossing, Steno Diabetes Center, Gentofte Professor Nick Finer, University College London Hospitals, Centre for Weight Loss, Metabolic and Endocrine Surgery The Faculty of Health Sciences, Copenhagen University, Denmark has approved this Ph.D. dissertation for public defense. The public lecture and defense will take place February 10th, 2012 at 14.00 in the Auditorium Gentofte University Hospital.

The Relationship between Ischemic Heart Disease and Diabetes – A population-based approach 3

Preface

My interest in cardiology evolved during my medical studies at Copenhagen University. Initially, I actually wanted to become a specialist in Ophthalmology. However, I found myself increasingly fascinated by Cardiology and the eye did not catch my interest as much as the heart. During my studies, I started working at The Heart Centre in Rigshospitalet as an assistant in Cardiology, a job that only made my interest in Cardiology even greater. After com-pletion of my internship in clinical medicine, I commenced my first year of clinical specialty in Cardiology at Bispebjerg Hospital. Pre-viously, At Bispebjerg Hospital, I had the great fortune to meet Professor Christian Torp-Pedersen, who introduced me to research by giving me an assignment which I by the way never managed to complete. Nevertheless, Christian offered me a position as a re-search assistant. At the time, Christian’s research-unit had moved from Bispebjerg to Gentofte Hospital. In September 2008 I started working on my PhD-thesis. Shortly thereafter, I had the great privilege to meet Dr. Gunnar H. Gislason – Dr. G, who became my mentor on the project. I also had the great fortune being introduced to Professors Lars Køber, Rigshospitalet, Allan Vaag, Steno Diabetes Center and Dr. Peter Riis Hansen, Gen-tofte hospital who soon became invaluable co-advisers on the Ph.D. thesis. Part of being associated with Christian Torp-Pedersen’s research group includes collaboration with the DANTRIP (Danish Trends in Pharmacological and Invasive Treatment of Cardiovascular Diseas-es) investigators; A collective of health researchers consisting of epidemiologists, clinicians and statisticians from Gentofte Hospital, The National Institute of Public Health (NIPH), Køge Hospital, and Rigshospitalet. Through monthly meetings where the younger researchers were given the opportunity to present their projects in differing stages of development with senior researchers imparting, valuable feedback as well as giving lectures on relevant topics provided an inspirational educational environment that has greatly influenced the research work. The DANTRIP collaboration has un-doubtedly played a large role furthering the publication of many papers in leading peer reviewed medical journals by the participat-ing DANTRIP researchers. I feel privileged to be a part of this group. The first half a year of researching was quite difficult and fru-strating, since both my computer skills and ability to do SAS pro-gramming were apparently lacking. I would like to thank my friend and colleague Dr. Søren Skøtt Andersen, who spent unreasonable amounts of time programming with me on the data for my first article and who listened patiently as ever on my daily outbursts of frustration. You are truly the best friend ever. I am forever grateful. I also received invaluable assistance and guidance from my talented fellow research assistant colleague Dr. Fredrik Folke with whom I had the great privilege of sharing office. Thank you for putting up with my talkative personality! Unfortunately, the evident worldwide financial crisis also had an impact on my research project, making the financing of the project problematic. That the project was able reach its conclusion in a satisfactory manner within the available time frame is in large part due to the diligent encouragement and support provided by my

academic advisors Christian Torp-Pedersen and Gunnar Gislason to whom I owe a great thanks. I am also very grateful for the econom-ic support provided by the FUKAP foundation. Finally, I would like to thank Head of Department Jan Kyst Madsen, who is doing an excellent job in leading the research department along with my academic advisors. During my tenure as aspiring researcher, I have also been graced with great colleagues, the fellow research assis-tants who never failed to provide key insights and keeping up the spirit when the data did not compute. Last but certainly not least, I would like to thank the ‘Harvard Study Group’ at the ‘Fjernarkiv’ for their fine companionship, support and friendship. Furthermore, I am forever indebted to my excellent colleague and dear friend Dr. Charlotte Andersson, without whom this project would not have been possible within the time frame available. Finally, I would like to thank my loving daughter Filippa as well as Johnny, my family, and my best friend Dr. Mette Rauhe Mourid-sen, who has believed in me and supported me through the good times as well as the rough times. Mette Lykke Norgaard July 2011

4 Mette Lykke Norgaard

Table of Contents

Preface 3

Table of Contents 4

List of Papers 4

Introduction 5

The role of diabetes in cardiovascular disease. 5

Diabetes and Heart Failure 6

Hypotheses 7

Objectives 7

Methods 8

Databases 8

Study Population 8

Pharmacotherapy 9

Co-morbidity 9

Outcomes 10

Statistical analyses 11

Ethics 11

Results – overview of papers 12

Paper I: 12

Paper II: 14

Paper III: 17

Methodological considerations 19

Study design 19

Poisson regression vs. Cox regression 19

Selection bias, protopathic bias, and confounding by indication 19

Discussion 20

Diabetes and cardiovascular risk 20

Temporal trends in type of first initiated GLM 21

MI and Cardiovascular risk 21

The development of diabetes in MI patients 21

Post-MI development of HF and risk of diabetes. 22

Development of diabetes in heart failure patients and the risk of death. 23

Study strengths 24

Study weaknesses 24

Novelty of the results 25

Conclusions/Implications 25

Future research 26

Summary 27

Dansk Resumé 28

References 29

Appendices 33

Appendix 1 33 Appendix 2 34 Appendix 3 35 Appendix 4 36

List of Papers

The present thesis is based on the following publications: I. Norgaard ML; Andersen SS ; Schramm TK; Folke F; Jørgensen CH; Hansen ML; Andersson C; Bretler DM; Vaag A Køber L; Torp-Pedersen C; Gislason GH; Changes in short- and long-term cardi-ovascular risk of incident diabetes and incident myocardial infarc-tion - a nationwide study. Diabetologia. 2010 Aug; 53(8):1612-9. Epub 2010 May 9. II. Norgaard ML; Andersson C; Andersen SS; Vaag A; Schramm TK; Folke F; Køber L; Riis Hansen P; Torp-Pedersen C; Gislason GH; Temporal trends in the initiation of glucose-lowering medications after first-time myocardial infarction – a nationwide study between 1997 and 2006. CardiovascDiabetol. 2011 Jan 19;10:5. III. Andersson C; Norgaard ML; Riis Hansen P; Fosbøl EL; Schmiegelow M; Weeke P; Bjerring Olesen J; Raunsø J; Jørgensen CH; Vaag A; Køber L; Torp-Pedersen C; Gislason GH; Heart failure severity, as determined by loop diuretic dosages, predicts the risk of develop-ing diabetes after myocardial infarction: a nationwide cohort study. Eur J Heart Fail. 2010 Dec; 12(12):1333-8. Epub 2010 Sep 23.


Introduction

A possible causal relationship between diabetes mellitus and the risk of developing cardiovascular disease was already suggested in 1922 (a published report on glucosuria in patients with myocardial infarction (MI)).1 The wealth of knowledge regarding the associa-tion of diabetes and the incidence of cardiovascular disease have increased massively during the last couple of decades firmly estab-lishing diabetes as an important riskfactor as well as prognostic factor for cardiovascular disease. 2-5 Furthermore, it is now well-established that diabetes is associated with impaired prognosis after MI. 2, 3, 6-9 The role of diabetes in cardiovascular disease Diabetes is a metabolic disorder of multiple etiologies characte-rized by chronic hyperglycaemia with disturbances of carbohy-drate, fat, and protein metabolism resulting from defects of insulin secretion, insulin action, or a combination of both.10 It is a chronic disease that causes serious health complications including renal

failure, heart disease, stroke and blindness. Type 2 diabetes is caused by a combination of decreased insulin secretion and de-creased insulin sensitivity. Typically, the early stage of type 2 di-abetes is characterized by insulin resistance and a decreased ability for insulin secretion that causes excessive post-prandial hypergly-caemia. In the early stage of type 2 diabetes the fasting glucose levels are usually normal or in near-normal range (impaired glu-cose tolerance (IGT)). It is not within the scope of the present thesis to account for the pathophysiology in depth, but in brief the abnormal metabolic state, including chronic hyperglycaemia, dyslipidemia, and insulin resistance that accompanies diabetes, causes arterial dysfunction and makes the arteries susceptible to atherosclerosis. Diabetes alters function of multiple cell types, including plate-lets, smooth muscle cells, and endothelium, indicating the extent of vascular disorder in this disease, see Figure 1 for an overview.

Figure 1

Excess Free Fatty Acids

Oxidative Stress

Protein Kinase C ActivationReceptor for Advanced GlycationEnd Product (RAGE) Activation

Diabetes Mellitus

Hyperglycemia Insulin Resistance

ENDOTHELIUM

Nitric Oxide

Nitric Oxide Activation of NF-кB Nitric Oxide

Endothelin-1 Angiotensin II Tissue Factor

Angiotensin II Activation of Plasminogen ActivatorActivator Protein-1 Inhibitor-1

Prostacyclin

Vasoconstriction

Hypertension

Vascular Smooth Muscle Cell Growth

Inflammation

Release of Chemokines

Release of Cytokines

Expression of Cellular Adhesion Molecules

Thrombosis

Hypercoagulation

Platelet Activation

Decreased Fibrinolysis

Atherogenesis

Thus the perception of type 2 diabetes encompasses a global me-tabolic disorder characterized by hyperlipidaemia, hypertension, and hypercoagulability in addition to hyperglycaemia. Each of these abnormalities plays an important role in cardiovascular

disease development and progression and provides targets for therapy. Because the history of diagnostic criteria in diabetes is of interest for the present thesis, the pathophysiology and diagnostic criteria will be briefly covered in appendix 1. Of particular interest,


the criterion on diabetes / pre-diabetes was not changed in Den-mark during the study period of the present thesis (1997-2006),11 opposite to what happened in the US in 2003, where the cut-off point of impaired fasting glucose was further lowered to 5.6 mmol/L by the American Diabetes Association (ADA).12 Diabetes is recognized as an important risk factor for the devel-opment of cardiovascular disease and a strong predictor of an adverse outcome after myocardial infarction.3, 13 Patients requiring Glucose lowering medications (GLM) have the same long-term risk of major cardiovascular outcomes as patients with a previous MI.4,

5 This increase in risk in diabetes patients is independent of age, gender and type of diabetes.4, 5A decline in all-cause- and cardi-ovascular mortality has occurred during the last decades among both diabetes patients and individuals without diabetes, although this decline appears markedly lower among diabetes patients than in non-diabetic patients.14, 15 Explanations for this decline involve e.g. the effects of cardiovascular disease prevention by tight blood pressure control, aspirin, statins and blockers of the renin-angiotensin system, which are well-established in patients at high cardiovascular risk.5, 16-20 Similar, intensive glycaemic control on microvascular complications in patients with diabetes is today well-established.21-25 Whereas previous studies have indicated a high risk of cardiovascular adverse outcomes early in diabetes course,26,

