Macrovascular Endpoints Research Articles

Levels of MDA-LDL in Circulating Immune Complexes Predict Myocardial Infarction in the Veterans Affairs Diabetes Trial (VADT) Cohort

Synopsis: In previous studies, authors have demonstrated a relationship between modified low-density lipoprotein (LDL) and cardiovascular disease (CVD); however, few have examined the relationship between the content of modified LDL in circulating immune complexes (ICs) and CVD, even though the majority of modified LDL in plasma circulates as part of immune complexes. Purpose: To determine whether high levels of oxidized LDL (oxLDL), malondialdehyde-LDL (MDA-LDL), and advanced glycation end products-LDL (AGE-LDL) in circulating IC are associated with incident cardiovascular events in the VADT cohort of type 2 diabetes (T2DM). Methods: We performed prospective analyses to determine associations between modified LDL-IC and vascular end points among 907 VADT subjects (mean age 59.8 years; 96.8% male; 40.9% minority). Modified LDL-IC were measured a median of 2 years after entry into the VADT study, and participants were subsequently followed an average of 3.7 years for outcomes. Cox proportional hazard models were used to calculate hazard ratios (HRs) for macrovascular end points in relation to modified LDL-IC quartile. The primary composite end point included documented myocardial infarction (MI); stroke; death from cardiovascular causes; new or worsening congestive heart failure; surgical intervention for cardiac, cerebrovascular, or peripheral vascular disease; inoperable coronary artery disease; and amputation for ischemic gangrene. Results: During follow-up, 16.8%, 4.7% and 6.4% of participants had a primary composite end point, MI or death, respectively. After wed adjusted for age, minority status, treatment arm, whether an individual had an event before the VADT, as well as systolic blood pressure (SBP) level, LDL-C level and statin use at the time of IC measurement, individuals in the highest quartile of MDALDL IC as compared with individuals in the lowest quartile of MDA-LDL IC were at greater risk of MI (hazard ratio [HR] 2.44; 95% confidence interval [95% CI] 1.0325.77) and the composite end point (HR 1.71; 95% CI 1.0422.80) but similar risk of all-cause mortality (HR 1.15; 95% CI 0.5222.52). In contrast, oxLDL-IC and AGE-LDL-IC were not associated with cardiovascular events. Moreover, subsequent analysis found that individuals with high MDA-LDL IC and low oxLDL-LDL IC were at particularly high risk of MI relative to individuals with low MDA-LDL IC and low oxLDL-IC (HR 3.46; 95% CI 1.5227.87). Results were similar when AGELDL IC was substituted for oxLDL-IC (HR 2.56; 95% CI 1.0626.20). Conclusions: Our study indicates that high levels of MDALDL in isolated IC predict future MI and cardiovascular events in patients with T2DM and supports distinct roles of different modified forms of LDL in the occurrence of macrovascular events.

Abstract P023: Relationship Between Vitamin D Status and Incidence of Macro-vascular Events in the Veterans Affairs Diabetes Trial (VADT)

BACKGROUND: Few studies have examined the relationship between vitamin D levels and incident cardiovascular events in large well-characterized type 2 diabetes cohorts. METHODS: We performed prospective analyses to determine associations between vitamin D status and vascular endpoints among 936 Veterans Affairs Diabetes Trial (VADT) participants (mean age 59.7 years; 96.7% male; 40.4% minority). 25 (OH)-vitamin D was measured a median of two years after entry into the VADT study and participants were subsequently followed an average of 3.7 years for outcomes. Cox proportional hazard models were used to calculate hazard ratios (HRs) for macrovascular endpoints in relation to vitamin D quartile. The primary composite endpoint included documented myocardial infarction; stroke; death from cardiovascular causes; new or worsening congestive heart failure; surgical intervention for cardiac, cerebrovascular, or peripheral vascular disease; inoperable coronary artery disease; and amputation for ischemic gangrene. RESULTS: On average VADT participants had high cardiovascular risk at entry into the study: 65.3% of the patients recruited were obese, 38.5% had previously had a vascular event, 78.7% had hypertension and 59.5% were using statins. During follow-up, 17.2%, 5.0%, 5.9%, 2.4% and 6.6% of participants had a primary composite endpoint, myocardial infarction, chronic heart failure, cardiovascular death or all-cause death, respectively. After adjusting for age, minority status, treatment arm and history of prior event, individuals in the lowest quartile of vitamin D (i.e., 1 to 15.9 ng/ml) were at similar risk of the primary composite endpoint [HR=1.26 (95% CI: 0.81, 1.96)], myocardial infarction [HR=1.13 (95% CI: 0.53, 2.42)], congestive heart failure [HR=1.44 (95% CI: 0.67, 3.06)], cardiovascular death [HR=0.86 (95% CI: 0.28, 2.63)], and death from any cause [HR=1.04 (95% CI: 0.53, 2.04)] as individuals in the highest quartile of vitamin D (i.e., 29.9 to 77.2 ng/ml). CONCLUSIONS: These data indicate that vitamin D status had no significant impact on the incidence of macrovascular events in a cohort of high-risk veterans with type 2 diabetes mellitus in which traditional risk factors were managed according to current treatment guidelines. SUPPORT: This work was supported by American Heart Association Grant-in-Aid AHA0755466U and the Research Service of the Charleston SC VA Medical Center.

