Strategies for the prevention of type 2 diabetes and cardiovascular disease

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1 European Heart Journal Supplements (2005) 7 (Supplement D), D18 D22 doi: /eurheartj/sui025 Strategies for the prevention of type 2 diabetes and cardiovascular disease Jaakko Tuomilehto 1,2,3 *, Jaana Lindström 2, and Qing Qiao 1,2 1 Department of Public Health, University of Helsinki, Helsinki, Finland 2 Diabetes and Genetic Epidemiology Unit, National Public Health Institute, Mannerheimintie 166, Helsinki, Finland 3 South Ostrobotnia Central Hospital, Seinäjoki, Finland Introduction The DECODE (Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe) study provides a clear overview of the outcomes of metabolic syndrome and type 2 diabetes in terms of cardiovascular mortality in a European population. The study demonstrates that the presence of the metabolic syndrome doubles the risk of cardiovascular mortality, with a stronger effect in women than in men. 1 Although each individual component of the metabolic syndrome confers an increased risk of cardiovascular mortality, this is not as pronounced as when the metabolic syndrome itself is present. The more the components of the metabolic syndrome, the higher cardiovascular mortality. 1 In addition, DECODE also demonstrates that the combination of metabolic syndrome and type 2 diabetes leads to a significantly increased risk of cardiovascular or all-cause mortality, with this risk again being higher in women (Table 1). Life expectancy for people with type 2 diabetes is decreased by 5 10 years and adults with diabetes have an annual mortality of about 5.4%, which is double the rate for non-diabetic adults. 2,3 The often devastating impact of these conditions has led to much interest in how outcomes for people with type 2 diabetes can be improved and how type 2 diabetes can be prevented in the first place. Prevention of type 2 diabetes Lifestyle interventions A number of studies have now demonstrated the efficacy of specific, goal-oriented lifestyle interventions in the * Corresponding author. address: jaakko.tuomilehto@ktl.fi prevention of type 2 diabetes. This is clearly demonstrated by the Finnish Diabetes Prevention Study (DPS), 4 in which 522 middle-aged, overweight subjects with impaired glucose tolerance (IGT) 5 were randomly assigned to either the intervention group or the control group. Each subject in the intervention group received individualized counselling 6 aimed at reducing weight and intake of total and saturated fat. Increased intake of dietary fibre and increased physical activity were also encouraged. The cumulative incidence of diabetes after 4 years was 11% in the intervention group and 23% in the control group. Thus, the risk of diabetes was reduced by 58% (P, 0.001) in the intervention group during the trial. The reduction in the incidence of diabetes was directly associated with changes in lifestyle and, importantly, when the subjects implemented each of the five lifestyle goals, none of them developed diabetes during the intervention period (Figure 1 ). In the case of the DPS, none of the changes in lifestyle were particularly drastic. For example, subjects in the intervention group were given individualized advice to increase their intake of high-fibre food items, which appears to be important for glycaemic control. Owing to an increase in the intake of dietary fibre, the risk of diabetes was clearly reduced. The effects of a moderate increase in physical activity were also pronounced. Those who changed their behaviour the most, increased their physical activity by 4 h per week. There was an 80% difference in the risk of developing diabetes between those who increased their physical activity and those who did not increase or actually decreased their amount of exercise. 7 In the DPS, the weight reduction during the first year of study had a great effect on the risk of diabetes. In the lowest weight change quintile (weight reduction.7% from baseline), hazard ratio was 0.35 compared with the quintile where weight did not change (quintile 4). An average weight reduction of 4.6% in the second & The European Society of Cardiology All rights reserved. For Permissions, please journals.permissions@oupjournals.org