27 at least one previous cohort study of MI patients demonstrated that diabetes had no independent influence on mortality immedi-ately following an acute MI, but increased in relative risk over time, conferring one of the strongest risk factors for mortality in MI patients after a couple of years.28 This could mean that diabetes is an accelerating disease and that primary prophylactic intervention with cardiovascular pharmacotherapy may first be beneficial some time after established diabetes. An increase in relative risk over time associated with diabetes may however not only reflect a progression of diabetes disease, but may partly or mainly reflect a decline in mortality risk in MI risk over time. Thus, for answering such a question, the relative risk of diabetes and MI needs to be compared with the background population at well-defined times. To the best of my knowledge, no previous study has done this. Furthermore, to date, studies comparing the risk in patients with MI and diabetes, respectively, have primarily focused on prevalent diagnoses and not on the risk following incident MI or incident diabetes, which, given the progressive nature of diabetes, may differ from a prevalent disease. Intensive glycaemic control on microvascular complications in patients with diabetes is today well-established.21-25 During the last couple of decades several novel treatment strategies have been implemented and new GLM have been introduced. Although the initial results from the UK Prospective Diabetes Study (UKPDS) did not conclusively document any beneficial effects of intensified glycaemic control on prevention of macrovascular complications, the epidemiological follow-up data from the UKPDS indicated that long term benefits on cardiovascular risk do occur. 29 Also, the Steno-2-Study showed that intensive multi-factorial treatment including blood pressure control, glucose and lipid lowering thera-pies along with lifestyle intervention prevents (or postpones) the development of micro- and macrovascular complications in type 2 diabetes patients.30, 31 This increasing amount of knowledge is assumed to have influenced diabetes management and prognosis over years, but studies on this subject are sparse. Therefore, in the present thesis, temporal changes in prognosis associated with diabetes and MI between 1997 and 2006 was investigated (paper I)

as was the trends in use of glucose-lowering agents following MI between 1997 and 2006 (paper II). The prevalence of diabetes in MI patients has been reported with a prevalence as high as 20 % 13 and several studies have shown that smaller degrees of dysgly-caemia is common in patients with MI, who have previously not been diagnosed with diabetes. In fact, previous studies have do-cumented that abnormal glucose metabolism is more common than normal glucose metabolism among patients with MI. 32,

33Among patients with MI without known diabetes up to 65% exhibit abnormal glucose regulation when studied using an oral glucose tolerance test (OGTT)34 of whom 25% have values diagnos-tic for diabetes and 40 % have IGT.32, 33, 35, 36 However, information on the actual number of patients receiving GLM (as a proxy for the development of diabetes) after first-time MI on a population basis is lacking, both prior to and after implementation of the novel guidelines (using OGTT as gold standard in revealing diabetes in first-time MI patients). Diabetes and Heart Failure MI is characterized by myocyte necrosis, loss of contractile func-tion and impaired myocardial relaxation. Thus, functional myocytes may be replaced by fibrotic tissue affecting both the left ventricu-lar systolic and diastolic function leading to various degrees of heart failure (HF). HF is common after MI and the incidence of HF 30 days post-MI was recently reported to be greater than 23% in a community-based sample.37 Diabetes has at least for three dec-ades been established as an independent risk factor for develop-ment of HF.38 More recently, a linear relationship between fasting plasma glucose and the risk of hospitalization for HF has also been demonstrated among patients without previous MI, with or with-out overt diabetes.39 Opposite the well-established relationship of diabetes increasing the risk of HF, the prevalence of diabetes ap-pears to increase with worsening of New York Heart Association (NYHA) functional class,40 indicating that HF may increase the risk of diabetes. Furthermore, it was recently reported that HF patients without diabetes have increased insulin resistance with worsening of NYHA class.41 Present thesis (paper III) aims to enlighten wheth-er patients developing HF after MI are at particular high risk of developing diabetes. This is at present time not well-known and remains to be established on a large-scale population. In summary, although much is already known about the influ-ence of diabetes on cardiovascular disease, information on changes in the cardiovascular risk over time in MI and diabetes is insufficiently investigated. Further, it is mainly unknown whether increased focus on diabetes in cardiovascular disease has increased diabetes-treatment in MI populations and whether the prognosis associated with diabetes has changed in recent years. Finally, recent evidence has suggested that heart failure increases the risk of developing diabetes, revealing a potential new population that could be target for early diabetes prevention and management – but this is also still insufficiently investigated.


Hypotheses

The present thesis aimed to investigate the following hypotheses: 1. Patients with a first-time MI have a high short-term risk of cardi-ovascular adverse outcomes compared with the general popula-tion. The risk may decline rapidly after some time and then stabil-ize. 2. Patients initiating GLM (as a proxy for incident diabetes) exhibit an approximately constant and elevated short- and long term risk of cardiovascular adverse outcomes compared with the general population. 3. For both patient groups (first-time MI or incident diabetes) a decrease in risk may be expected when comparing the early with the late study period. 4. The incidence rates of GLM initiation in patients with first-time MI as well as in the general population is increasing during the 10 year study period (1997-2006). 5. Development of HF after first-time MI increases the risk of de-velopment of diabetes requiring GLM.

Objectives

The present thesis had the following objectives on the subject: The relationship between ischemic heart disease and diabetes. 1. To assess secular trends of cardiovascular outcomes following first-time MI or following incident diabetes compared with the general population. 2. To investigate the temporal trends in initiation of GLM (as a proxy for diabetes) among patients discharged after first-time MI and among the general population. 3. To assess whether HF severity predicts the risk of developing diabetes after MI.


Methods

Databases In Denmark there are unique opportunities for epidemiological register-based research because there is a long tradition for tho-rough registration in the national healthcare system. Nationwide administrative registers can be cross-linked on the individual level through access on Statistics Denmark where all information is held. This is possible in Denmark since all residents have a unique and permanent individual personal registration number. In this thesis following Danish registers were employed: The Danish National Patient Register keeps records of all patients admitted to Danish hospitals since 1978. At discharge, one prima-ry, and if applicable one or more secondary diagnoses are regis-tered according to the International classification of Diseases (ICD) – (ICD-8) the 8th revision until 1994 and the 10th revision (ICD-10) from 1994. The Danish Register of Medicinal Product Statistics (national prescription register) contains all prescriptions dispensed from pharmacies since 1995. Each medication is coded according to an international classification of pharmaceuticals, the Anatomical Therapeutical Chemical classification (ATC) System. The prescrip-tion register also includes information about the date of dispens-ing, the strength, formulation and quantity dispensed, and the affiliation of the doctor issuing the prescription (hospital-based doctor or general practitioner). The database has previously been described in detail and validated.42 The Danish Cause of Death Register contains data concerning immediate, contributory and underlying causes of death classified using the ICD-10. The information held in this register is based on information obtained from the death certificate filled out by a doctor. The Central Population Register contains information on vital status (dead or alive) and the date of death. All deaths are record-ed in this register within two weeks of their occurrence.

Study Population Overall this thesis studies individuals ≥ 30 years of age and alive on January 1, 1997 who are hospitalized for a first-time MI during the study period (January 1, 1997 until December 31, 2006). In paper I, we furthermore study individuals initiating GLM for the first time during the study period. Paper II includes individuals who develop diabetes requiring GLM after first-time MI and finally, in paper III MI patients who develop heart failure are studied. Since the populations in the papers in this thesis are somewhat different, the populations will be described in detail separately. Paper I The general population: All inhabitants in Denmark who were at least 30 years of age and alive on January 1, 1997 were identified. Patients with prior history of myocardial infarction (MI) or patients claiming glucose-lowering medication (GLM) prior to January 1, 1997 were not included in the study. The incident MI-population: Incident MI was identified as first-time hospitalization with MI (ICD-10 code I21 or I22). First-time diagnosis of MI was considered, if the diagnosis of MI was not registered during the last 19 years prior to the study period. The incident diabetes population: Patients with incident diabetes requiring anti diabetic treatment were identified as individuals initiating GLM (oral or insulin) (ATC code A10) for the first time during the study period (January 1, 1997-December 31, 2006). Patients claiming prescriptions on GLM during the period 1995-1997 were not included. Depending on which diagnosis came first, patients were regis-tered as either having incident MI or incident diabetes. Paper II The general population: Comprised all individuals, aged ≥ 30 years and alive on January 1, 1997. The population was updated on a yearly basis allowing entrance of new subjects aged ≥ 30 years of age per January 1, the following year. Patients with previous MI, incident MI as well as patients claiming GLM prescriptions (ATC code A10) prior to January 1, 1997 were excluded from the general population. The MI-population: Comprised all patients, aged ≥ 30 years alive at discharged after a first-time MI (ICD-10 code I21 or I22) between 1997 and 2006 (January 1, 1997-December 31, 2006). First-time admission for MI implied that the National Patient Register had not registered any prior admission for MI in the previous 19 years. Patients initiating GLM (ATC code A10) during the study period were assessed. Patients previously claiming any prescriptions on GLM (during the period 1995-1997) were not included.