The role of antihypertensive therapy in reducing vascular complications of type 2 diabetes. Findings from the DIabetic REtinopathy Candesartan Trials-Protect 2 study

Recent trials question previously accepted low blood pressure targets in type 2 diabetes to reduce complication risk. We explored this question in the DIabetic REtinopathy Candesartan Trials-Protect 2 clinical trial. A total of 1905 normoalbuminuric participants with type 2 diabetes and mild-moderate retinopathy were randomized to candesartan or placebo. Participants were normotensive [untreated, blood pressure (BP) < 130/85 mmHg] or treated hypertensive [(62%), BP < 160/90 mmHg]. The effects of candesartan on microvascular and macrovascular endpoints alone and in combination were analysed, including subgroup analyses by baseline hypertension status. Mean age was 57 ± 8 years, 50% were men, mean diabetes duration was 9 ± 5 years and baseline HbA1c was 8.2 ± 1.6%. Mean randomization BP was 123/75 mmHg in the normotensive, and 139/79 mmHg in the treated hypertensive subgroups. During the median 4.7-year follow-up, achieved systolic pressure on candesartan was 128 mmHg in baseline normotensive individuals, and 136 mmHg in treated hypertensive patients. Candesartan reduced combined macrovascular and microvascular complication risk; the age and baseline SBP overall adjusted hazard ratio for candesartan vs. placebo was 0.85 [95% confidence interval (CI) 0.72-0.99], P = 0.040, reflecting hazard ratios of 0.86 (0.66-1.13) for baseline normotensive individuals and 0.83 (0.68-1.02) for hypertensive patients. Hazard ratios were 0.87 (0.74-1.04) for microvascular and 0.84 (0.57-1.25) for macrovascular complications, when analysed separately. However, an interaction (P = 0.06) between hypertensive [hazard ratio 0.67 (0.42-1.07)] and normotensive (1.45, 0.71-2.94) subgroups was observed for macrovascular events. Candesartan modestly reduces vascular complication risk in treated hypertensive diabetic individuals at low risk of cardiovascular disease. Separate analyses of microvascular and macrovascular events suggest that candesartan may not reduce macrovascular events in normotensive persons with type 2 diabetes.

Clinical practice and implications of recent diabetes trials

Diabetes is an increasingly prevalent risk factor for coronary and other vascular disease. Recent trials in patients with diabetes have examined the effects of intensive glycemic control on cardiovascular outcomes, and treatment of common concomitant risk factors, in particular hypertension and dyslipidemia. Optimal revascularization strategies have also been examined. Intensive glycemic control has a beneficial effect on microvascular but not macrovascular endpoints, with one major trial reporting increased mortality out to 5 years with intensive treatment. Similarly, aggressive lowering of SBP to below 120 mmHg produced no advantage over treatment to 130-140 mmHg. Statins are the best treatment for diabetic dyslipidemia, with little benefit from adding a fibrate. Medical treatment may be appropriate for many with diabetes and stable coronary disease. When revascularization is needed, coronary bypass graft surgery has an advantage over percutaneous coronary intervention in those at the severe end of the coronary disease spectrum. Patients with type 2 diabetes often have multiple cardiovascular risk factors and require multiple cardiac and diabetes medications. Caution over aggressive glucose and blood pressure lowering is needed, at least with currently available drugs.

