Major Macrovascular Events Research Articles

Intensive glucose control and macrovascular outcomes in type 2 diabetes

Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes. A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified. A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84-0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76-0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90-1.20) and 1.10 for cardiovascular death (95% CI 0.84-1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91-3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89-1.13, vs HR 0.84, 95% CI 0.74-0.94, respectively; interaction p = 0.04). Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.

Combined Effects of Routine Blood Pressure Lowering and Intensive Glucose Control on Macrovascular and Microvascular Outcomes in Patients With Type 2 Diabetes

OBJECTIVETo assess the magnitude and independence of the effects of routine blood pressure lowering and intensive glucose control on clinical outcomes in patients with long-standing type 2 diabetes.RESEARCH DESIGN AND METHODSThis was a multicenter, factorial randomized trial of perindopril-indapamide versus placebo (double-blind comparison) and intensive glucose control with a gliclazide MR–based regimen (target A1C ≤6.5%) versus standard glucose control (open comparison) in 11,140 participants with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. Annual event rates and risks of major macrovascular and microvascular events considered jointly and separately, renal events, and death during an average 4.3 years of follow-up were assessed, using Cox proportional hazards models.RESULTSThere was no interaction between the effects of routine blood pressure lowering and intensive glucose control for any of the prespecified clinical outcomes (all P > 0.1): the separate effects of the two interventions for the renal outcomes and death appeared to be additive on the log scale. Compared with neither intervention, combination treatment reduced the risk of new or worsening nephropathy by 33% (95% CI 12–50%, P = 0.005), new onset of macroalbuminuria by 54% (35–68%, P < 0.0001), and new onset of microalbuminuria by 26% (17–34%). Combination treatment was associated with an 18% reduction in the risk of all-cause death (1–32%, P = 0.04).CONCLUSIONSThe effects of routine blood pressure lowering and intensive glucose control were independent of one another. When combined, they produced additional reductions in clinically relevant outcomes.

Blood Pressure Lowering and Outcomes in type 2 Diabetes: Implications of the Blood Pressure-Lowering Arm of the Advance Trial

This review focuses on trials that have examined the relationship between blood pressure (BP) lowering strategies and cardiovascular and renal outcomes in subjects with type 2 diabetes. In particular, we highlight the results of the recently completed BP-arm of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation) study. Active therapy with perindopril and indapamide compared with placebo significantly reduced blood pressure (134.7/74.8 vs 140.4/77.0 mmHg) and the primary endpoint of the trial, a composite of major macrovascular and microvascular events. Active therapy also reduced the secondary end points of cardiovascular death and development of renal events. Importantly, the study shows that in a group of patients with BP levels within the range that would not usually be classified as hypertensive, further reductions in BP resulted in clinically significant cardiovascular and renal benefits. It supports the combination of perindopril and indapamide as an effective BP lowering strategy in type 2 diabetes. However, as other BP lowering strategies were not compared, the BP-lowering arm of the ADVANCE study does not answer the question as to what is the best medication or combination of medications that should be employed to reduce BP levels in type 2 diabetes.

Blood pressure and glucose control in subjects with diabetes: new analyses from ADVANCE

To evaluate among individuals with diabetes whether major microvascular and macrovascular events are reduced by: (1) blood pressure lowering with a perindopril/indapamide combination compared with placebo; (2) intensive glucose control (targeting a haemoglobin A1c level of < or =6.5%) with a gliclazide MR-based regimen, compared with usual care. Participants with diabetes aged 55 years and older with at least one additional vascular risk factor were randomly assigned, using a 2 x 2 factorial design, to additional blood pressure lowering versus placebo and intensive versus standard glucose control. The primary outcomes were macrovascular (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) and microvascular (new or worsening nephropathy or retinopathy) events jointly and separately. A total of 11 140 participants were randomly assigned to the blood pressure and glucose-lowering arms, which ended after 4.3 and 5.5 years, respectively. The effects of the two interventions were independent and additive on prespecified endpoints. Compared with placebo, additional blood pressure lowering of 5.6/2.2 mmHg was associated with reductions of 9% in the primary endpoint (P = 0.041), 18% in cardiovascular death (P = 0.027), 14% in total mortality (P = 0.025), and 21% in total renal events (P < 0.01). Compared with standard glucose control, intensive control (mean in-trial 0.67 percentage point reduction in haemoglobin A1c level) was associated with reductions of 10% in the primary endpoint (P = 0.013), 14% in major microvascular events (P = 0.01) and 11% in total renal events (P < 0.001). Additional blood pressure lowering and intensive glucose control, as achieved in ADVANCE, produce independent benefits and, when combined, substantially reduced cardiovascular mortality and all-cause mortality and improved renal outcomes.

Routine blood pressure lowering and intensive glucose control in patients with Type 2 diabetes: the ADVANCE trial

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial investigated the effects of routine blood pressure lowering and intensive blood glucose control on major vascular events in people with Type 2 diabetes. In this factorial randomized study, 11,140 individuals with Type 2 diabetes were randomly assigned to a fixed combination of perindopril and indapamide or matching placebo, and to intensive glucose control with the use of modified-release gliclazide plus other drugs required to achieve a hemoglobin A1c of 6.5% of less, or standard guideline-based glucose control. The primary outcomes were composites of major macrovascular and major microvascular events (major vascular events), analyzed jointly and separately. Active treatment in the blood pressure-lowering arm reduced blood pressure by 5.6/2.2 mmHg compared with placebo, and the relative risks of major vascular events, all deaths and cardiovascular deaths by 9% (p = 0.043), 14% (p = 0.025) and 18% (p = 0.027), respectively. These effects appeared independent of the initial blood pressure level or the use of concomitant treatments. Intensive glucose control lowered glycated hemoglobin levels to a mean of 6.5% and reduced the relative risk of major vascular events by 10% (p = 0.01), primarily through a 21% (p = 0.006) reduction in nephropathy. Intensive glucose control was not associated with a significant reduction in macrovascular events; however, unlike reports from the recently reported Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, there was no evidence of any increase in all-cause mortality or cardiovascular death with more intensive glucose control. This trial has provided important new evidence with direct implications for clinical management of blood pressure and blood glucose in patients with Type 2 diabetes.