Paper III The MI-population: All patients hospitalized for MI (ICD-10 code I21 or I22) between 1997 and 2006 and who were alive 90 days after discharge were included. Patients with a prior MI in 1978-1996 were excluded (ICD-10 code I21 or I22, or ICD-8 code 410) to ensure a homogenous population. Patients claiming prescriptions of any GLM (ATC code A10) prior to, or during the first 90 days after discharge were also excluded, as were patients who had claimed a prescription of loop diuretics (ATC code C03C) prior to hospitalization. Development of diabetes: Was defined as the first claimed pre-scription for GLM (ATC code A10). The diagnosis of MI in the National Patient Register has proved to be valid; with a sensitivity of 91 % and a positive predictive value of 93 %.43 Pharmacotherapy From the Danish Register of Medicinal Product Statistics medical treatment was defined as followed: Glucose-lowering medications Paper I & II: Oral or insulin treatment commencing during the study period (ATC-code A10). Applying for Paper II only: For determination of first initiated GLM, the following agents (ATC-codes) were identi-fied: insulin (A10A), metformin (A10BA02), sulfonylureas (A10BB), glitazones (A10B); acarbose (A10F01), repaglinide (A10BX0) and metformin+repaglinide (A10BD03).No concomitant treatment was assessed. Paper III: Treatment initiation of oral or insulin agents (ATC-code A10). Loop diuretics Paper III: As a proxy for the diagnosis heart failure in patients with MI, we used dispensed prescription on loop diuretics (ATC C03C) used at day 90 after discharge. The approximated dosages were achieved by consideration of the amount of dispensed tablets, their strengths, and dispensing time intervals (for up to 7 consecutively claimed prescriptions), as done before44, 45 HF severity was defined according to arbitrary loop diuretic dosages: no HF (no loop diuret-ics), mild HF (loop diuretic dosage ≤40 mg/day), moderate HF (>40-120 mg/day), and severe HF (>120 mg/day). This way of defining HF severity was supported by previous work, which demonstrated loop diuretic dosages to be positively correlated with worsened NYHA functional class and increased risk of mortality, and not correlated with glomerular filtration rate in HF patients.46 More-over, as patients with use of loop diuretics prior to myocardial infarction hospitalization were excluded from the present study cohort, the indication for loop diuretic treatment was in most cases likely to be HF. The sensitivity of using loop diuretics as a

proxy for HF was considered acceptable, as the majority of HF patients previously have been reported to use loop diuretics.47, 48 Concomitant treatment in paper III: Patients were considered to be in treatment with a specific agent if they claimed a prescription during the first 90 days following dis-charge, or in the year preceding MI hospitalization. The following ATC codes were used: beta-blockers (C07); statins (C10A); renin–angiotensin system inhibitors (RASi) (C09); thiazides (C03A); aldos-terone antagonists (spironolactone/eplerenone) (C03D); calcium channel blockers (C08); digoxin (C01AA05); vitamin K antagonists (B01AA0); aspirin (B01AC06); and clopidogrel (B01AC04). Co-morbidity Paper I: Incident MI-population and incident diabetes population: Co-morbidities were assessed by registration of pre-specified hospital discharge diagnoses up to one year before the inclusion date (date of the incident). The general population: Co-morbidity was assessed one year prior to June 30, 2001 for individuals surviving beyond June 30, 2001, and a year prior to January 1, 1997 for individuals who died before June 30, 2001, respectively. Applying for both the incident MI, incident diabetes and the general population following diagnoses were used: Chronic ob-structive pulmonary disease (ICD-10 code ‘J42’ and ‘J44’), renal disease (ICD-10 code ‘N03’, ‘N04’, N17’ ‘N18’, ‘N19’, ‘R34’ ‘I12’, ‘I13’ ) cancer ‘ C00’- C97’ and congestive heart failure ‘I50’. Paper II and III: Comorbidity was assessed using the Ontario Myocardial Infarction Mortality Prediction Rules for ICD-10 codes based on 9 predefined diagnoses from the index hospitalization with MI and up to one year prior to discharge from index hospitalization (diabetes diag-noses excluded in paper II and III and heart failure excluded in paper III).The Ontario Myocardial Infarction Mortality Prediction Rules are validated for predicting prognosis for post-MI popula-tions.49


Outcomes

The following endpoints were assessed: Paper I All-cause mortality, cardiovascular death (ICD-10 codes I00-I99), and new onset MI (ICD-10 codes I21, I22) Paper II Development of diabetes in the MI population: Defined as initia-tion of GLM (defined as claimed prescription of GLM (ATC-code A10) within the first year following discharge for first-time MI according to the year of the MI. Development of diabetes in the general population: Since the general population had no index event, the GLM initiation was registered according to the year of GLM commencement. Initiation of GLM was defined as claimed prescription of GLM (ATC-code A10). Determination of temporal trends in type of first initiated GLM: The following agents (ATC-codes) were identified: insulin (A10A), metformin (A10BA02), sulfonylureas (A10BB), glitazones (A10B); acarbose (A10F01), repaglinide (A10BX0) and metfor-min+repaglinide (A10BD03). Paper III Development of diabetes after study start and the subsequent risk of death associated with diabetes: Diabetes being defined as first claimed prescription of GLM (ATC-code A10).


Statistical analyses

Paper I Multivariable analysis assessing risk of all-cause mortality, cardi-ovascular death and MI/recurrent MI was performed using Poisson regression analysis, adjusted for age, gender and calendar year. Kaplan-Meier estimates were used to assess temporal risk of car-diovascular death stratified by sex. The multivariable analysis revealed statistically significant interaction with sex and calendar time. Consequently, the study period was divided into two time periods January 1, 1997 to June 30, 2001 and July 1, 2001 to De-cember 31, 2006 and analyzed separately as were the two genders. Paper II Incidence rates of GLM initiation in the MI population as well as in the general population were calculated. In order to assess tempor-al trends in GLM initiation, the study period was divided into five two-year periods (not applied in the incidence rates analyses). Multivariable Cox proportional-hazard models, adjusted for age, gender and calendar year, were used to investigate the likelihood of initiating GLM within a year post-MI according to the different year-groups using the year 1997-1998 as the reference group. Test for temporal trends in pharmacological types of first GLM initiated were doneby Cochran-Armitage trend test. Paper III Kaplan-Meier’s method was used to generate cumulative incidence curves of diabetes. Equality over strata was tested using the log-rank test. Cox proportional-hazard models were used for analyses of the risk of developing diabetes and the subsequent risk of death associated with diabetes. The mortality analysis was additionally adjusted for HF severity group. A time-dependent Cox analysis with age as the underlying time variable was performed to investigate the prognostic importance of having developed diabetes. The model allowed for a continuous update on diabetes status (every day) and all patients were initially classified as not having diabetes. At the day of first claimed prescription of GLM, patients were classified as having diabetes. For all analyses, the statistical level of significance was set at 0.05. Applying for all three papers analyses were performed using SAS version 9.1 (SAS institute Inc., Cary, NC, USA). For the incidence rates analyses in Paper II Stata version 11.0 (StataCorp, College Station, Tx, USA) was used. Continuous variables are presented as mean with standard deviation (SD). Categorical data are presented as percentages.

Ethics

All the used Danish registers are placed in Statistics Denmark. Researchers can apply for access and when granted access is pro-vided, the researcher has access to selected data. The access is provided with encrypted person identification and tight rules are preventing detailed output of individual people from being downloaded by researchers. Retrospective register studies require permission from the Danish Data Protection Agency and this is granted for Statistics Denmark to allow research use with the above mentioned limitations. The Danish Data Protection Agency approved the study (No. 2007-41-1667). According to the Danish regulations no ethical approval is required for retrospective regis-ter studies in Denmark.


Results – overview of papers

This section provides an abstracted overview of the three papers which are included in the thesis. For each paper a brief presenta-tion of the aims, material and methods, results, and main conclu-sions is provided. For details of the studies please refer to the appendix section wherein all 3 papers are apparent in full. Paper I Changes in short- and long-term cardiovascular risk of incident diabetes and incident myocardial infarction - a nationwide study. Aim The aim of this study was to assess secular trends of cardiovascular outcomes following first diagnosis of MI or diabetes in an unse-lected population. Materials and methods All Danish residents aged ≥ 30 years without prior diabetes or MI were identified by individual-level-linkage of nationwide registers. Individuals hospitalised with MI or claiming a first-time prescription

for a glucose-lowering medication (GLM) during the period from 1997 to 2006 were included. Analyses were done by Poisson re-gression models. Primary endpoints were death by all causes, cardiovascular death and MI. Results The study included 3,092,580 individuals of whom 77,147 had incident MI and 118,247 new-onset diabetes, Table 1. MI patients had an increased short-term risk of all endpoints compared with the general population. The rate ratio (RR) for cardiovascular death within the first year after MI was 11.1(95% CI 10.8-11.5) in men and 14.8(14.3-15.3) in women, respectively. The risk rapidly de-clined and 1 year after the index MI, RR was 2.1 (2.00-2.23) and 2.80 (2.64-2.97) in men and women, respectively, Table 2. Patients with diabetes carried a constantly elevated risk of all endpoints compared with the general population. The cardiovascu-lar death RR was 1.90(1.77-2.04) and 1.92(1.78-2.07) in men and women, respectively during the 1st year after GLM initiation. Main conclusions Incident MI is associated with high short-term risk, which de-creases rapidly over time. Incident diabetes is associated with a persistent excessive cardiovascular risk after initiation of GLM therapy. This further strengthens the necessity of early multi-factorial intervention in diabetes patients for long-term benefit.

Table 1.Demographic characteristics according to exposure-group and time period Variables Incident MI Incident diabetes Reference

Early perioda Late periodb Early perioda Late periodb Participants

All (n) 33.378 43.769 49.199 69.048 2.897.186 Men (n) 20.463 26.560 26.992 38.223 1.364.120

Women (n) 12.915 17.209 22.207 30.825 1.533.066 Male sex (%) 61 61 55 55 54

Age (years) c All participants 69.7 (13.0) 70.5 (13.3) 62.7 (13.6) 63.0 (12.5) 52.7 (15.7)

Men 66.9 (12.8) 67.5 (12.9) 61.0 (12.9) 61.7 (11.8) 51.1 (14.7) Women 74.2 (12.1) 75.1 (12.5) 64.8 (14.1) 64.7 (13.1) 54.1 (16.4)

Prior hospital admissionsd COPD (%) 5.8 7.4 2.3 2.4 0.3

Renal disease (%) 1.5 2.5 0.4 0.4 0.05 Cancer (%) 2.9 3.4 2.5 2.9 0.5

Congestive heart failure (%) 11.9 12.3 2.2 2.0 0.2 Values are mean + (SD) unless otherwise indicated aTime period 1 January 1997 to 30 June 2001, bTime period 1 July 2001 to 31 December 2006, cDefined on 1 January 1997,d Hospitalisation up to 1 year before incident event; for the reference population the date was set to 1 year prior to 30 June, 2001, unless death occurred before that date, in which case date was set to 1 year prior to 1 January, 1997 COPD, chronic obstructive pulmonary disease.