Early and Intensive Therapy for Management of Hyperglycemia and Cardiovascular Risk Factors in Patients With Type 2 Diabetes

Background Type 2 diabetes mellitus (T2DM) results in significant morbidity and mortality. Results of recent randomized controlled trials demonstrated the ability of early and intensive therapy to reduce the risk of microvascular complications. However, controversy surrounds the ability of such therapy to reduce the risk for macrovascular complications. Objectives This article reviews results from recent clinical trials in patients with T2DM as well as extended follow-up of earlier trials to determine if early, intensive, and individualized therapy aimed at the underlying pathogenesis of the disease could decrease the risk for long-term complications, including cardiovascular disease (CVD). Methods Information was obtained by a search of the PUBMED and EMBASE databases using the search terms type 2 diabetes mellitus, glycosylated hemoglobin, pathophysiology of type 2 diabetes, glycemic control, early intervention, multifactorial intervention, cardiovascular disease, β-cell function, and antidiabetes therapy for the period between 1995 and 2010. Articles dealing with outcomes trials, impact of therapy on microvascular and macrovascular complications, effects of therapeutic agents on the pathophysiology of T2DM, and the impact of agents on CV risk factors were then preferentially selected for in-depth review. Results Large-scale clinical trials in patients with T2DM, although largely negative at 5 years for macrovascular end points, suggested benefit for patients with a shorter duration of T2DM (ie, <10 years) and still supported a treatment strategy of early, intensive, and individualized therapy to prevent long-term complications of the disease. In Steno-2, after 13 years of follow-up, early, intensive, multifactorial therapy was associated with a 56% lower risk of all-cause death ( P = 0.02) and a 57% lower risk of death from CVD ( P = 0.04). In the 10-year follow-up to the United Kingdom Prospective Diabetes Study, intensive therapy was associated with a significant 15% reduction in the risk of myocardial infarction ( P = 0.01) and a significant 13% reduction in the risk of death from any cause ( P = 0.007). Therapy should be aimed at correcting underlying pathophysiologic defects, including β-cell failure and insulin resistance, and should also correct underlying risk factors for CVD whenever possible. Conclusions Early and intensive antidiabetes treatment was recommended in patients with T2DM, particularly those with a shorter duration of disease and without a history of CVD. The goal was to safely lower glycosylated hemoglobin to <7%, therefore providing beneficial effects on the risk for complications. Hypoglycemia should be avoided. In addition, less aggressive treatment might be suitable for older patients with longstanding diabetes and a history of CVD events. Clinical trial results also provided support for a second important aspect of individualized treatment for patients with T2DM—multifactorial intervention aimed at controlling CVD risk factors.

ACCORD: Blood Pressure and Lipid Results

The ACCORD trial is best known for its findings, published in 2008, on the effect of glycemic control on macrovascular endpoints. Older patients (mean

Shifting the Disease Management Paradigm From Glucose

With the worldwide growing prevalence of obesity and type 2 diabetes, cardiovascular disease (CVD), diabetic nephropathy, retinopathy, and neuropathy as principal complications of diabetes are expected to become a major public health challenge. Diabetes accounts for at least double the number of death rates compared with otherwise healthy individuals. Hyperglycemia represents the hallmark of diabetic metabolic changes, but whether antihyperglycemic treatment alone is sufficient to prevent cardiovascular and other organic complications in type 2 diabetes is a matter of debate. A recent meta-analysis of epidemiological studies reported an 18% increase in CVD risk for every 1% increase in A1C (1). Two major studies have underlined the importance of optimal glycemic control in reducing diabetes-related complications. The U.K. Prospective Diabetes Study (UKPDS) showed that intensive glycemic control (mean A1C below 7%) by means of insulin or oral agents in type 2 diabetic patients reduces the relative risk for microvascular outcomes by 25% over a period of 10 years (relative risk reduction). The reduction in macrovascular end points (myocardial infarction) was of borderline significance (16% relative risk reduction, P = 0.052) (2). The Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) trial reported a 50% reduction in CVD outcomes in type 1 diabetic patients treated intensively over a period of 6.5 years and followed for a further 12 years (3). In contrast to these data, the intensive glucose-lowering arm of the Action to Control Cardiovascular Risk (ACCORD) trial—a major trial in type 2 diabetic patients—has been recently stopped because of increased mortality in this group (4). The ACCORD trial was set up to test three complementary medical treatment strategies for type 2 diabetes to reduce CVD morbidity and mortality. Aggressive reduction of A1C below 6%, combined increase in HDL cholesterol, and reduction of LDL cholesterol and lowering of blood …

HOME reveals new data on a cornerstone of treatment

A question often asked by health-care providers is whether metformin has added benefits if continued after patients with type 2 diabetes mellitus switch to insulin. Beneficial effects on macrovascular end points observed in response to sustained metformin therapy argue in favor of this approach, according to new research from The netherlands.

