Key words: Cardiovascular – Diabetes – Outcomes – Pioglitazone – PROactive – Thiazolidinediones
ABSTRACT
Background: Outcome studies are used to measure clinically meaningful primary end points, such as mortality and cardiovascular morbidity. However, few outcome trials have been conducted exclusively in people with diabetes; the majority of conventional diabetes trials use surrogate end points that may or may not translate into clinical benefits. Our current knowledge of the effects of pharmacotherapies on cardiovascular risk in patients with diabetes has been gained from subgroups included in large-scale studies. Several trials with lipid-modifying, antiplatelet and/or antihypertensive therapy, for example the recent Collaborative AtoRvastatin Diabetes Study, have included sufficient numbers of patients with diabetes to indicate that effective management can reduce cardiovascular risk in this patient population. The United Kingdom Diabetes Study and the Diabetes Control and Complications Trial provide important, but inconclusive data on the impact of glucose-lowering therapy on the incidence of cardiovascular complications in diabetes. Thiazolidinediones have only become available during the past few years, thus their effects were not assessed in these landmark trials. Ongoing studies in diabetic populations at high risk for further macrovascular events, such as the PROspective pioglitAzone Clinical Trial In macroVascular Events, have been designed to assess the effect of thiazolidinediones on cardiovascular outcome in patients with diabetes and should help to reinforce the importance of broad-based treatment of the multiple metabolic risk factors for cardiovascular disease in people with diabetes.
Scope: This paper (based upon MEDLINE and EMBASE literature searches in the year range 1990-2005) reviews what we have learned from outcome studies up to the end of 2004 and looks at what we hope to learn from ongoing studies.
Introduction
Those with metabolic syndrome ideally require an integrated approach to manage weight loss, glucose levels, hypertension and dyslipidaemia. The most effective and frequently used management options for the different underlying causes of the metabolic syndrome include:
* Preventing and managing obesity.
* Modulating lipid levels, e.g. LDL-cholesterol and triglyceride reduction as well as increase in HDL-cholesterol.
* Managing hypertension.
* Addressing subclinical inflammation.
* Treating insulin resistance.
Outcome studies are used to show if these management options deliver clinically meaningful benefits by using primary endpoints that are of direct importance to patients, e.g. overall mortality. However, there are few outcome studies that have tested the effects of pharmacotherapies on outcomes in diabetes and most data on endpoints related to macrovascular disease (e.g. all-cause death, cardiac death and cardiovascular morbidity) are from trials with surrogate end points or are subgroup analyses of cardiovascular outcome trials.
Nevertheless, there are important data from a small number of landmark outcome trials using lipid-lowering agents, antihypertensives and/or antiplatelets, but the United Kingdom Prospective Diabetes Study (UKPDS) is the only outcome study to date to assess specifically the effects of oral glucose-lowering agents on vascular risk reduction in patients with type 2 diabetes. Although we learned a considerable amount from this study, several questions were left unanswered.
In 2005, the results of PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive), the first large-scale outcome study of an oral glucose-lowering agent in the management of type 2 diabetes, will be revealed.
This paper reviews what we have learned from outcome studies up to the end of 2004 and looks at what we hope to learn from ongoing studies. It is based upon MEDLINE and EMBASE literature searches using the search terms outcome trials, cardiovascular risk reduction, mortality, morbidity, statins, fibrates, diabetes, antihypertensives, antiplatelets and glucose-lowering and the year range 1990-2005.
Landmark outcome trials
Studies in people with diabetes
Several landmark trials provide important data on the impact of glucose-lowering therapy on the incidence of cardiovascular (CV) complications. There are also two completed studies that assess the impact of lipid-lowering therapy on reduction of surrogate macrovascular endpoints in a population of people with diabetes exclusively (Table 1).
The University Group Diabetes Program (UGDP) was one of the earliest outcome studies that was conducted in the 1960’s in patients with type 2 diabetes (n = 823) during an 8-year period. Five groups of patients were studied: diet plus placebo, standard insulin doses, variable insulin doses, tolbutamide and phenformin. The findings for the two insulin groups were inconclusive in terms of delaying or preventing CV complications and there were no significant differences in incidence of overall mortality in all of the groups1.