Table 2. Age-adjusted Poisson regression analyses using the background population as a reference Variables Incident MI Incident diabetes

Early perioda Late periodb Early perioda Late periodb

All-cause mortality

Events (n) 17.360 14.230 15.341 7.704

RR 0–1 years

Men 6.46 (6.27-6.65) 6.17 (5.98-6.36) 2.23 (2.13-2.33) 2.29 (2.18-2.93)

Women 8.53 (8.27-8.79) 8.67 (8.41-8.94) 2.16 (2.05-2.27) 2.51 (2.40-2.64)

RR 1–3 years

Men 1.42 (1.36-1.49) 1.47 (1.39-1.55) 1.63 (1.57-1.70) 1.42 (1.35-1.50)

Women 1.90 (1.81-2.00) 2.02 (1.91-2.15) 1.50 (1.43-1.57) 1.49 (1.41-1.58)

RR 3–5 years

Men 1.38 (1.31-1.45) 1.46 (1.32-1.62) 1.59 (1.52-1.66) 1.42 (1.29-1.56)

Women 1.84 (1.74-1.94) 1.80 (1.60-2.02) 1.51 (1.44-1.58) 1.42 (1.27-1.58)

Cardiovascular death

Events (n) 14.508 11.923 8.486 3.636

RR 0–1 years

Men 11.1 (10.8-11.5) 10.4 (10.1-10.8) 1.90 (1.77-2.04) 1.97 (1.84-2.12)

Women 14.8 (14.3-15.3) 14.8 (14.3-15.3) 1.92 (1.78-2.07) 2.10 (1.94-2.28)

RR 1–3 years

Men 2.11 (2.00-2.23) 2.14 (2.00-2.28) 1.79 (1.69-1.88) 1.51 (1.40-1.63)

Women 2.80 (2.64-2.97) 2.92 (2.72-3.13) 1.70 (1.60-1.80) 1.67 (1.54-1.81)

RR 3–5 years

Men 1.99 (1.88-2.11) 2.10 (1.86-2.34) 1.89 (1.79-2.00) 1.61 (1.41-1.84)

Women 2.63 (2.46-2.81) 2.77 (2.42-3.17) 1.78 (1.68-1.89) 1.65 (1.42-1.91)

MI/recurrent MI

Events (n) 11.422 9.942 3.668 1.613

RR 0–1 years

Men 21.7 (21.1-22.4) 20.2 (19.5-20.9) 1.78 (1.62-1.96) 1.72 (1.55-1.90)

Women 43.3 (41.8-44.9) 42.6 (41.1-44.2) 1.93 (1.70-2.20) 2.05 (1.80-2.34)

RR 1–3 years

Men 2.99 (2.80-3.18) 2.92 (2.69-3.17) 1.62 (1.51-1.74) 1.29 (1.16-1.44)

Women 5.67 (5.25-6.11) 5.64 (5.13-6.21) 1.93 (1.75-2.12) 1.72 (1.51-1.96)

RR 3–5 years

Men 2.67 (2.48-2.87) 2.70 (2.30-3.17) 1.58 (1.46-1.71) 1.33 (1.10-1.62)

Women 4.33 (3.93-4.78) 5.15 (4.24-6.25) 1.97 (1.78-2.17) 1.89 (1.49-2.40)

Values are RR (95% CI) unless otherwise indicated aTime period 1 January 1997 to 30 June 2001; btime period 1 July 2001 to 31 December 2006


Paper II Temporal changes in the initiation of glucose-lowering medications after a first-time myocardial infarction- a nationwide study between 1997 and 2006 Aim The aim of the study was to investigate temporal trends in the initiation of glucose-lowering medications (GLM) among patients discharged after first-time myocardial infarction and among the general population. Furthermore, temporal trends in type of first GLM were assessed. Material and methods All Danish residents aged ≥ 30 years without prior diabetes hospi-talised with first-time MI between 1997 and 2006 were identified by individual-level-linkage of nationwide registers. Initiation of GLM during follow-up was assessed by claimed prescriptions from pharmacies. The study population was divided into five two-year periods (with exception of the calculated incidence rates). Tempo-ral trends in initiation of GLM were assessed by incidence rate calculations in the MI population as in the general population. Temporal trends in initiation of different pharmacological types of first GLM was done in percentages also dividing the study period into five two year periods.

Results In total 77, 147 patients ≥ 30 years of age were hospitalized with first-time MI, of whom 66,788 patients were alive at discharge and had previously never used GLM. Within the first year post dis-charge from first-time MI 1567 patients initiated GLM. Of these 1452 patients were included in the incidence rate analysis since 115 patients initiated GLM in 2006 were excluded due to incom-plete follow-up time. Demographic characteristics are shown in Table 3.The incidence rate of GLM initiation within the first year after discharge for first-time MI in 1997 was approximately 19.6 per 1000 person-years. This incidence rate increased until year 2001. After year 2001 the incidence rate stabilized, Figure 1. A similar trend was observed in the general population. The inci-dence rate increased from 2.8 to 4.0 per 1000 person-years in 2004. Following year 2004 the incidence rate stabilized, Figure 2.In the entire population initiating GLM after first-time MI, the two predominantly prescribed GLMs were sulfonylureas and metfor-min, Table 4. During the study period the use of metformin as first GLM increased significantly from 30.5% in 1997-1998 to 40.0% in 2005-2006 (p for trend < 0.0001). Conversely, the use of sulfonylu-reas decreased from 59.0% in 1997-1998 to 45.5% in 2005-2006 (p for trend < 0.0001). The use of insulin as first-GLM also increased from 9.1% in 1997-1998 to 14.3% in 2005-2006 (p for trend < 0.002).

Table 3.Demographic characteristics at the time of first-time myocardial infarction according to year of occurrence.

1997-1998 1999-2000 2001-2002 2003-2004 2005-2006 Patients with first-time MIa 11.968 12.383 14.734 14.650 13.053 Patients initiating GLMb within a year post-MI 227 266 389 389 296

Men (%) 64.0 62.4 61.6 62.1 62.4 Mean age (SD) 67.8 (12.9) 68.5 (13.1) 69.3 (13.1) 69.4 (13.2) 69.4 (13.2) Comorbidityc Congestive heart failure (%) 9.3 12.1 12.9 11.4 10.3 Cardiac arrhythmias (%) 7.3 9.4 10.9 11.5 11.1 PVDd (%) 1.9 2.3 2.5 2.3 2.3 CVDe (%) 3.4 4.5 4.9 5.1 4.8 Renal disease (%) 0.8 1.7 2.1 2.3 2.3 Cancer (%) 2.0 2.4 2.9 2.9 2.9 Shock (%) 0.6 0.7 1.2 1.3 1.3 COLDf(%) 4.4 6.0 7.4 7.0 6.4 Peptic ulcer 1.5 1.5 2.0 1.6 1.6

aMI: myocardial infarction;bGLM:glucose-lowering medication; ccomorbidity up till one year prior to discharge from index hospitalization;dPVD: peripheral

vascular disease; e CVD: cerebrovascular disease; fCOLD: chronic obstructive lung disease.


Figure 1. Incidence rate per 1000 person-years of initiation of glucose-lowering medication (GLM) within a year following for first-time myocardial infarction.

Figure 2. Incidence rate per 1000 person-years of initiation of glucose-lowering medication (GLM) in the general population.

Table 4. Distribution of first prescription claimed for glucose-lowering medications according to year of first-time myocardial infarc-tion.

1997-1998 1999-2000 2001-2002 2003-2004 2005-2006 p for trend. Metformin (%) 30.47 33.83 36.62 38.03 39.94 <0.0001 Insulin (%) 9.07 9.59 12.70 13.25 14.29 0.002 Sulfonylurea (%) 59.07 55.43 48.90 48.01 45.48 <0.0001 Other GLM(%)a 1.38 1.16 1.78 0.71 0.29 0.15

aGLM: glucose-lowering medications: Other GLM: glitazones, acarbose, repaglinide, and repaglinide+metformin.


Main conclusions The study demonstrated increased incidence rates of GLM initia-tion within the first year post-MI. A similar trend was shown in the general population. The results of the study suggest that the in-crease in the initiation of GLM in the MI population was primarily the effect of a general increased awareness of diabetes in the population as a whole. From a public health perspective, this study underscores a continuous need for diagnostic and therapeutic improvement in the care of MI patients that develop diabetes, and such strategy is likely to provide long-term benefits.


Paper III Heart failure severity, as determined by loop diuret-ic dosages, predicts the risk of developing diabetes after myocardial infarction: a nationwide cohort study. Aim The aim of the study was therefore to investigate the relationship between HF severity and risk of diabetes in patients discharged after MI and to investigate the prognostic importance of incident diabetes after MI. Material and methods All Danish residents, without prior diabetes (claiming GLM prior to 1997) or previous use of loop-diuretics, hospitalized with first-time MI between 1997 and 2006 and alive 90 after discharge were identified by individual-level-linkage of nationwide registers. Pa-tients were followed until first claimed prescription of GLM, death, or until the end of 2006. The risks of diabetes and the subsequent risk of death associated with diabetes were analyzed by multivari-able Cox proportional-hazard models. Additionally, the mortality analysis was adjusted for HF severity group. HF severity was de-termined by loop diuretic dosage after discharge. Results The study included 50,874 patients. Of these, 9,516 (19%) had HF at study baseline. In this HF population 3,006 (6%) had mild ([loop-diuretic dosage] ≤40 mg/day), 5,383 (11%) moderate (>40-120 mg/day), and 1,127 (2%) severe (≥120 mg/day) HF. In total, 2,531 (5%) patients developed diabetes during follow-up. Table 5 presents the baseline characteristics stratified by HF severity. Overall, patients with HF were older than patients with-out HF (73±11 years, vs. 64±13 years, p<0.0001) and a greater proportion of patients with HF were women, compared to patients without HF (43% vs. 31%, p<0.0001). Increasing HF severity was associated with increased risk of diabetes, Table 6 (in selection). Patients who developed diabetes had an adjusted HR for death of 2.85 (95% confidence interval 2.57-3.14). Increasing HF severity was associated with increasing HR for death, i.e., 1.35 (1.27-1.44), 1.57 (1.50-1.65), and 2.13 (1.96-2.32), for mild, moderate, and severe HF, respectively, compared to patients without HF. Main conclusions This nationwide study indicates that HF increases the risk of devel-oping diabetes in a severity-dependent manner after MI. The re-sults of the present study suggest that increased focus should be put on prevention of diabetes in post-MI HF patients. This strategy will enable effectuation of early and aggressive evidence based treatment, hereby reducing the mortality and morbidity in these high risk patients.