Preventive strategies for type 2 diabetes and cardiovascular disease D19 Table 1 Relative risk for mortality in subjects with either metabolic syndrome, or diabetes, or both 1 Table 2 DPS 7,8 Changes

2 Preventive strategies for type 2 diabetes and cardiovascular disease D19 Table 1 Relative risk for mortality in subjects with either metabolic syndrome, or diabetes, or both 1 Table 2 DPS 7,8 Changes in clinical and metabolic parameters Relative risk (95% CI) Men Women Cardiovascular diseases Normal Metabolic syndrome 1.52 ( ) 1.23 ( ) Diabetes 1.71 ( ) 1.96 ( ) Metabolic syndrome 2.28 ( ) 3.41 ( ) þ diabetes mellitus All causes Normal Metabolic syndrome 1.32 ( ) 1.26 ( ) Diabetes 1.68 ( ) 1.58 ( ) Metabolic syndrome 1.81 ( ) 2.55 ( ) þ diabetes mellitus Intervention Control P-value for change Weight (kg) Waist circumference (cm) fp-glucose (mmol/l) n-p-glucose (mmol/l) HbA 1c (%) Total cholesterol ns HDL cholesterol þ0.05 þ0.02 ns Triglycerides Systolic BP (mmhg) Diastolic BP (mmhg) BP, Blood pressure. P, 0.05; P, 0.01; P, Adjusted for age, centre, smoking, and cholesterol. demonstrated a 58% risk reduction of developing diabetes following lifestyle changes (and a 31% risk reduction for metformin alone), and the Da Qing study in China, which demonstrated a 31% risk reduction with diet, a 46% risk reduction with exercise, and a 42% risk reduction with the combination of diet and exercise. 9,10 Pharmacotherapy as an adjunct to lifestyle change Figure 1 Proportion of subjects becoming diabetic by success in achieving intervention targets at 1 year examination DPS. 4 Copyright & 2001 Massachusetts Medical Society. All rights reserved. N Engl J Med 2001; 344: quintile (weight reduction ranging from 3 to 7%) halved the diabetes risk when compared with quintile 4. 7 Importantly, even a small weight loss seems to have a significant impact. In this study, the mean amount of weight lost between the baseline and the end of year 1 was 4.5 kg in the intervention group. It is assumed that the average person in the study weighed 100 kg and would, therefore, be 20 kg overweight (assuming a normal weight of 80 kg). So, while a 5 kg reduction represents only 5% of the patient s initial body weight, it is also a more meaningful 25% reduction of the excess weight. Of the subjects included in the DPS, 74% had the metabolic syndrome. 8 The interventions in the DPS clearly had a significant impact on the components of the metabolic syndrome, including waist circumference, glucose tolerance, triglycerides, and blood pressure (Table 2 ). A number of other prevention studies have demonstrated similar positive results for quantified and clearly communicated lifestyle interventions, including the Diabetes Prevention Program (DPP) in the US, which The use of pharmacotherapy as an adjunct to lifestyle change is a strategy that is increasingly being investigated, with encouraging results. In the XENDOS study (XENical in the Prevention of Diabetes in Obese Subjects), 3305 obese patients with both IGT and normal glucose tolerance were randomized to lifestyle changes plus either orlistat or placebo for a 4 year treatment period. Compared with lifestyle changes alone, orlistat plus lifestyle changes resulted in a greater reduction in the incidence of type 2 diabetes and produced greater weight loss. Differences in diabetes incidence were detectable only in the IGT group. 11 Interestingly, subjects with IGT who were allocated into the lifestyle plus placebo group in XENDOS had a very similar incidence of diabetes to those in the lifestyle intervention group in the DPP. In the TRIPOD (TRoglitazone In the Prevention Of Diabetes) study, Hispanic women with previous gestational diabetes were randomized to placebo or the insulin-sensitizing drug troglitazone. Gestational diabetes is a strong predictor of future type 2 diabetes. During a median follow-up period of 30 months on blinded medication, the average annual diabetes incidence rates in the 236 women who returned for at least one follow-up visit were 12.1% in the placebo group and 5.4% in the troglitazone group (P, 0.01). This demonstrated that treatment with troglitazone delayed or prevented the onset of type 2 diabetes in high-risk women. 12 Troglitazone is no longer available for clinical use, and data are not yet available on other drugs in this class.