Table 1. Diabetes trials investigating cardiovascular outcome
The UKPDS is the most important clinical trial in patients with type 2 diabetes. During a 20-year period over 5000 patients with newly diagnosed type 2 diabetes were studied to determine whether intensive pharmacological blood glucose control could reduce the risk of diabetic micro- and macrovascular complications. A large number of endpoints, including myocardial infarction, heart failure, angina, renal failure and stroke, were measured. The study demonstrated that intensive glycaemic control of type 2 diabetes was effective in reducing HbA^sub 1c^ (which is a risk factor for vascular disease itself) and in all microvascular complications (25% decrease; median follow-up of 11.1 years). For every 1% decrease in HbA^sub 1c^ there was an associated 37% reduction in microvascular complications2,3. The reduction in the risk of macrovascular disease was less pronounced than the improvements in microvascular disease, with a modest 16% reduction in myocardial infarction that was of borderline significance3. However, in the metformin subgroup analysis (n = 342) there were significant reductions in diabetes- related deaths (42% reduction), any diabetes-related endpoint (32% reduction) and myocardial infarction (39% risk reduction)4.
In the Diabetes Intervention Study (DIS), 1139 people with type 2 diabetes were followed for 11 years to determine the effect of intensified versus conventional health education in improving metabolic control and reducing the level of coronary risk factors and incidence of ischaemic heart disease5. This study showed that triglycerides were an important risk factor for myocardial infarction. Clofibrate efficacy was assessed at 5 years within the intensified group (379 out of 761 patients) and decreased triglyceride levels6. Although clofibrate was effective in reducing triglycerides, it did not appear to prevent CV complications and myocardial infarction and mortality increased more with postprandial than with fasting hyperglycaemia. The incidence rate per 1000 for myocardial infarction was 30.3 for control subjects, 53.6 for the intensive group and 55.6 for the intensive group receiving clofibrate therapy.
The Diabetes Control and Complications Trial (DCCT) was a 10- year, multicentre, prospective randomized trial in 1441 people with type 1 diabetes [n = 726 in the primary prevention cohort and 715 in the secondary intervention cohort) designed to determine the effect of intensive management versus conventional management on the prevention of retinopathy (the primary outcome) and other vascular complications in type 1 diabetes7. The study found that intensive glycaemic control reduced HbA^sub 1c^ by 1.9% over the 10-year period, with a 76% decrease in the risk of retinopathy in the primary prevention cohort and a delayed progression in 54% of those with established retinopathy. The risk of albuminuria and microalbuminuria were also reduced by intensive insulin therapy (decreases of 54% and 39%, respectively). There were also non- significant risk reductions for all macrovascular CV events combined (41%).
The Diabetes Atherosclerosis Intervention Study (DAIS) is the first clinical trial involving randomized lipid-lowering therapy in a population of people with diabetes exclusively. In this 3-year study in 418 patients with diabetes and characteristic diabetic dyslipidaemia, with or without previous cardiac interventions, fenofibrate reduced coronary atherosclerosis (measured by angiography) by 40%. However, the study was not powered to detect significant differences in clinical cardiac endpoints8.
The Collaborative AtoRvastatin Diabetes Study (CARDS) is the first ever primary prevention study of cholesterol-lowering specifically in patients with type 2 diabetes at low risk for CV events (they had no previous history of CVD and had normal LDL- cholesterol levels). Nearly 3000 patients with type 2 diabetes were randomized to either atorvastatin or placebo. The trial was halted 2 years early (mean duration of follow-up of 3.9 years) as the prespecified efficacy endpoint criteria (a significant difference in favour of atorvastatin) was met during an interim analysis. Those patients treated with the statin had a 37% reduction in the risk of a major CV event. In addition, acute coronary event rate was reduced by 36% and stroke by 48% in the atorvastatin-treated group9.
\In addition, two recent trials, the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Lorsartan (RENAAL), showed the effects of antihypertensives on microcirculatory endpoints in patients with type 2 0 diabetes10,11. IDNT looked at the effects of therapy with an angiotensin II receptor antagonist (irbesartan); a calcium channel blocker (amlodipine) or placebo as add-on to standard antihypertensive therapy in patients with type 2 diabetes (n = 1715). The composite microvascular endpoint of doubling of baseline serum creatinine concentration, the onset of end-stage renal disease or death from any cause (surrogates of progression of diabetic nephropathy and development of end-stage renal failure) were improved by the use of the angiotensin II antagonist. However, there were no significant differences between groups for the secondary CV composite endpoint (death from CV causes, non-fatal myocardial infarction, heart failure, neurological defects caused by a cerebrovascular event or lower limb amputation)10.
Subgroup analyses of patients with diabetes in large outcome trials
Several trials with lipid-modifying, antiplatelet and/ or antihypertensive therapy have included sufficient numbers of patients with diabetes to indicate that effective management of dyslipidaemia, endothelial dysfunction and/or hypertension can slow the progression of coronary atherosclerosis and reduce the risk of future coronary events in patients with diabetes (Table 2).