Table 5. Baseline characteristics:

No HF Mild HF (≤40 mg/day)

Moderate HF (>40 - 120 mg/day)

Severe HF (>120 mg/day)

Number: 41,358 3,006 5,383 1,127 % of study population: 81% 6% 11% 2% Gender, female (%) 31% 41% 43% 46% Age at hospitalization (years) 64 (±13) 72 (±11) 74 (±11) 75 (±11) Year of hospitalization:

1997-1998 76% 8% 13% 3% 1999-2000 78% 7% 12% 3% 2001-2002 79% 7% 12% 2% 2003-2004 82% 6% 11% 2% 2005-2006 93% 2% 5% 1%

Concomitant diseases*:

Pulmonary edema 0% 2% 2% 3% Atrial flutter/fibrillation 4% 8% 10% 11% Cerebro-vascular disease 3% 3% 5% 6% Peripheral occlusive artery disease 1% 1% 1% 1% Renal disease 1% 1% 1% 3% COPD 3% 7% 7% 9%

Concomitant medications:

Statins 58% 41% 40% 32% RASi 39% 60% 62% 67% Beta blockers 81% 76% 72% 69% Calcium blockers 24% 28% 30% 35% Thiazides 20% 20% 26% 34% Spironolactone 3% 14% 17% 25% Digoxin 5% 16% 22% 32% Aspirin 59% 55% 57% 57% Clopidogrel 44% 25% 23% 19% Vitamin K antagonists 6% 13% 15% 17%

(*) refers to a hospitalization diagnosis in one year prior to acute myocardial infarction hospitalization. HF: heart failure. RASi: renin–angiotensin system inhibitors. COPD: chronic obstructive pulmonary disease. Table 6. Risk of diabetes according to HF severity group. Overall

HR (95% CI): No HF 1.00 (ref.) Mild HF (≤40 mg/day) 1.39 (1.19-1.62) Moderate HF (>40-120 mg/day) 1.71 (1.52-1.94) Severe HF (>120 mg/day) 1.99 (1.57-2.53)


Methodological considerations

Study design We decided only to include new-onset diabetes and first-time MI and this approach was particularly important since we made a direct comparison between the cardiovascular risks in patients with first-time MI, incident diabetes and incident heart failure. This model enabled the establishment of incident diabetes and first-time MI study populations with comparable disease durations, although it should be recognized that the precise time of onset of chronic diseases, e.g. diabetes, is not possible to determine in these administrative databases. This composes a limitation of our study. However, it is reasonable to assume duration of diabetes of 7 to 10 years prior to initiation of GLM treatment.50, 51 Poisson regression vs. Cox regression Cox regression is the most frequently used analysis for epidemio-logical cohort studies of censored data but is very inefficient and time-consuming when large datasets are analyzed, as it considers one day at time. It furthermore prioritizes one time scale (the underlying time of the analysis) beyond other time-scales. In con-trast, Poisson regression is an efficient alternative to Cox regres-sion analyses of cohort studies with multiple timescales, time-varying covariates, and is easier to handle when the aim is to investigate risks in certain time-bands (although time-stratification it is doable in Cox regression analyses). The interpretation of inci-dence rate ratios provided by Poisson regression and hazard ratios provided by Cox regression is comparable. Unlike a time-dependent Cox regression, Poisson regression assumes a constant incidence rate in each of the time-bands investigated. If these circumstances are fulfilled, both analyses provide very similar results.52 Selection bias, protopathic bias, and confounding by indication Selection bias is a systematic error in epidemiological studies that arises from the population selection where the association be-tween exposure and outcome differs between those included and those not included. In this thesis, the data cover the entire popula-tion of Denmark independent of socioeconomic status, age or participation in specific health-insurance programs. Therefore, the risk of selection bias is reduced, and the study notably includes citizens both in and out of the labor market. The Danish health care system partially reimburses drug expenses, and all Danish pharmacies are required to register all dispensed drug prescrip-tions, ensuring complete registration. The use of pharmacological treatment to identify the main exposure (in this thesis - GLM treatment as a proxy for diabetes) in epidemiological studies may lead to important bias and misleading

conclusions. The term protophatic bias refers to the situation in which the initial symptoms of the outcome of interest is the very reason for the initiation of the pharmacological treatment used as the exposure measure, i.e if GLM was initiated because of early manifestation of cardiovascular disease. GLM however, with ex-ception of metformin as monotherapy in young women presenting with PCOS (polycystic ovarian syndrome), are only used in patients with diabetes. Therefore, there is no reason to suspect any impact of such bias in the presented studies. Along this line, confounding by indication, a source of bias in non-randomized studies with potentially important differences in determinants of the outcome of interest between exposed and unexposed, is unlikely to be an important issue in our studies. Indeed in our study design, the treatment used to define exposure (GLM) was initiated because of diabetes (which is associated with increased cardiovascular risk) but merely served as a specific indicator of diabetes.


Discussion

Overall, the present thesis aimed to enlighten several uncertainties in the relationship between ischemic heart disease and diabetes: Explore the short and long-term prognosis in patients with incident diabetes and incident MI. To clarify the extent to which incident MI patients developed diabetes requiring GLM both as dependent on HF severity and within a year after discharge for first-time MI in a nationwide setting. In the thesis following was demonstrated: 1. Incident diabetes is associated with a persistent twofold higher risk of cardiovascular adverse outcomes after initiation of GLM. 2. A trend towards a risk reduction in men but not in women with diabetes was demonstrated when comparing the 1997-mid 2001 cohort (early period) with the mid-2001–2006 cohort (late period). 3. Incident MI is associated with a high short-term risk, which decreases rapidly over time. 4. The incidence rates of diabetes (GLM-initiation) have increased in the MI population from year 1997 to 2001. Following year 2001 the incidence rates stabilized. 5. The incidence rates of diabetes (GLM-initiation) have increased accordingly in the general population from year 1997 to 2004. Corresponding to the MI population a stabilisation in incidence rate was observed in the general population after 2004. 6. The use of metformin as first initiated GLM has increased from 30.5% to 40.0 % during the study period. Conversely, the use of sulfonylurea has decreased from 59.0% to 45.5%. The use of insulin as first initiated GLM has increased from 9.1% to 14.3%. 7. HF predicts development of diabetes in a severity-dependent manner among patients with MI. 8. Incident diabetes was found to be associated with nearly a threefold increase in risk of death in patients with MI. Diabetes and cardiovascular risk In this thesis incident diabetes was found to be associated with a persistent two-fold higher risk of cardiovascular adverse outcomes after initiation of GLM. Our results are consistent with previous studies by Haffner et al. and Schramm et al, respectively. Haffner et al. have demonstrated that patients with diabetes without prior MI exhibit the same risk of MI as patients without diabetes, but with prior MI. 5Schramm et al. confirmed those results in a nation-wide cohort of diabetes patients and provided evidence that di-abetes patients requiring GLM therapy have a cardiovascular risk comparable to non-diabetic patients with a prior MI in all ages and among both sexes. 4These findings applied for the prevalent diag-nosis and only in patients requiring GLM therapy. As for the di-abetes population, the results of our study extend the findings of

Schramm et al. in that we document that patients with diabetes already carry a twofold higher risk of cardiovascular death, from the point in time when GLM therapy is initiated. Furthermore, this thesis documents an increase in the incidence rates of diabetes (GLM-initiation) in the MI population from year 1997 to 2001, stabilizing following year 2001. Accordingly, the incidence rates of diabetes (GLM-initiation) have increased in the general population from year 1997 to 2004, stabilizing after year 2004. We also document only a trend towards a risk reduction in men but not in women with diabetes when comparing the 1997-mid 2001 cohort (early period) with the mid-2001–2006 cohort (late period). During the ten year study period several novel treatment mod-alities have been implemented and new glucose lowering agents have been introduced. Moreover, the use of all GLM, including insulin alone or in supplement to oral GLM has increased substan-tially following the UKPDS. Initially, the results from the UKPDS did not conclusively document any beneficial effect of intensified glycaemic control on prevention of macrovascular complications. However, epidemiological data from the UKPDS and observational follow-up data from Epidemiology of Diabetes Intervention and Complications (DCCT-EDIC) found that intensive glycaemic control was associated with a 16 % and 57% reduction in major CVD out-comes, respectively. The results from the abovementioned study support the possibility that such benefits occur. Furthermore, recent data have shown a beneficial legacy effect of early intensive glycaemic control on prevention of cardiovascular disease in pa-tients with type 2 diabetes. 29 The Steno-2 study showed that early multi-factorial treatment including blood-pressure-, glucose- and lipid-lowering therapies, along with lifestyle interventions prevent (or postpone) both micro- and macrovascular complications in patients with type 2 diabetes. 30, 31 Over the last decade, these findings have been implemented in both national and international guidelines. Generally, the awareness on diabetes and its cardiovascular com-plications has increased significantly during the study period launching a broad range of large randomized clinical trials in the search of documenting a beneficial effect of intensified glycaemic control on prevention of macrovascular complications. Recently, three randomized controlled trials compared the effect of inten-sive vs. standard glycaemic control on cardiovascular disease (CVD) outcomes in relatively high risk participants with type 2 diabetes. 53-55 Surprisingly, all three studies failed to show a reduction in CVD outcomes. Speculations on why these three randomized trials failed to demonstrate a reduction in CVD outcomes have been many. First, all three trials were carried out on patients with estab-lished diabetes (mean duration 8-11 years) with either a large burden of risk factors or established CVD. Secondly, the additive beneficial effect of intensive glycaemic control may be difficult to demonstrate on top of the effects of CVD prevention by tight blood pressure control, aspirin, statins and blockers of the renin-angiotensin system. Finally, it can be hypothesized that if these


randomized trials had included participants with shorter duration of diabetes and/or absence of CVD, a benefit from intensive gly-caemic control could have been evident. Despite the negative outcome of the abovementioned studies, The American Diabetes Association (ADA) currently stated that glycaemic control early in the course of type 2 diabetes may pro-vide CVD benefits and that glycaemic control may play a greater role for CVD prevention in patients with a shorter duration of diabetes before macrovascular disease is established. (class 2b recommendation, level of evidence A, for the benefit of glycaemic control on cardiovascular disease).56 A metaanalysis in the Lancet in 2009 found that intensive glucose-lowering treatment signifi-cantly reduced events of non-fatal MI by 17% and a reduction of coronary heart disease events by 15%. The effect of co-morbidity on the relationship between glycae-mic control and cardiovascular outcomes in diabetes has also recently been studied. Not surprisingly, this study revealed that the burden of co-morbidity does indeed affect this relationship.57 This study concludes that patients with high levels of co-morbidity may have diminished cardiovascular benefits from intensive blood glucose control. Taking the body of the abovementioned evidence into account, it is somewhat surprising and disappointing that this thesis docu-ment only a trend towards a risk reduction in men but not in women with diabetes when comparing the 1997-mid 2001 cohort (early period) with the mid-2001–2006 cohort (late period). Fur-thermore, since current evidence points toward a beneficial effect on cardiovascular events in patients with a shorter duration of diabetes we could have hoped for a steeper increase in incidence rates in GLM initiation in the post MI patient group than in the general population, since these results indicate that the increase is primarily an effect of a general increased awareness of diabetes in the population as a whole. On the basis of extensive trial evidence, following conclusion can be drawn: Glucose-lowering therapy may require many years to yield apparent benefits. Further evidence is needed from studies with extended follow-up before the true benefits of achieving a near normoglycaemia in patients with type 2 diabetes can be as-sessed. For the time being, until specific guidelines are established, a pragmatic approach differentiating between new-onset diabetes patients with a lesser burden of co-morbidity and patients with a longer duration of diabetes/higher degree of co-morbidity should be made. Since the beneficial effect on cardiovascular adverse events are seemingly more apparent in relative “low risk” patients the intensive glucose-lowering regimes should be preserved for this patients group and lesser stringent targets might be appropri-ate for patients with more advanced disease of longer duration and higher baseline HbA1c concentration. Importantly, the glu-cose-lowering treatment should aim for the lowest glycaemia that can safely be sustained. Temporal trends in type of first initiated GLM This thesis also briefly examined the temporal trends in initiation of different pharmacological type of first initiated GLM during our 10-year study period and found that the use of metformin has increased significantly from 30.5% in 1997-1998 to 40.0% in 2005-2006. Conversely, the use of sulfonylureas decreased from 59.0% in 1997-1998 to 45.5% in 2005-2006. The use of insulin as first-