Long-term Effects of Metformin on Metabolism and Microvascular and Macrovascular Disease in Patients With Type 2 Diabetes Mellitus

We investigated whether metformin hydrochloride has sustained beneficial metabolic and (cardio) vascular effects in patients with type 2 diabetes mellitus (DM2). We studied 390 patients treated with insulin in the outpatient clinics of 3 hospitals in a randomized, placebo-controlled trial with a follow-up period of 4.3 years. Either metformin hydrochloride, 850 mg, or placebo (1-3 times daily) was added to insulin therapy. The primary end point was an aggregate of microvascular and macrovascular morbidity and mortality. The secondary end points were microvascular and macrovascular morbidity and mortality, as separate aggregate scores. In addition, effects on hemoglobin A(1c) (HbA(1c)), insulin requirement, lipid levels, blood pressure, body weight, and body mass index were analyzed. Metformin treatment prevented weight gain (mean weight gain, -3.07 kg [range, -3.85 to -2.28 kg]; P < .001), improved glycemic control (mean reduction in HbA(1c) level, 0.4% percentage point [95% CI, 0.55-0.25]; P < .001) (where CI indicates confidence interval), despite the aim of similar glycemic control in both groups, and reduced insulin requirements (mean reduction, 19.63 IU/d [95% CI, 24.91-14.36 IU/d]; P < .001). Metformin was not associated with an improvement in the primary end point. It was, however, associated with an improvement in the secondary, macrovascular end point (hazard ratio, 0.61 (95% CI, 0.40-0.94; P = .02), which was partly explained by the difference in weight. The number needed to treat to prevent 1 macrovascular end point was 16.1 (95% CI, 9.2-66.6). Metformin, added to insulin in patients with DM2, improved body weight, glycemic control, and insulin requirements but did not improve the primary end point. Metformin did, however, reduce the risk of macrovascular disease after a follow-up period of 4.3 years. These sustained beneficial effects support the policy to continue metformin treatment after the introduction of insulin in any patient with DM2, unless contraindicated. Trial Registration ClinicalTrials.gov Identifier: NCT00375388.

Prevalence, Characteristics, and Prognostic Significance of HFE Gene Mutations in Type 2 Diabetes

OBJECTIVE—To examine the relationship between iron status, hereditary hemochromatosis (HFE) gene mutations, and clinical features and outcomes of type 2 diabetes in a well-characterized representative sample of community-based patients.RESEARCH DESIGN AND METHODS—HFE genotype data were available for 1,245 type 2 diabetic patients from the longitudinal observational Fremantle Diabetes Study (FDS), representing 96.2% of the total FDS type 2 diabetes cohort. Data were collected at recruitment between 1993 and 1996 and annually until the end of June 2001. Hospitalization and mortality data were available until the end of June 2006. The presence of the C282Y HFE mutation was determined in all subjects and H63D in C282Y heterozygotes. Fasting serum iron, transferrin, and ferritin were measured in all C282Y homozygotes and C282Y/H63D heterozygotes and in 286 randomly selected wild-type subjects. Multiple logistic regression analysis was performed to determine independent baseline associates of prevalent complications (myocardial infarction, cerebrovascular disease, retinopathy, neuropathy, and nephropathy), as was Cox proportional hazards modeling to determine predictors of incident complications and mortality.RESULTS—Although there were expected positive associations between HFE gene mutations and serum iron and transferrin saturation, there were no independent positive associations between HFE gene status and either microvascular or macrovascular complications in cross-sectional and longitudinal analyses. HFE gene status did not independently predict cardiac or all-cause mortality. Measures of iron metabolism including serum ferritin were not associated with combined microvascular or macrovascular end points.CONCLUSIONS—Directed screening for iron overload and/or HFE mutations appears unwarranted in patients with type 2 diabetes.