Outcome trials using statins
Data from secondary prevention studies confirm a link between cholesterol levels and coronary heart disease (CHD) risk and the benefits of statins on CV risk factor modification apply to subgroups with diabetes.
The Heart Protection Study (HPS) was a randomized, placebo- controlled trial in over 20 000 people with CHD, other occlusive arterial disease or diabetes (mean follow-up of 5 years). The study aimed to determine the potential long-term benefits of cholesterol- lowering therapy (simvastatin) in people at increased risk of CHD. Approximately 6000 people with diabetes (mainly type 2) were enrolled and one-third of these also had concomitant CHD. In the subgroup with diabetes, simvastatin reduced the risk of myocardial infarction, stroke and other vascular complications by one-third12.
Four smaller studies (Long-term Intervention with Pravastatin in Ischaemic Disease [LIPID]13, Cholesterol And Recurrent Events [CARE]14, Scandinavian Simvastatin Survival Study [4S]15,16 and the West of Scotland Coronary Prevention Study [WOSCOPS]17), which were conducted in patients with CHD, also assessed data from subgroups of patients with diabetes.
The LIPID study was conduced in patients with a history of myocardial infarction or unstable angina and a wide range of plasma cholesterol levels on entry, with a mean follow-up of 6.1 years. When treated with pravastatin, the subgroup of patients with diabetes (n = 782 out of the total study population of 9014 people) showed a 19% reduction in CHD risk of death and non-fatal myocardial infarction (the primary outcome) compared with a decrease of 25% in non-diabetics13.
Table 2. Landmark trials with subgroup analyses of patients with diabetes
The CARE study looked at pravastatin treatment in patients with prior CHD and average LDL-cholesterol levels. Analysis of the subgroup of patients with a history of diabetes (n = 586 out of 4159) showed a 25% reduction in relative risk of coronary events after 5 years of treatment with pravastatin14.
In 4S (median follow-up of 5.4 years), simvastatin therapy resulted in a risk reduction of 43% in total mortality (the primary endpoint) and 55% risk reduction in major CHD events in a subgroup of 202 patients with diabetes15. This did not reach statistical significance, probably due to the small patient number. A post-hoc analysis, extending this into a larger cohort of 483 patients that met ADA criteria for diabetes, showed a 42% reduction in major CHD risk and a 21% reduction in total mortality with simvastatin16. It is thought that the greater effect of statin therapy on CHD risk in 4S than in the CARE and LIPID studies may be due to more marked effects in those with elevated LDL-cholesterol concentrations.
WOSCOPS examined the development of a new diagnosis of diabetes in men with moderate hypercholesterolaemia, but no history of myocardial infarction. The primary endpoint was non-fatal myocardial infarction or death from CHD. Only 1% of the study population had diabetes on entry into the study so no subgroup information is available; however, a retrospective subgroup analysis showed that the risk of developing diabetes was reduced by about 30% in patients receiving pravastatin17. One hundred and thirty nine of the 6595 men developed diabetes during the 3.5-6.1 year follow-up.
Outcome trials using fibrates
There are two analyses of fibrate therapy (gemfibrozil) in people with diabetes from larger studies in CHD. In the first, the Veterans Affairs High-density lipoprotein Intervention Trial (VA-HIT), the role of fibrate therapy in preventing CHD events in men with known CHD was studied (median follow-up of 5.1 years). A total of 769 people out of the 2531 with CHD also had diabetes. Gemfibrozil use in this subgroup of patients with diabetes reduced the composite endpoint of CHD death, non-fatal myocardial infarction or confirmed stroke by 32% and stroke by 40%18.
Of the 4081 males in the Helsinki Heart Study, 135 patients had diabetes. Gemfibrozil reduced CV risk by 68% in this subgroup, however, there was no statistically significant difference between the gemfibrozil and placebo groups, with a low incidence of cardiac events in both groups (3.4% in the gemfibrozil group and 10.5% in the placebo group), probably due to the small patient number19.
Outcome trials using antihypertensives
Studies assessing the effects of antihypertensive agents on CHD risk have also shown reductions in risk rate in people with diabetes. In particular, the Heart Outcomes Prevention Evaluation (HOPE) trial, GISSI-3 and the UKPDS, all showed that blood pressure lowering interventions were beneficial in reducing CHD and stroke in patients with diabetes20-22.