GLM also increased from 9.1% in 1997-1998 to 14.3% in 2005-2006. The change in the pattern of type of GLM used in MI patients during the period is likely to reflect the results of the UKPDS as well as the DIGAMI1 study signaling increased survival among users of metformin in general as well as the value of early insulin treatment after a recent MI.24, 58 This has shown to be valid also for patients undergoing percutaneous intervention (PCI), in whom the use of metformin or thiazolidinediones seem to attenuate the re-stenosis formation.59 Opposite, the effect of sulfonylureas or insulin on outcomes in MI patients treated with and without PCI seems to be less beneficial.60, 61 It is therefore somewhat surprising that al-though the proportion of patients treated with metformin has increased significantly during the study period the relative risk of all-cause mortality, cardiovascular death and recurrent MI in the incident diabetes population largely remain constant. The extents to which these changes of clinical practice may change the long-time survival in Danish MI patients with diabetes remain to be determined. MI and Cardiovascular risk The main focus of the present thesis was not to explore the rela-tionship between MI and cardiovascular risk, but nevertheless, no relative risk reduction was documented when comparing the inci-dent MI patients from the two time periods ((1997 to mid 2001) and (mid 2001 to 2006). Significant improvements in the treatment of patients with acute MI have been implemented during the last decade. In 2003 percutaneous coronary intervention was applied a gold-standard in Denmark for acute ST-elevation MI 62 and the use of beta-blockers, platelet inhibitors, and statins has increased significantly.63-66 Insuf-ficient treatment with beta-blockers and statins following hospita-lization after MI could be a plausible explanation for the lack of a risk reduction. It has been documented previously that if treatment with these agents are not initiated in close proximity to discharge,44, 67 the probability of ever receiving treatment is low. Possibly, the lack of risk reduction could partially be explained by the need for a longer observation time after the improved use of secondary prophylactic treatment before the prognosis changes. Nevertheless, our study emphasizes the need to maintain focus on intensifying the secondary prophylactic treatment in extension to hospitalization and post-discharge for first-time MI. Interestingly, our study indicates that women with first-time MI have a higher risk of recurrent MI than men event after adjusting for age. The poorer outcomes in women than in men after MI have widely been attributed to the fact that women tend to have infarc-tions at an older age and more co-morbidities than men. Sex has generally not been interpreted as constituting an independent association.68 In part, the explanation of the higher risk in women could be explained by the fact that women with acute MI are ap-proached in a much less aggressively invasive way and receive less interventional treatment.69 However, full reason remains to be explored taking into account discrepancies in both invasive treat-ment as well as discrepancies in concomitant medical treatment.69 Future studies on the subject are greatly warranted. The development of diabetes in MI patients In paper II we aimed to investigate the temporal trends in the initiation of GLM in the period 1997 to 2006 prior to the guidelines recommending an OGTT in both MI patients as well as in the gen-


eral population. As outlines previously, our study demonstrated an increase in the incidence rate of GLM initiation within the first year after first-time MI from the year 1997 until 2001. Following year 2001 the incidence rates stabilized. Our finding was confirmed in adjusted Cox-analyses. Moreover, our study demonstrated a simi-lar trend in the initiation of GLM in the general population during the 10 year study period. Corresponding to the MI population a stabilisation in incidence rate was observed in the general popula-tion after 2004. We expected to find an increase in the incidence rates of GLM initiation in both the MI population as well as in the general popu-lation. Furthermore, we anticipated that the increase in GLM initia-tion would be more pronounced in the MI-population population viewed in the light of an increased focus on diabetes as an inde-pendent risk factor for further cardiovascular adverse events in patients with established cardiovascular disease. The increased incidence of diabetes in the general population was in consistency with a previous study employing the Danish National Diabetes Register, where Carstensen et al. demonstrated an increase in the incidence of diabetes. 70 It is questionable whether the increase in incidence rates of diabetes in Denmark represents a true epidemi-ologic increment. Other possible explanations include 1) in-creased diagnostic intensity due to an augmentation of the aware-ness of diabetes in the general population, and 2) a large undiag-nosed population of patients with diabetes early in the study pe-riod being diagnosed during the rest of the study period, and 3) a decrease in mortality rates in the general population leading to increased numbers of subjects at risk of diabetes. The extent to which these individual factors each contribute to the increase in incidence of diabetes is speculative. Emphasis on differences in the inclusion criteria between our study and that of Carstensen et al. must be acknowledged in that we only documented an increase in incidence of patients with diabetes requiring GLM. Several previous studies have indicated that a large proportion of post-MI patients have undiagnosed diabetes or develop diabe-tes during admission or within a short time-span after discharge.32,

33, 35, 36, 71 We therefore anticipated that a much larger proportion of patients would have initiated GLM shortly after discharge for MI, than observed in our current study. There are several plausible explanations for the finding. First, diabetes in many patients was probably left undiagnosed, because the majority of patients pre-sented with normal fasting glucose values and therefore in accord with contemporary guidelines, did not undergo an OGTT, although many would here have impaired glucose tolerance or overt diabe-tes. 35 Importantly, however, because our study was conducted prior to publication of prevailing international guidelines, these numbers should not be interpreted as representing a predominant negligence from clinicians. Second, guidelines at the time of the study generally recommended lifestyle intervention and dietary treatment as first-line treatment for patients with newly detected diabetes. Conceivably, a substantial number of patients not initiat-ing GLM were in fact being managed by non pharmacological in-tervention. However, since diabetes is well-established as an im-portant independent long-term prognostic factor after MI that predicts increased mortality even 17 years after MI,3 our study underscores the importance of an aggressive diagnostic and thera-peutic approach in diabetes patients with MI. Lifestyle interven-tions were highly unlikely to be sufficient treatment in reaching target blood glucose values for all diabetes patients not initiating GLM. Our results indicate that a considerable number of post-MI

patients do not receive GLM as appropriate. Indeed the incidence rates are, not surprisingly, much higher in the MI population than in the general population. MI patients are at much higher risk of developing diabetes. If the higher incidence rates in the MI popula-tion compared with the general population were solely to be ex-plained by a true increased awareness of diabetes in the MI popu-lation and not in the general population as a whole, a steeper, linear or even exponential increment of incident diabetes in the MI population would be expected. Since we did not find such steep increase, it is most likely that the increased initiation of GLM in the MI population was, in fact, primarily the effect of a general in-creased awareness of diabetes in the population as a whole. Focus on early initiation of GLM is of utmost importance and the current results shows that when it comes to early GLM initia-tion in those with newly detected diabetes, there remains a con-siderable room for improvement in modern clinical practice. Post-MI development of HF and risk of diabetes Several factors may, in part, explain the current findings of increas-ing diabetes incidence with increasing HF severity. First, heart failure, the metabolic syndrome, and diabetes are low-grade in-flammatory states, and it is notable that tumor necrosis factor-a, a central pro-inflammatory mediator, can promote both insulin resistance and HF in experimental models.72, 73Moreover, in pa-tients with heart failure, circulating levels of tumor necrosis factor-a correlate with disease severity and prognosis, and renin- angi-otensin-system inhibitors (RASi) are associated with reduced levels of tumor necrosis factor-a in these patients.73 Another contributing factor may relate directly to reduced cardiac output in heart failure causing diminished blood flow and thereby diminished delivery of insulin and glucose to major insulin-sensitive tissues, such as the skeletal muscle74. Heart failure is also associated with physical inactivity and peak oxygen capacity has previously been shown to correlate with insulin resistance in patients with heart failure75. This latter association may also to some extent be mediated by reduced peripheral blood flow. A high adrenergic tone, as is com-monly seen in heart failure patients, may also contribute to our findings by increasing peripheral insulin resistance in the skeletal muscle and increasing hepatic gluconeogenesis. 76, 77 It is also possible that diminished skeletal muscle blood flow by a-adrenergic-mediated vasoconstriction plays a role in this relation-ship. While it is well known that treatment with thiazides increases the risk of development of diabetes, no such direct relationship has, to our knowledge, been documented in relation to treatment with loop-diuretics.78-82 The mechanisms accounting for the in-creased risk of diabetes when treated with thiazides is not com-pletely understood. However, it has been suggested that hypoka-laemia and/or excess aldosterone levels play part in this interrela-tionship.79, 83, 84 Indeed, increased plasma aldosterone levels have been reported in patients with untreated HF subjected to loop diuretics,85 and increasing aldosterone levels were recently con-firmed to be positively correlated with insulin resistance in patients with HF.86 Therefore, a direct effect of loop-diuretics on the risk of developing diabetes must be considered. One mechanism underly-ing the association between high aldosterone levels and risk of diabetes could potentially relate to diminished insulin secretion secondary to hypokalaemia, as several experimental studies have


found insulin secretion to decrease with low-potassium state.83 In line with these observations, we found that the increase in the risk of diabetes was attenuated by the concomitant use of RASi, which potentially could be a consequence of either decreased aldoste-rone levels or increased potassium levels. The latter observation should be interpreted with caution since the indication for treat-ment with RASi were unknown to us (e.g. some patients receiving RASi, but no diuretics, may have suffered from hypertension as part of the metabolic syndrome). The findings are in concordance with the findings in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) trial. In this study heart failure patients (mainly NYHA class II–III) were randomly assigned to candesartan or placebo. They found candesartan to decrease the risk of diabetes by 22% (relative risk 0.78, 95% CI 0.64–0.96).87 However, other studies exploring the effect of RASi on glucose metabolism (in different populations) have demon-strated varying results.88-90 Studies including hypertensivepatients receiving thiazides reported that RASi attenuated the risk of di-abetes, 89, 90 but the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial, (aiming to compare the effects of ramipril with placebo on the risk of developing di-abetes in patients without cardiovascular disease, but with glucose intolerance at baseline), found no differential risk of diabetes in the two groups.88 This could suggest that the potential diabetes risk-lowering effect of RASi is limited to patients with elevated aldosterone concentrations, such as those with HF and/or on di-uretic treatment.