3 D20 J. Tuomilehto et al. Prevention of cardiovascular events in type 2 diabetes Excess cardiovascular risk in type 2 diabetes The ADA and NCEP ATP III recommend that people with diabetes (without cardiovascular disease) be treated with the same intensity as non-diabetics with established cardiovascular disease. Thus, when calculating an individual s cardiovascular risk, diabetes is now given equivalent weighting to preexisting cardiovascular disease. 13 For women with diabetes the cardiovascular risk is even higher. Unpublished data from a large cohort of Finnish men and women followed for 12 years demonstrate a five-fold increase in the risk of death from coronary heart disease (CHD) in women with diabetes who had no history of a previous myocardial infarction (MI). Women who had a previous MI but no diabetes had a 2.5-fold increase in CHD death and women who had both diabetes and a previous MI had an extremely high risk (almost a nine-fold increase) of CHD death. 14 MRFIT (Multiple Risk Factor Intervention Trial) demonstrates that no matter which cardiovascular risk factors individuals have (hypertension, smoking, dyslipidaemia, all three, or none), the presence of diabetes further increases the risk of cardiovascular death. 15 Treatment of diabetic dyslipidaemia Addressing this excess cardiovascular risk requires careful consideration of the atherogenic dyslipidaemia evident in diabetes, which includes raised triglycerides, lowered HDL cholesterol (HDL-C), and a preponderance of small dense LDL particles and elevated levels of apolipoprotein B. All these changes are associated with increased risk of atherosclerosis. 16,17 The most common pattern of lipid abnormality observed in patients with type 2 diabetes consists of hypertriglyceridaemia and decreased levels of HDL. The Heart Protection Study demonstrates that patients with type 2 diabetes significantly benefit from statin therapy, with no difference reported between diabetic and non-diabetic subjects in terms of cardiovascular outcome and an overall risk reduction of 27% for the endpoint of major coronary events. 18 A recent update of the NCEP ATP III guidelines recommends more intensive cholesterol treatment for people at very high risk of an MI or cardiovascular death (including people with existing cardiovascular disease plus diabetes or metabolic syndrome), stating that an LDL goal of,1.8 mmol/l (70 mg/dl) is a therapeutic option for this group. 19 This is in line but even more drastic than the most recent European guidelines that recommend the goal LDL of 2.5 mmol/l (100 mg/dl) in high-risk subjects. 20 Although this provides a clear endorsement of the use of statins in people with diabetes, there are less data to guide decisions about therapy for patients with low levels of HDL-C and high triglycerides but without high levels of LDL-C. Additional information on the treatment of diabetic dyslipidaemia will come from the FIELD study, a multicentre, randomized, double-blind trial which aims to assess whether treatment with fenofibrate will reduce CHD in people with type 2 diabetes. VA-HIT (Veterans Affairs High-Density Lipoprotein Intervention Trial) tested the hypothesis that drug therapy to increase HDL-C levels would decrease the incidence of major CHD events, and was designed to exclude patients with a high concentration of LDL-C. Active treatment was with the fibrate gemfibrozil. VA-HIT was the first lipid intervention trial to show that raising HDL-C concentration in people with established CHD and both a low HDL-C and a normal low LDL-C level will significantly reduce the incidence of major coronary events (24% risk reduction). 21 In men with CHD and a low HDL- C level, gemfibrozil use was associated with a reduction in major cardiovascular events in subjects with diabetes and in non-diabetic subjects with a high fasting plasma insulin level. 22 Treatment of hypertension The prevalence of type 2 diabetes is higher in hypertensive patients than in the general population, and the value of normalizing blood pressure in reducing cardiovascular risk in diabetic patients is unequivocal. 