The HOPE study assessed the effects of the ACE inhibitor, ramipril, in more than 9500 patients with a high risk for CV events. In the population of patients with diabetes (n = 3577; The MICRO- HOPE Study), ramipril provided significant clinical benefits on the primary outcome (25% risk reduction of combined myocardial infarction, stroke or CV death) and also on other outcomes (reductions of 22% in myocardial infarction, 33% in stroke, 24% in total mortality and 37% in CV death)20. The effect appeared to be independent of, and additive to, the effects of antiplatelet and lipid-lowering agents.
In GISSI-3, 2790 of the 18131 patients enrolled had diabetes. The ACE inhibitor, lisinopril, was given within 24 hours from the onset of symptoms of acute myocardial infarction and continued for 6 weeks to see if mortality and morbidity could be reduced. Treatment with lisinopril reduced 6-week mortality (30% risk reduction)21.
In the UKPDS, intensive blood pressure control with either an ACE inhibitor or a β-blocker, gave a 37% improvement in microvascular endpoints with a 21% reduction in myocardial infarction and 44% in stroke in a subgroup of people with hypertension22. Although this subgroup was very small, it does suggest that there are benefits of combining treatments for the modification of multiple CV risk factors in patients with diabetes.
Outcome trials using antiplatelets
Only one outcome study using antiplatelet therapy has assessed effects in a subgroup of patients with diabetes. Hypertension Optimal Treatment (HOT) is the largest study of the effects of aspirin on major CV events (n = 18 790). Mean follow-up was 3.8 years. All patients received the long-acting calcium antagonist, felodipine, and ACE inhibitors, beta-blockers and/ or diuretics were added according to a preassigned regimen of intensive versus conventional hypertension management. The effects of add-on therapy with aspirin were compared with placebo. In patients with diabetes, those intensively treated experienced a 51% decrease in major CV events. Aspirin reduced major CV events by 15% and myocardial infarction by 36% in the total population23.
Outcome trials using combination therapies
Controlling one risk factor alone does not eliminate the risk of CHD in patients with type 2 diabetes and the combined use of two or more agents with complementary mechanisms of action may provide greater improvements in CV risk factors than the use of single agents.
The Multiple Risk Factor Intervention Trial (MRFIT) provided evidence that tight control of hypertension, cholesterol and smoking reduced cardiovascular mortality in patients with type 2 diabetes24. In addition, the small, 9-year study (mean follow-up of 7.8 years) Steno-2, looked at reduction in risk factors for CVD in 160 patients with type 2 diabetes and microalbuminuria given intensive multifactorial, stepwise treatment with an ACE inhibitor or an angiotensin II receptor blocker (regardless of blood pressure levels), a lipid-modifier (statin or fibrate) and a glucose- lowering agent, in addition to aspirin, vitamin supplements plus diet and lifestyle changes25. Intensively treated patients were much more likely to achieve therapeutic goals and had a mean reduction in macrovascular disease of 53% relative to conventional therapy given in accordance with national guidelines. This large reduction in CV disease risk is substantially higher than that observed in previous single intervention trials using lipid-modulators or antihypertensives, suggesting that targeting multiple risk factors is necessary in people with diabetes.
New outcome trials in people with diabetes
A number of outcome studies of macrovascular endpoin\ts in patients with type 2 diabetes exclusively are currently underway.
Glucose-lowering studies in patients with diabetes
Thiazolidinediones (TZDs) have only become available during the past few years, thus their effects have not been reported previously from any long-term outcome-based trials. A series of studies evaluating the effects of pioglitazone on the progression of atherosclerosis are ongoing.
The PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive) in patients with type 2 diabetes and clinical evidence of macrovascular disease is one of these studies26.
Rationale for PROactive
Pioglitazone is known to improve glycaemic control and also possesses additional properties that may have an impact on clinical vascular outcomes. Assessment of the non-hypoglycaemic effects of pioglitazone show improvements in several CV risk factors, including modification of lipids and independent predictors of CHD (e.g. microalbuminuria and plasminogen activator inhibitor1) and reductions in carotid intima-media thickness that could decrease morbidity for macrovascular disease27-34. PROactive tests the hypothesis that pioglitazone reduces total mortality and macrovascular morbidity in high-risk patients with type 2 diabetes and also examines its effects on individual risk factors for vascular complications.
Design of PROactive
PROactive is a randomized, double-blind, placebo-controlled outcome study in more than 5000 patients with type 2 diabetes, managed with diet and/or oral blood glucose-lowering drugs, who are at increased CV risk. Patients are randomized to receive ‘add-on’ therapy with pioglitazone (increased stepwise from 15 mg to 30 mg to 45 mg, dependent on tolerability), or placebo, to their existing medications for management of hyperglycaemia, dyslipidaemia, thrombosis and hypertension, which are to be continuously optimized throughout the trial according to the International Diabetes Federation (IDF) Europe Guidelines35 to allow patients to receive the best possible available therapy. The primary endpoint is the time from randomization to occurrence of a new macrovascular event or death. Follow-up is estimated to span 4 years and the first presentation of the results is expected in late 2005.