Concluding words

As you will have read in this supplement, we are riding the crest of a wave for improving the management of type 2 diabetes mellitus (T2DM). On a day-to-day basis, it is important to manage glycaemic control, and the introduction of insulin glargine into daily practice has provided an excellent cornerstone therapy to help the patient reach goals. In this supplement, the authors have provided an in-depth discussion on how patients can better reach these goals and ways to overcome barriers commonly associated with insulin therapy. On a long-term basis, one would expect the improved glycaemic control to reduce the risk of microvascular and macrovascular complications, as demonstrated by the Kumamoto study and the UKPDS (United Kingdom Prospective Diabetes Study), for example. Moreover, the options discussed by George Dailey, which point towards a combined approach for the treatment of glycaemic control and other cardiovascular risk factors, should better reduce the overall risk of cardiovascular disease. We have now acquired in excess of 10-years experience with insulin glargine, including 7 years of clinical use, which unequivocally demonstrates consistent improvements in glycaemic control with low risk for hypoglycaemia. As discussed earlier, a combined approach is warranted to provide patients with the best level of care, and studies to evaluate the impact of insulin glargine on microvascular and macrovascular end-points as well as related complications are essential. Moreover, T2DM is characterized by a progressive insulin deficiency. At the time of diagnosis, β-cell function may be less than 50% of that in the ‘healthy’ state. This suggests that artificially restoring β-cell function, by providing exogenous insulin, could help prevent or delay the ongoing decline in function. The ongoing Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial will help address this question, which we hope will demonstrate a reduced risk of progression to overt diabetes in a population of people with impaired glucose tolerance or impaired fasting glucose. Because there is a continued β-cell function loss over time, to keep patients to a target haemoglobin A1c (HbA1c), one may have to institute a rapid-acting analogue such as insulin glulisine, aspart or lispro. In fact, when glycaemic control deteriorates, a basal–plus approach (basal insulin plus one injection of rapid-acting insulin analogue), with injection of the prandial component before breakfast or a major meal, may help more patients reach the desired HbA1c value of <7% or, better still, ≤6.5%. Eventually, many patients with T2DM will require a basal–bolus regimen to maintain target HbA1c values. In the future, I feel that it is of interest to investigate the pairing of insulin glargine with alternative therapeutic agents, such as a cannabinoid receptor 1 blocker (e.g. rimonabant) and/or incretins (glucagon-like peptide-1 agonists or dipeptidyl peptidase-IV antagonists), to evaluate the added benefits of these approaches on cardiovascular risk factors, including obesity and lipid profiles. In summary, exciting times are still ahead both for us as clinicians and also our patients with the potential for ever improving management of their diabetes. I would like to sincerely thank all the authors for their hard work and I hope you enjoyed reading this special supplement, especially with an aim to improve lives of patients with diabetes.

Focussed Section “Effect of Oral Antidiabetic Drugs on Micro- and Macrovascular Complications in Patients with Diabetes Mellitus – Update 2008”

Patients with diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. In addition, these patients have an increased risk to develop both microand macrovascular complications. Recent data suggest that this increase in cardiovascular risk is due to a clustering of risk factors in these patients like hypertension, dyslipidemia, increased platelet aggregation, endothelial dysfunction and inflammation [1]. Each of these factors is independently associated with an increased risk for cardiovascular events. Over the last years many clinical trials have focused on the reduction of cardiovascular risk in these diabetic patients. As such, studies have shown that reducing low-density lipoprotein cholesterol by a statin therapy has a major impact on the incidence of myocardial infarction and stroke [2]. In addition, lowering blood pressure is also a major tool to decrease cardiovascular morbidity and mortality in this high risk population [3]. In this context, it has been shown that some antihypertensive drugs may be more favourable in this particular population than others but overall, tight blood pressure control is one of the cornerstones to modify cardiovascular risk in patients with diabetes [4]. In addition, good evidence exists that the initiation of anti-platelet therapy decreases cardiovascular events [5]. But what about blood glucose control? Data from the United Kingdom Prospective Diabetes Study suggest that a reduction of HbA1C levels by 1% decreases the risk for both myocardial infarction and stroke by about 12–14% [6]. However, the effect of intensive glucose control on the incidence of myocardial infarction was barely significant while the effect on microvascular complications was much more pronounced [7]. The results of this landmark trial in diabetology has led to the conclusion that blood glucose lowering is also crucial to reduce cardiovascular risk in diabetic patients. Still, in contrast to many large hypertension and lipid trials, the number of clinical studies investigating the effect of anti-diabetic drugs on the incidence of macrovascular events is pretty scarce. Only a few trials directly assessed the effect of certain anti-diabetic drugs on cardiovascular morbidity and mortality and we are still lacking strong evidence that lowering HbA1C will significantly decrease cardiovascular events in diabetic patients. Given the clinical importance of this question we decided to dedicate the current issue of Current Drug Targets to the effects of different oral antidiabetic drugs and insulin on microand macrovascular complications in patients with diabetes. Five review articles address the clinical evidence of a treatment with sulfonylurea, metformin, glitazones, acarbose, or insulin and summarize the current knowledge on this topic. Overall, future studies are warranted to determine the clinical benefit of HbA1C lowering in particular with respect to macrovascular endpoints; within the next few years data from on-going trials will increase our knowledge concerning this question. Hopefully, these studies will close the gap and clarify whether glucose lowering—in addition to lipid lowering, blood pressure lowering and anti-platelet therapy—is the fourth “tool” to modify cardiovascular risk in diabetic patients. Cardiovasc Drugs Ther (2008) 22:205–206 DOI 10.1007/s10557-008-6102-2