Development of diabetes in heart failure patients and the risk of death In paper III in this thesis, we document that patients who devel-oped diabetes have a nearly three-fold increased risk of death. This result emphasizes the importance of identification of individuals at high risk of diabetes, whom potentially would benefit from primary diabetes prevention programmes and a more aggressive therapeu-tic approach, where metformin and acarbose may be attractive pharmacological options. Acarbose inhibits intestinal glucose up-take, leading to diminished post-prandial hyperglycaemia and improved insulin sensitivity, and has been documented to decrease the risk of diabetes in patients at high risk.91 Treatment with met-formin has also been reported to decrease the risk diabetes by improves insulin sensitivity92 indeed, because insulin resistance may compromise myocardial metabolism,93 metformin has been suggested as a new option for improving outcomes in patients with HF, irrespective of diabetes status. 94 In the presence of stressors such as pressure/volume overload and tachycardia, a compromised myocardial metabolism is incapable of meeting energy demand, leading to worsened HF93. In this context, we and others have previously found metformin to be associated with better outcomes than sulfonylureas or insulin agents in patients with heart failure and established diabetes.95, 96 Although it is well known that a poor glucose regulation increases the risk of HF,39 it remains unknown whether a strict glycaemic control can improve cardiac function in these patients. The mechanisms underlying the blood glucose-lowering effects of available pharmacological agents may therefore be of greater importance for their clinical effects than specific target glucose levels.


Study strengths

The studies presented in this thesis were strengthened by the large number of participants, the nationwide coverage of prospectively recorded registries, the use of validated endpoints, the real-life contemporary clinical setting, and the completeness of follow-up. The data cover the entire population of Denmark independent of socioeconomic status, age or participation in specific health-insurance programs. Notably, the studies in the thesis included citizens in and out of the labour market. Therefore, the risk of selection bias is avoided. Moreover, the Danish Health Care System partially reimburses drug expenses, and all Danish pharmacies are required to register all drug prescriptions, ensuring complete regis-tration. The cardiovascular endpoints of the studies were streng-thened by the study design which controlled for important meas-ured confounders (i.e comorbidity, concomitant pharmacotherapy, and age).

Study weaknesses

Observational studies may reveal disease associations but cannot establish causal relationships, and the results of this thesis should be interpreted in this context. The potentially important sources of bias have been mentioned in section “selection bias, protopha-ticbias, and confounding by indication”. As mentioned previously these types of bias are unlikely to have important influence on the results in this thesis. Still, it is impossible to completely refute an impact of one or more of these biases on the results presented in this thesis. The Danish population is predominantly of Caucasian descent; therefore, the results presented in this thesis should only be extrapolated to other ethnicities with caution. In addition, the possibility of residual confounding is present in all observational studies, and the registers, hold no information on no well known risk factors for cardiovascular disease such as hypertension, body mass index, physical activity, lipid disorders, dietary factors, micro-albuminuria, blood glucose levels, HbA1c levels, smoking or results from echocardiography (latter in paper III) . Therefore, these po-tentially important confounders are not controlled for in this the-sis. An important limitation of this thesis is that diabetes was defined by a claimed prescription for GLM. This fact is likely to have underestimated the true incidence/prevalence of diabetes (diet-treated and undiagnosed patients could not be identified). Moreover, it is important to mention the fact that the diabetes population was not diagnosed in connection to an admission to a hospital. Therefore, the initial risk in the diabetes population (in paper I) is not completely comparable to that of the MI population of the study. The diagnostic criteria for MI changed in 1999, with more sensi-tive markers being introduced (i.e. troponins) during the study period. Nevertheless, this has not resulted in dramatic changes in the prognosis for MI patients, and it is unlikely that this has af-fected our study. 97 Loop-diuretic treatment and dosages were used as a proxy for heart failure, since the diagnosis of heart failure in The Danish National Patient Register has a low sensitivity (29%) and we also had no information on clinical symptoms or left ventricular ejec-tions fraction. 98 We furthermore, acknowledge the heterogeneity in the baseline characteristics across the study groups and cannot exclude that the relationship between heart failure severity and risk of diabetes to be influenced by unmeasured factors.


Novelty of the results

The present thesis extents the knowledge from the previous work by Haffner et al. and Schramm et al., that patients with established diabetes carry a twofold higher risk of cardiovascular adverse outcomes compared with patients without diabetes 4, 5 .We docu-ment that this twofold higher risk also applies for the incident diabetes patient. The general awareness of diabetes has increased and the thesis shows that there is an increased incidence rate of GLM initiation in the general population as well as in the MI population suggesting that the increased incident rate of GLM initiation primarily reflects the generally increased awareness of diabetes more than an in-creased awareness among high risk patients with established car-diovascular disease. Furthermore, this thesis describes the proportion of patients hospitalized with first-time MI who within a year post MI develops diabetes requiring GLM. The poor prognosis in patients with MI and heart failure is well- known99-101 as is the increased risk of HF in diabetes patients. 38 However, to our knowledge it has not previously been docu-mented that HF increases the risk of diabetes according to the severity of HF after MI. This thesis suggests that heart failure in-creases the risk of diabetes in a severity-dependent manner after MI.

Conclusions/Implications

This thesis focuses on the relationship between ischemic heart disease and diabetes. This thesis confirm previous knowledge that diabetes patients exhibit an elevated risk of death and cardiovascu-lar morbidity and mortality and extend this knowledge to applying also to the incident diabetes patients. This knowledge is of utmost importance in caring for the diabetes patients and also for the ischemic patient since special attention is needed when treating these patient groups in order to reduce their morbidity and mortal-ity. The extent to which glycaemic control adds to the reduction of future cardiovascular events and reduction of macrovascular com-plications still remains to be determined. However, it is of great importance to emphasize that control of hyperglycaemia should not take precedence over control of hypertension and cholesterol levels among adults with diabetes as part of an evidence-based global cardiovascular risk reduction effort. Nevertheless, screening for diabetes in patients hospitalized with first-time MI cannot be stressed enough. It has only recently been confirmed that fasting glucose measurements are insufficient in finding patients with diabetes in MI-population settings102. In 2007 and 2008 the OGTT was implemented in the international and Danish national guidelines, respectively as the gold-standard test for revealing diabetes and dysglycaemic states in MI patients.103, 104The secondary prophylactic treatment in diabetes patients with established cardiovascular disease differs from that of the non-diabetic patient with cardiovascular disease in both target blood pressure values as in target cholesterol levels. These target values cannot be reached if diabetes remains undiagnosed. Importantly, if only fasting blood glucose levels are measured; two-thirds of the MI patients with abnormal glucose metabolism re-main undiagnosed.32 Hopefully, the present thesis underscores the importance of usage of OGTT testing in patients with MI. Furthermore, this thesis emphasizes the importance of diabetes prevention through lifestyle intervention a continuous monitoring for the development of diabetes in patients with heart failure.


Future research

The primary objective of the future research on the role of glycae-mic control in the prevention of CVD must be to conduct random-ized clinical trials including patients with a short duration of diabe-tes, preferably at the point in time, where the patient is diagnosed with diabetes. The first study of this thesis demonstrated that the diabetes patients exhibit an elevated risk of death and cardiovascu-lar morbidity and mortality from the point of time when treatment with GLM is initiated. Previously, the elevated risk has been docu-mented in patients with prevalent diabetes. The randomized clini-cal trials ACCORD, VADT, and ADVANCE failed to document a re-duction in CVD outcomes with intensive glycaemic control (HbA1c less than 6,0 % and 6,5 %, respectively). However, all three trials comprised patients with long diabetes duration from 8 to 11 years. At this time, it is plausible that the additive beneficial effect of intensive glycaemic control may be difficult to demonstrate on top of the effects of CVD prevention by tight blood pressure control, aspirin, statins and blockers of the renin-angiotensin system. It can be hypothesized that if these randomized trials had included par-ticipants with shorter duration of diabetes and/or absence of CVD, a benefit from intensive glycaemic control could have been evi-dent. Therefore, large randomized clinical trials including patients with low prevalence of comorbidity and short duration of diabetes are urgently warranted. However, on the basis of current informa-

tion, and the urgent need to address the residual risk of CVD in a rapidly expanding population with type 2 diabetes, it is premature to conclude that glucose control has no part to play especially in patients with short duration of diabetes. These prospective studies will more precisely define the diagnostic, therapeutic and prognos-tic implications of glucose controlin the context of cardiovascular disease and such data will form the background for guidelines aimed at cardiovascular risk management in patients with di-abetes. A second objective of future research is to reinvestigate the true impact of the change of both diabetes treatment guidelines and changes in the guidelines on diagnosing diabetes in this real life population-scale setting. Paper II was conducted prior to publi-cation of prevailing guidelines on diagnosing diabetes in MI pa-tients with an OGTT, and all three papers in this thesis prior to prevailing guidelines on management of diabetes (where lifestyle intervention was first line treatment of newly detected diabetes). Hopefully, as time goes by, a larger number of patients are tested with an OGTT after hospitalization after first-time MI, thereby, enabling both early diagnosing of diabetes in patients with CVD but certainly also enabling early and aggressive multi-factorial inter-vention in these high-risk patients ultimately resulting in reduction of future cardiovascular events.


Summary

Diabetes is a well-established risk factor for cardiovascular disease and is common among patients with acute myocardial infarction (MI), where the prevalence is as high as 20%. Patients with di-abetes requiring glucose-lowering medication (GLM) have been reported as having the same long-term risk of major cardiovascular outcomes as patients with a previous MI. Focus on the adverse prognosis carried by diabetes in the post-MI patients has caused new guidelines to be developed recommending similar preventive strategies to reduce the risk in these patients. Furthermore, heart failure is common after myocardial infarction and smaller studies have recently indicated that heart failure (HF) may be associated with insulin resistance. Nevertheless, larger scale studies investi-gating this topic are currently missing. Because of the adverse prognosis carried by patients with both diabetes and MI it is of great importance to explore the short and long-term risk of having these diseases and furthermore to investigate the extent to which patients with MI develop diabetes in order to commence early and aggressive evidence based therapy providing long term benefit in these high risk patients. The present thesis had the following objectives on the subject: The relationship between ischemic heart disease and diabetes 1. To examine the short- and long-term risk of death and cardi-ovascular outcomes in patients with incident diabetes and in pa-tients with first-time MI during a 10 year period in Denmark, using the general population as a reference. 2. To investigate the temporal trends in initiation of GLM following discharge for first-time MI between 1997 and 2006. 3. To assess whether HF severity, as determined by loop diuretic dosages, predicts the risk of developing diabetes after myocardial infarction. The thesis was based on national administrative registers. The registers primarily employed for this thesis were: The Danish Regis-ter of Medicinal Product Statistics (the National Prescription Regis-ter), the Danish National Patient Register, The Central Population Register and the Danish Causes of Death Register. Patients admitted to the hospital with first-time MI or patients developing diabetes requiring GLM during the study period of 10 years (1. January 1997-31. December 2006) were included in the study.