Summary of the baseline PROactive data
A total of 5238 patients have been randomized from 19 European countries. At entry into the study, patients were a mean age of 61.8 years with type 2 diabetes for a mean of 9.5 years. Patients met one or more of the entry criteria of: a history of myocardial infarction (46.7%), coronary artery revascularization (30.8%), or stroke (18.8%) for ≥6 months, acute coronary syndrome for ≥ 3 months (13.7%), other evidence of coronary artery disease (48.1%) or symptomatic peripheral arterial disease (19.9%). Half (48.5%) of the patients had two or more of these risk factors. In addition, three- quarters (75.4%) had hypertension. Almost all patients were on CV medications (95%) and 84% were on antiplatelet therapy. However, only half of the patients (52%) were receiving lipid-lowering therapy (mainly statins) and 63% were receiving ACE inhibitors. With respect to glucose-lowering therapies, 60.9% and 61.5% were taking metformin or a sulfonylurea, respectively, and 33.6% were using insulin in addition to oral glucose-lowering drugs.
Potential implications of PROactive
The cohort of patients enrolled in PROactive is a typical type 2 diabetic population at high risk for further macrovascular events. The characteristics of this population are ideal for assessing the ability of pioglitazone to reduce the cardiovascular risk of patients with type 2 diabetes. Despite the fact that the patients entered into the PROactive study are at high risk for CV events, it is clear from the baseline data that not all patients were receiving adequate therapies during everyday clinical practice. Hopefully, the results of the PROactive study will go someway to helping clinicians understand the unique nature of vascular disease in diabetes and the importance of broad-based treatment of the multiple metabolic risk factors for CVD in people with diabetes.
RECORD
The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study is assessing whether the combination of rosiglitazone plus either metformin or sulfonylurea may be superior to the combination of metformin plus sulfonylurea for cardiovascular outcomes in people with type 2 diabetes. This 6- year study, planned to be completed in 2009, involves 3966 subjects with diabetes inadequately controlled on metformin or sulfonylurea36.
Statin studies in patients with diabetes
A primary prevention strategy is currently being tested in the Atorvastatin Study in Preventing Endpoints in type 2 diabetes (ASPEN).
Fibrate studies in patients with diabetes
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study involves more than 9000 people with type 2 diabetes. Patients have been randomized to fenofibrate or placebo. The primary endpoint of this study is coronary mortality and completion is due in early 200537.
Conclusions
There are few data on the effects of pharmacological intervention on the risk of CV events in patients with diabetes exclusively. Most of what we know to date comes from subgroups of people with diabetes that have been included in large-scale, landmark trials. There is a growing body of evidence that demonstrates the impact of lipid- lowering agents on CV outcome in subgroups of people with diabetes. A recent study, CARDS, has assessed the use of a statin in the primary prevention of CV events exclusively in patients with diabetes. Randomized clinical trials suggest that the TZDs have a positive effect on diabetic dyslipidaemia, but no studies have so far investigated if this will translate into clinical outcome benefits. Ongoing trials, such as PROactive, have been designed to look at the influence of glycaemic control on CV outcome in patients with diabetes and data are expected in late 2005.
Acknowledgements
I have received consulting fees/honoraria for lectures/ consultation from Bayer-AG, GlaxoSmithKline, Astra-Zeneca, Merck, Sharp and Dohme, Takeda, Aventis, Sanofi and local healthcare organizations in Germany.
I would like to thank Takeda for supporting this supplement with an educational grant. The views presented in this article are entirely my own and have not been influenced in any way by Takeda, nor has Takeda been involved in its preparation.
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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com
Paper CMRO-2863C_4, Accepted for publication: 04 February 2005
Published Online: 07 March 2005
doi:10.1185/030079905X36477
M. Hanefeld
Centre for Clinical Studies, GWT Technical University, Dresden, Germany
Address for correspondence: Direktor Prof. Dr. med. Habit. M. Hanefeld, Forschungshereich Endokrinologie und Stoffwechsel, Zentrum fur Klinische Studien, GWT-TUD mbH, Fiedlerstrasse 34, U1307 Dresden, Germany. Tl.: +49-3514-40-06-82; Fax: +49-3514-40-06-81; email: [email protected]
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