Insulin as a First-Line Therapy in Type 2 Diabetes

Because a tidal wave of type 2 diabetes is presently rolling on a global scale, owing to the ever-increasing prevalence of obesity along with overnutrition, increasing physical inactivity, and aging populations worldwide, the debate is still ongoing over the appropriate first-line therapy. Recently, the International Diabetes Federation and the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) suggested distinct treatment algorithms (Fig. 1) (1), which have sparked the discussion even further, although there is strong agreement that weight-regulating nutrition and a prudent lifestyle are the cornerstones of any treatment. Here, the pro and con discussion explores the use of insulin versus sulfonylureas as first-line pharmacotherapy. Figure 1— ADA/EASD consensus: management of hyperglycemia in type 2 diabetes (1). ### Evidence base The landmark UK Prospective Diabetes Study (UKPDS) has published evidence-based outcome results comparing the randomized addition of insulin or sulfonylurea treatment (with glibenclamide) to lifestyle therapy after diagnosis of type 2 diabetes (2). To make a long story short, no difference between these two treatment options was observed. Both gave a similar degree of (yet overall unsatisfactory) metabolic control long term and both reduced microvascular complications significantly, but failed to reduce macrovascular end points. Both therapies were burdened by significant weight gain and the risk of serious hypoglycemic episodes (2). These downsides appeared to be more marked with insulin therapy. So, based on these data, very little evidence exists that first-line insulin therapy is superior to sulfonylurea treatment, since no other long-term studies are available at present. ### Limitations of present information Insulin therapy in the UKPDS was not very well structured and was mainly based on long-acting insulin, which more or less has been abandoned. Newer concepts of insulin therapy have not been tested, e.g., combination therapies with intermediate-acting insulins or insulin analogs with flat action profile together with oral agents, in particular with metformin. …

New insights from ADVANCE

ADVANCE (Action in Diabetes and Vascular Disease - PreterAx and DiamicroN MR Controlled Evaluation) is a large-scale clinical trial designed to investigate the benefits of blood pressure lowering and intensive glucose control in patients with type 2 diabetes mellitus. ADVANCE is a 2 x 2 factorial randomized trial evaluating the benefits of the low-dose fixed combination of perindopril and indapamide versus placebo to lower blood pressure and of an intensive gliclazide-MR-based regimen, targeting glycosylated haemoglobin (HbA1c) levels of 6.5% or less versus standard therapy to lower blood glucose. The two primary outcomes, taken separately and jointly, are a composite macrovascular endpoint and a composite microvascular endpoint. A total of 11 140 participants were randomized between July 2001 and March 2003 from among 12 878 individuals with type 2 diabetes recruited from 215 centres in 20 countries, who entered a 6-week run-in phase. The average (SD) baseline blood pressure of 145(22)/81 (11) mmHg fell by 8/3 mmHg during the run-in phase during which participants received one tablet of open-labelled perindopril 2 mg-indapamide 0.625 mg. Only 3.6% of the 12 878 patients who entered the run-in phase withdrew because of suspected intolerance to perindopril-indapamide. With over 4 years of follow-up on average so far, over 80% of participants are still adhering to randomized therapy. Follow-up of the blood pressure arm will be completed during 2007. The safety and efficacy of perindopril-indapamide in lowering blood pressure and of a gliclazide-MR-based regimen in lowering blood glucose have been established with the completion of a 6-week run-in phase and of more than 4 years of post-randomization follow-up. It is anticipated that ADVANCE will provide many new insights including: whether blood pressure lowering with perindopril-indapamide reduces the risk of both macrovascular and microvascular events irrespective of baseline blood pressure; whether more intensive blood pressure lowering with a gliclazide-MR-based regimen targeting on HbA1c levels of 6.5% or less reduces these two outcomes compared with standard guidelines therapy; and finally whether the separate benefits of these two treatment regimens are additive.