The thesis revealed the following main results

1. 1) Patients developing GLM requiring diabetes carried an approximately two-fold risk of death of all causes, cardiovascular death and MI immediately following initiation of GLM treatment, compared to the general population. There was a high short-term risk of death, cardiovascular death and recurrent MI in the incident MI population with a rapid decline during the 1st year. No decline of relative risk was demonstrated when comparing the MI population in the two the time-periods 1997 to mid-2001 and mid-2001 to 2006. 2) An increased incidence rate of GLM initiation within the first year following discharge for first-time MI from the year 1997 until 2001. From 2001 and onwards the incidence rate stabilized. A similar trend was documented in the general population with an increased incidence rate from the year 1997 until 2004. Following 2004 the incidence rate stabilized. A temporal shift in type of first initiated GLM to first-time MI patients was demonstrated. The use of metformin and insulin increased significantly during the study period. Correspondingly, the use of sulfonylurea declined. 3) Our study demonstrated a linear relationship between HF sever-ity post-MI and risk of developing diabetes, with patients using loop diuretics > 120 mg/day carrying an approximately two-fold increase in risk of diabetes, compared to patients without HF. Incident diabetes was found to carry nearly a threefold increase in relative risk of death. Conclusion 1. Patients developing GLM requiring diabetes carry an approxi-mately two-fold increased risk of cardiovascular death compared with the general population. Patients with first-time MI have a high short-term risk of cardiovascular death rapidly declining and nearly resembling the risk carried by the diabetes population. 2. Development of diabetes is frequent after first-time MI and probably under-diagnosed. 3. The risk of developing diabetes increases with increasing severi-ty of heart failure. Focus on the development of diabetes in patients with ischemic heart disease with or without the presence of heart failure still compose a public health matter, because early and aggressive evidence-based therapy is thought to reduce the morbidity of patients with diabetes thereby improving the prognosis for these patients.


Dansk Resumé

Diabetes er hyppigt forekommende hos patienter, der har haft akut myokardieinfarkt(AMI) med en rapporteret prævalens op mod 20 %. Patienter med behandlingskrævende diabetes har samme kardiovaskulære risiko som patienter, der tidligere har haft et AMI og samtidig forekomst af begge sygdomme er associeret med en dårlig prognose. Øget fokus omkring den dårlige prognose hos patienter med både iskæmisk hjertesygdom og diabetes har af-stedkommet udarbejdelsen af guidelines, der anbefaler ensartede forbyggende tiltag hos de to patientgrupper. Endvidere er hjerte-svigt hyppigt efter et AMI og mindre studier har indikeret at hjerte-svigt er associeret med insulin resistens. Der mangler viden om området fra større studier. Set i lyset af den markant dårligere prognose hos patienter med både AMI og diabetes er det af stor samfundsmæssig værdi at få klarlagt korttids- samt langtidsrisikoen forbundet med AMI og nydiagnosticeret diabetes samt udviklingen af diabetes efter AMI, således at man i fremtiden kan målrette den forbyggende indsats og dermed nedsætte risikoen for kardiovasku-lære hændelser hos disse højrisikopatientgrupper. Afhandlingen havde til formål at belyse følgende områder inden for forholdet mellem iskæmisk hjer-tesygdom og diabetes Korttids- og langtidsrisiko for død og kardiovaskulære hændelser i tiden efter indlæggelse for førstegangs AMI og i tiden efter opstart af antidiabetisk medicin (oral/insulin). Ændringer over tid i opstart af antidiabetika efter udskrivelse for førstegangs AMI. Betydningen af hjertesvigt for udvikling af behandlingskrævende diabetes hos patienter indlagt med førstegangs AMI. Afhandlingen bygger på data fra nationale registre. De nationa-le registre er samlet hos Danmarks Statistik og krypterede CPR-numre muliggør sammenføring af de forskellige registre på individ-niveau. Afhandlingen bygger på data fra primært 4 registre: læge-middeldatabasen, landspatientregistret, CPR-registret samt døds-årsagsregisteret. Vi identificerede patienter indlagt med et førstegangs AMI samt personer, der opstartede antidiabetisk behandling indenfor den 10-årige studieperiode (1. januar 1997 til 31. december 2006). Afhandlingen har vist følgende 1) at patienter, der udvikler behandlingskrævende diabetes, har en konstant fordobling i risiko for kardiovaskulær død, AMI samt død af alle årsager sammenlignet med den danske baggrundsbefolk-ning. Den øgede risiko er allerede til stede ved opstart af antidiabe-tika. Patienter med førstegangs AMI derimod har en høj korttids-risiko men denne risiko falder hurtigt inden for det første år efter indlæggelsen for et AMI. Til trods for store forbedringer i behand-lingsregimerne for AMI patienter samt i behandlingen af diabetike-re i løbet af studieperioden er der intet, der tyder på en relativ

risiko reduktion for kardiovaskulær død, AMI eller død af alle årsa-ger i AMI populationen, når perioden 1997 til medio 2001 og me-dio 2001 til 2006 sammenlignes. 2) at incidensraten af patienter, der opstarter i antidiabetika inden for et år efter udskrivelse efter et AMI er stigende fra 1997 til 2001, hvorefter raten stabiliseres. I baggrundsbefolkningen ses samme tendens med en stigning i incidensraten fra 1997 til 2004, hvoref-ter denne stabiliseres. Der er sket et skift i valg af første initierede antidiabetiske medicin til behandling af diabetes hos patienter med iskæmisk hjertesygdom. Brugen af metformin og insulin er signifikant steget, hvorimod brugen af sulfonylurinstoffer er faldet. 3) at der er en lineær sammenhæng mellem sværhedsgraden af HF (vurderet ud fra loop diuretika dosis) og risikoen for udvikling af behandlingskrævende diabetes. Risikoen for død øges med stigen-de grad af HF, ligesom at udvikle diabetes markant øger risikoen for død. Konklusion 1. Patienter, der udvikler behandlingskrævende diabetes, udviser dobbelt så stor risiko for kardiovaskulær død i forhold til den raske danske baggrundsbefolkning. Patienter med et førstegangs AMI har en høj korttidsrisiko, der er rapidt faldende nærmende sig en sammenlignelig risko med diabetes patienterne. 2. Udvikling af diabetes efter et førstegangs AMI er hyppigt men formentlig underdiagnosticeret. 3. Der er stigende risiko for udvikling af diabetes ved tiltagende sværhedsgrad af hjertesvigt. Fokus på udviklingen af diabetes hos patienter med iskæmisk hjertesygdom både med eller uden tilstedeværelsen af hjertesvigt har fortsat stor samfundsmæssig vigtighed, idet tidlig opsporing og behandling af diabetes hos denne patient gruppe potentielt vil reducere antallet af kardiovaskulære hændelser og dermed bedre prognosen hos disse højrisiko patienter.


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Appendices

Appendix 1 Pathophysiology of diabetic vascular disease Diabetes alters function in multiple cell types, including endothe-lium, smooth muscle cells and platelets, indicating the extent of vascular disarray in this disease. The endothelium consists of a single layer of endothelium cells, providing a metabolically active interface between blood and tissue and modulates blood flow, nutrient delivery, thrombosis and leukocyte diapedesis. This cell layer synthesizes important bioactive substances including nitric oxide (NO), other reactive oxygen species, prostaglandins, endo-thelin, and angiotensin II that regulate vessel structure and func-tion. NO potently dilates vessels and mediates much of the endo-thelium’s control of vascular relaxation. Furthermore, it inhibits platelet activation and limits inflammation by reducing leukocyte adhesion to endothelium and migration into the vessel wall, and diminishes vascular smooth muscle cell proliferation and migra-tion. Taken together, these properties inhibit atherogenesis and protect the blood vessel. Diabetes impairs endothelium-dependent NO-mediated vasodila-tion. Insulin resistance leads to excess liberation of free fatty acids (FFA) from adipose tissue that indirectly through other complex mechanisms results in impaired NO production and diminished bioavalability, thereby resulting in vasoconstriction, inflammation and thrombosis leading to accelerated atherogenesis. In smooth muscles diabetes alters the function in ways that promote atheros-clerotic lesion formation, plaque instability and clinical events. Diabetes also impairs the platelet function and this circumstance participates significantly in thrombus formation. Elevated blood glucose levels lead to activation of protein kinase C, decreased production of platelet-derived NO. Through complex mechanisms diabetic abnormalities increase intrinsic platelet activation and decrease endogenous inhibitors of platelet activity. Moreover, in diabetes a tendency toward coagulation, coupled with impaired fibrinolysis, favors formation and persistence of thrombi. Thus the perception of type 2 diabetes encompasses a global metabolic disorder characterized by hyperlipidaemia, hyperten-sion, and hypercoagulability in addition to hyperglycaemia. Each of these abnormalities plays an important role in cardiovascular disease development and progression and provides targets for therapy. Diagnostic criteria on diabetes The diagnosis of diabetes has traditionally been based on a fasting glucose level exceeding an arbitrary threshold, which has mainly been based on data from epidemiological studies and reflecting the risk of developing microvascular complications in the form of retinopathy and nephropathy.103 However, the majority of health related complications in patients with diabetes, is caused by ma-crovascular disease 105 e.g. cerebrovascular disease, peripheral

arterial disease and ischaemic heart disease. It has been demon-strated that the current diagnostic threshold poorly reflect the risk of developing the above mentioned macrovascular complications, as the progressive relationship between glucose levels and cardi-ovascular risk extends far below the current diabetic threshold.103,

106-108 The diagnostic criteria on diabetes have previously differed throughout the world and the differences in diagnostic criteria play an important role in the diagnostic process in patients presenting with ischaemic heart disease. Therefore, the criteria will be clari-fied for. Table 1: Criteria for glucometabolic classification according to the WHO and ADA. Glucometabolic category

Source Classification criteria mmol/l

Normal glucose regulation

WHO FPG < 6.1 + 2-h PG < 7.8

ADA (1997) FPG < 6.1 ADA (2003) FPG < 5.6 Impaired fasting glucose (IFG)

WHO FPG < 6.1 and < 7.0 + 2-h PG < 7.8

ADA (1997) FPG < 6.1 and < 7.0 ADA (2003) FPG < 5.6 and < 7.0 Impaired glucose tolerance (IGT)

WHO FPG < 7.0 + 2-h PG ≥ 7.8 and ≤ 11.1

Diabetes Mellitus WHO FPG ≥ 7.0 + 2-h PG ≥ 11.1

ADA (1997) FPG ≥ 7.0 ADA (2003) FPG ≥ 7.0 ADA (2010) HbA1c > 6,5 % WHO 2011 HbA1c > 6,5 %

FPG= fasting plasma glucose. 2-h PG= two hour post load plasma glucose. ADA = American Diabetes Association. WHO = World Health Organization.




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Ph.D. thesis

The Relationship between Ischemic Heart Disease

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Mette Lykke Norgaard

Ph.D. thesis ● Mett

e Lykke Norgaard

Faculty of Health Sciences,University of Copenhagen

Gentofte University Hospital, Department of Cardiology

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