23 For example, the blood pressure control study embedded in the UKPDS (United Kingdom Prospective Diabetes Study) showed that cardiovascular risk is strongly associated with raised blood pressure and that improved blood pressure control reduces the risk of cardiovascular events. In the study, lowering blood pressure below 150/ 85 mmhg using angiotensin-converting enzyme (ACE)- inhibitors or beta-blockers led to reductions in risk of 34% in macrovascular events and 32% in mortality. 24 A number of other studies have clearly demonstrated that reduction in blood pressure significantly reduces the risk of major cardiovascular events in patients with diabetes, including the Systolic Hypertension in Europe (Syst-Eur) trial and the HOT study. 25,26 The HOPE (Heart Outcomes Prevention Evaluation) study reported a 22% reduction in the risk of major cardiovascular events with ACE-inhibitor treatment in high-risk patients (those with diabetes or evidence of vascular disease plus another cardiovascular disease risk factor). 27 The recent VALUE study demonstrated a significant 23% risk reduction in new-onset diabetes among high-risk hypertensive patients treated with the angiotensin II blocker valsartan compared with the calcium channel blocker amlodipine (13.1% incidence with valsartan, 16.4% with amlodipine, P, ). 28 Treatment of hyperglycaemia Another important target in the prevention of cardiovascular events in type 2 diabetes is the management of hyperglycaemia. UKPDS 49 provides data on long-term glycaemic control in patients with type 2 diabetes. The proportion of patients achieving the target of HbA 1C, 7% after 9 years of follow-up is low (ranging from 9 to 28% depending upon treatment group). 29 An earlier publication from the UKPDS demonstrated that

4 Preventive strategies for type 2 diabetes and cardiovascular disease D21 phase insulin secretion, and a decrease in endothelial function. Epidemiological data from the DECODE study show a linear correlation between 2 h plasma glucose levels and cardiovascular mortality (Figure 3 ). 32 It is possible to speculate that by lowering these postchallenge glucose levels by 20% in all patients with asymptomatic type 2 diabetes or all patients who have IGT, there could be a 28 and 21% reduction in mortality, respectively, given that mortality was 30% in subjects with asymptomatic diabetes and 23% in those with IGT (unpublished results). Figure 2 Summary of effect on risk factors (Steno-2). 31 Copyright & 2001 Massachusetts Medical Society. All rights reserved. N Engl J Med 2001; 348: Acknowledgements This work has been supported by the Academy of Finland (8473/2298, 40758/5767, 38387/54175, 46558), the Finnish Diabetes Research Foundation, the Yrjö Jahnsson Foundation, the Juho Vainio Foundation, and the Paulo Foundation. References Figure 3 DECODE: cardiovascular disease mortality by 2 h plasma glucose. 32 (Copyright & 2003 American Diabetes Association. From Diabetes Care, Vol. 26, 2003; Reprinted with permission from The American Diabetes Association.) intensive glucose control (HbA 1C, 7% compared with,7.9% in the conventional treatment arm) is associated with a significant reduction in risk for microvascular complications (e.g. retinopathy and nephropathy) and a reduction in risk of MI with borderline significance. 30 The Steno-2 study compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria, and found that intensive therapy reduced the risk of both cardiovascular and microvascular events by 50%, and the absolute risk of cardiovascular events by 20%. 31 This means that five patients would need to adhere to the treatment programme for the study duration (7.8 years) to prevent one cardiovascular event. Many of the patients enrolled in Steno-2 had long-established type 2 diabetes and, therefore, it was more straightforward to achieve cholesterol and blood pressure targets than to achieve targets for HbA 1C (Figure 2 ). It is important to note that one of the limitations of most studies conducted so far is that they have studied HbA 1C and fasting glucose and that there is a great need for outcome studies focussing on controlling postprandial glucose levels. This is important because excessive post-prandial hyperglycaemia is associated with increased insulin resistance, a deterioration in early 1. Hu G, Qiao Q, Tuomilehto J et al. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in non-diabetic European men and women. Arch Intern Med 2004; 164: Goodkin G. Mortality factors in diabetes. A 20 year mortality study. J Occup Med 1975;17: Donnelly R, Emslie-Smith AM, Gardner ID. Vascular complications of diabetes. BMJ 2000;320: Tuomilehto J, Lindström J, Eriksson JG. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344: World Health Organization. Diabetes Mellitus: Report of a WHO Study Group. Geneva, Lindström J, Louheranta A, Mannelin M. The Finnish Diabetes Prevention Study (DPS): Lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care 2003;26: Laaksonen DE, Lindstrom J, Lakka TA et al. Physical activity in the prevention of type 2 diabetes: the Finnish diabetes prevention study. Diabetes 2005;54: Ilanne-Parikka P, Eriksson JG, Lindstrom J et al. Prevalence of the metabolic syndrome and its components: findings from a Finnish general population sample and the Diabetes Prevention Study cohort. Diabetes Care 2004;27: The Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346: Pan XR, Li GW, Hu YH et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20: Torgerson JS, Hauptman J, Boldrin MN et al. XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27: Buchanan TA, Xiang AH, Peters RK et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high- risk hispanic women. Diabetes 2002;51: Haffner SM, Lehto S, Ronnemaa T et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339: Hu G, Jousilahti P, Qiao Q et al. Sex differences in cardiovascular and total mortality among diabetic and non-diabetic individuals with or without history of myocardial infarction. Diabetologia 2005;48:

5 D22 J. Tuomilehto et al. 15. Stamler J, Vaccaro O, Neaton JD. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16: Stout R. Insulin and atheroma: 20-year perspective. Diabetes Care 1990;13: Laakso M. How good a marker is insulin level for insulin resistance? Am J Epidemiol 1993;137: Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet 2003;361: Grundy SM, Cleeman JI, Bairey Merz CN et al. for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004;110: De Backer G, Ambrosioni E, Borch-Johnsen K et al. European Society of Cardiology Committee for Practice Guidelines. European guidelines on cardiovascular disease prevention in clinical practice: third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Eur J Cardiovasc Prev Rehabil 2003;10:S1 S Rubins HB, Robins SJ, Collins D et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of HDL-C. Veterans Affairs High-density Lipoprotein Cholesterol Intervention Trial (VA-HIT) Study Group. N Engl J Med 1999;341: Rubins HB, Robins SJ, Collins D et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Intern Med 2002;162: British Hypertension Society. Guideline on the Management of Hypertension, UKPDS Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ 1998;317: Tuomilehto J, Rastenyte D, Birkenhäger WH et al. for The Systolic Hypertension in Europe Trial Investigators. Effects of Calcium- Channel Blockade in Older Patients with Diabetes and Systolic Hypertension. N Engl J Med 1999;340: Hansson L, Zanchetti A, Carruthers SG et al. for the HOT study group. Effects of intensive blood pressure lowering and low dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351: The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342: Julius S, Kjeldsen SE, Weber M et al. for the VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363: Turner RC, Cull CA, Frighi V et al. UKPDS 49 Glycaemic control with diet, sulphonylurea, metformin and insulin therapy in patients with type 2 diabetes: progressive requirement for multiple therapies. JAMA 1999;281: UKPDS Study Group. UKPDS 33 Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998;352: Gaede P, Vedel P, Larsen N et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Eng J Med 2003;348: The DECODE Study Group. Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes Care 2003;26:

The American Diabetes Association estimates

The American Diabetes Association estimates DYSLIPIDEMIA, PREDIABETES, AND TYPE 2 DIABETES: CLINICAL IMPLICATIONS OF THE VA-HIT SUBANALYSIS Frank M. Sacks, MD* ABSTRACT The most serious and common complication in adults with diabetes is cardiovascular