ADVANCE: breaking new ground in type 2 diabetes

ADVANCE (Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation) is a large-scale trial designed to investigate the benefits of blood pressure lowering and intensive glucose control in patients with type 2 diabetes, and to address a number of unresolved issues: whether blood pressure-lowering therapy and intensive glucose control therapy will reduce the risk of major vascular disease regardless of initial blood pressure or glucose concentration; whether more intensive glucose control targeting a haemoglobin A1c (HbA1c) level of 6.5% or less will confer greater protection against microvascular disease; and whether the benefits of the two interventions are additive. ADVANCE is a 2 x 2 factorial randomized clinical trial evaluating the risks and benefits of the low-dose fixed combination of perindopril and indapamide versus placebo to lower blood pressure and of an intensive gliclazide-MR-based glucose control regimen, targeting an HbA1c of 6.5% or less versus standard guidelines based therapy for glucose control. There are two primary outcomes: a composite macrovascular endpoint and a composite microvascular endpoint. A total of 12 878 participants from 215 centres in 20 countries entered a 6-week run-in phase between June 2001 and January 2003, and 11 140 patients were randomly assigned by March 2003. The average (SD) systolic and diastolic blood pressure fell from 145 (22)/81 (11) to 137 (20)/78 (10) mmHg during the 6-week run-in phase, during which participants received one tablet of open-labelled perindopril 2 mg/indapamide 0.625 mg. Of the 12 878 patients who entered the run-in, only 3.6% withdrew because of suspected intolerance to perindopril/indapamide. The study is half way through follow-up and both the study medications (perindopril 2 mg/indapamide 0.625 mg and gliclazide-MR) continue to be well tolerated. Completion is expected in 2007. Safe and effective blood pressure lowering with the fixed low-dose combination of perindopril and indapamide was confirmed during the run-in phase in 11 140 patients with type 2 diabetes, who were subsequently randomly assigned. Post-randomization study treatments have been well tolerated, and the completion of follow-up is scheduled in 2007.

Pioglitazone: an antidiabetic drug with cardiovascular therapeutic effects

The antidiabetic compound pioglitazone, an activator of the intracellular peroxisome proliferator-activated receptor-γ, and decreases metabolic and vascular insulin resistance. The drug is well tolerated, and its metabolic effects include improvements in blood glucose and lipid control. Vascular effects consist of improvements in endothelial function and hypertension, and a reduction in surrogate markers of artherosclerosis. In a large, placebo-controlled, outcome study in secondary prevention, PROactive study, the use of pioglitazone in addition to an existing optimized macrovascular risk management resulted in a significant reduction of macrovascular endpoints within a short observation period that was comparable to the effect of statins and angiotensin converting enzyme inhibitors in other trials. These results underline the value of pioglitazone for managing the increased cardiovascular risk of patients with a metabolic syndrome or Type 2 diabetes mellitus.

The Effectiveness of Intensive Glycemic Control for the Prevention of Vascular Complications in Diabetes Mellitus

Obesity and type 2 diabetes mellitus have reached epidemic proportions in the US, and indeed, globally. While microvascular complications contribute to considerable morbidity, much of the excess mortality (around 70%) is due to macrovascular disease. Hyperglycemia has predictable toxic effects on multiple organs ('glucotoxicity') including the pancreas, where it impairs insulin secretion and insulin gene expression through mechanisms that lead to glucose densensitization and beta-cell exhaustion, eventually resulting in irreversible beta-cell failure. There is robust evidence to suggest that strict glycemic control reduces diabetic microvascular complications (retinopathy, nephropathy, and neuropathy) in both primary- and secondary-prevention settings. While unequivocal evidence that intensive glycemic control reduces the risk of death due to macrovascular disease is lacking, meta-analytic data and controlled clinical trial data suggest there may still be clinically significant lowering of the risk for macrovascular endpoints through strict glycemic control. Cardiovascular disease in a diabetic patient is a collusion of several factors besides hyperglycemia, such as hypertension, dyslipidemia, diffuse endothelial dysfunction, hypercoagulability, and inflammation. It is important to address lifestyle issues such as maintenance of ideal bodyweight, good dietary practice, smoking cessation, and regular exercise in the comprehensive risk management of a diabetic patient, in order to reduce the vascular complications. Large, ongoing clinical trials such as ACCORD (Action to Control Cardiovascular Risk in Diabetes) are likely to establish the potential benefits of glycemic control in preventing or postponing macrovascular complications of diabetes.

ADVANCE: action in diabetes and vascular disease

The burden of Type II diabetes is growing rapidly worldwide, across high-, middle- and low-income countries. This burden is associated primarily with increased risks of macrovascular and microvascular diseases, and it is agreed that multifactorial treatment regimens are required to reduce it. ADVANCE (Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation) is a large-scale, 2 x 2 factorial, randomised clinical trial. It will investigate the potential benefits of blood pressure lowering, using a fixed low-dose combination of perindopril and indapamide vs placebo, and of tighter glucose control, using an intensive gliclazide-MR-based glucose control regimen vs a standard guidelines-based regimen, separately and together. The two primary outcomes are a composite macrovascular end point of nonfatal stroke, nonfatal myocardial infarction and cardiovascular death; and a composite microvascular end point of new or worsening nephropathy or microvascular eye disease. Following successful recruitment and randomisation of 11,140 participants by March 2003, the study is currently half way through its planned follow-up of 4.5 years. Adherence to randomised study treatment is good; and loss to follow-up is minimal. It is hoped that the study will answer a number of unresolved issues. The blood pressure lowering arm will investigate the possible reduction in major vascular disease in patients with Type II diabetes whether or not they have hypertension, and the possible benefits of blood pressure lowering in such patients already receiving background therapy with the ACE inhibitor perindopril. The glucose control arm will investigate the possible reduction in both macrovascular and microvascular disease achieved with tighter glucose control, targeting an HbA1c of 6.5% and a fasting blood glucose of 6.0 mmol/l. Finally, the factorial design will enable investigation of the combined effects of more intensive glucose control and tighter control of blood pressure.

The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review.

The UKPDS 34 showed that intensive treatment with metformin significantly reduces macrovascular end-points and mortality in individuals with newly diagnosed type 2 diabetes compared with intensive treatment with insulin or sulphonylurea derivatives, despite similar glycaemic control. How this should be explained is as yet unclear. We hypothesized that metformin may have a glucose-lowering independent effect on blood pressure and lipid profile. In order to test this hypothesis we systematically reviewed the literature and pooled the data obtained in a meta-analysis. Included were randomized-controlled trials in patients with type 2 diabetes mellitus and metformin treatment lasting at least 6 weeks. To identify all eligible trials we conducted electronic searches using the bibliographic databases Medline and Embase, contacted the manufacturer and checked obtained publications for cross-references. Forty-one studies (3074 patients) provided data on blood pressure and/or lipid profile. When compared with control treatment, metformin associated effects on systolic and diastolic blood pressure and HDL cholesterol were small and statistically not significant [-1.09 mmHg 95% confidence interval (-3.01-0.82), P = 0.30; -0.97 (-2.15-0.21) mmHg, P = 0.11 and +0.01 (-0.02-0.03) mmol L(-1), P = 0.50, respectively]. Compared with control treatment, however, metformin decreased plasma triglycerides, total cholesterol and LDL cholesterol significantly [-0.13 (-0.21--0.04) mmol L(-1), P = 0.003; -0.26 (-0.34--0.18) mmol L(-1), P < 0.0001 and -0.22 (-0.31--0.13) mmol L(-1), P < 0.00001, respectively]. We found no indications for publication bias. Of note, glycaemic control as assessed by HbA1c was better with metformin than with control treatment [-0.74 (-0.84--0.65) percentage point; P < 0.00001]. When studies were subdivided into tertiles according to increasing difference in glycaemic control between metformin and control treatment, it appeared that in case of near similar glycaemic control metformin had no effect versus control treatment on triglycerides, whereas still there was a significant effect on total and LDL cholesterol. This meta-analysis of randomized-controlled clinical trials suggests that metformin has no intrinsic effect on blood pressure, HDL cholesterol and triglycerides in patients with type 2 diabetes. This drug, however, independent of its effect on glycaemia, reduces total and LDL cholesterol significantly, but the reductions in these variables are relatively small.

Metformin and vascular protection: a cardiologist's view

The predicted global epidemic of type 2 diabetes highlights the importance of identifying the most effective ways to reduce the risk of long-term diabetic complications. Although hyperglycaemia is undoubtedly a risk factor for microvascular complications, intensive glycaemic management has delivered only modest improvements in macrovascular endpoints thus far. A multidisciplinary approach addressing the components of the dysmetabolic syndrome, including insulin resistance, dyslipidaemia, hypertension, obesity and impaired fibrinolysis, will be required to protect the cardiovascular system more effectively. The potential vascular protective effects of metformin, demonstrated by the UK Prospective Diabetes Study, may complement other strategies within such a framework.