Intensive glucose control did not prevent important complications in type 2 diabetes

A Patel Dr A Patel, University of Sydney, Sydney, New South Wales, Australia; apatel@george.org.au In type 2 diabetes, does intensive glucose control prevent adverse outcomes more than standard glucose control?...

Efficacité et tolérance de lʼassociation fixe perindopril / indapamide dans le diabète de type 2: résultats de lʼétude ADVANCE

Objectives The ADVANCE trial was designed to determine the effects of routine blood pressure lowering using a fixed combination of perindopril–indapamide on major vascular outcomes in patients with type 2 diabetes, regardless of initial blood pressure levels or the use of other blood pressure-lowering drugs, including angiotensin-converting enzyme inhibitors. Methods After a 6-week run-in period, 11 140 high-risk individuals with type 2 diabetes were randomized to fixed combination perindopril–indapamide or matching placebo, in addition to current therapy. The two primary outcomes were composites of major macrovascular and major microvascular events, analysed jointly and separately by intention to treat. Results The reduction in blood pressure in participants assigned to active treatment was 5.6/2.2 mmHg greater than that observed in the control group. Active treatment reduced the risk of the combined primary outcome, a major macrovascular or microvascular event by 9% (P = 0.041) and resulted in a 14% (P = 0.025) reduction in all-cause mortality and an 18% (P = 0.027) reduction in cardiovascular mortality. There were reductions of 14% (P = 0.02) in total coronary events and 21% (P < 0.0001) in total renal events. The treatment was well tolerated, with 73% and 74% of patients in the active treatment and placebo groups still adherent to randomized therapy after an average of 4.3 years of follow-up. Conclusions Routine treatment with the fixed combination of perindopril and indapamide was well tolerated and reduced the risk of death and major vascular events, regardless of the initial blood pressure level or concomitant treatments received. The results suggest that for every 79 patients treated in this manner, one death would be avoided over 5 years.

Efficacy and safety of fixed combination of perindopril and indapamide in type 2 diabetes: results from ADVANCE in context of available evidence

The ADVANCE trial was designed to determine the effects of routine blood pressure lowering using a fixed combination of perindopril-indapamide on major vascular outcomes in patients with type 2 diabetes, regardless of initial blood pressure levels or the use of other blood pressure-lowering drugs, including angiotensin-converting enzyme inhibitors. After a 6-week run-in period, 11,140 high-risk individuals with type 2 diabetes were randomized to fixed combination perindopril-indapamide or matching placebo, in addition to current therapy. The two primary outcomes were composites of major macrovascular and major microvascular events, analysed jointly and separately by intention to treat. The reduction in blood pressure in participants assigned to active treatment was 5.6/2.2 mmHg greater than that observed in the control group. Active treatment reduced the risk of the combined primary outcome, a major macrovascular or microvascular event by 9% (P = 0.041) and resulted in a 14% (P = 0.025) reduction in all-cause mortality and an 18% (P = 0.027) reduction in cardiovascular mortality. There were reductions of 14% (P = 0.02) in total coronary events and 21% (P < 0.0001) in total renal events. The treatment was well tolerated, with 73% and 74% of patients in the active treatment and placebo groups still adherent to randomized therapy after an average of 4.3 years of follow-up. Routine treatment with the fixed combination of perindopril and indapamide was well tolerated and reduced the risk of death and major vascular events, regardless of the initial blood pressure level or concomitant treatments received. The results suggest that for every 79 patients treated in this manner, one death would be avoided over 5 years.

Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes

In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain. We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), assessed both jointly and separately. After a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006), with no significant effect on retinopathy (P=0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001). A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. (ClinicalTrials.gov number, NCT00145925.)

Blood pressure lowering with fixed combination perindopril–indapamide: key findings from ADVANCE

ADVANCE was planned to investigate the effects of routine blood pressure lowering with the fixed combination perindopril-indapamide on major vascular events in people with type 2 diabetes, irrespective of initial blood pressures or the use of other blood pressure-lowering drugs, including angiotensin-converting enzyme inhibitors. A total of 11140 individuals with type 2 diabetes were randomly assigned to fixed combination perindopril-indapamide or matching placebo, after a 6-week run-in period. The primary outcomes were composites of major macrovascular and major microvascular events, analysed jointly and separately, by intention to treat. Active treatment reduced blood pressure by 5.6/2.2 mmHg compared with placebo and the relative risks of all deaths, cardiovascular deaths and major vascular events, by 14% (P = 0.025), 18% (P = 0.027) and 9% (P = 0.041), respectively. There were also reductions in total coronary events (14%; P = 0.02) and total renal events (21%; P < 0.0001). Study treatment was well tolerated, with 73% and 74% of participants who received active treatment and placebo, respectively, still adherent to randomized therapy after an average of 4.3 years of follow-up. Routine treatment with the fixed combination perindopril-indapamide, on top of all concomitant protective therapies, was well tolerated and reduced the risks of death and vascular disease irrespective of the initial level of blood pressure. The results suggest that for every 79 patients so treated, one death would be averted over 5 years.

Perindopril plus indapamide reduced death and major macrovascular and microvascular events in type 2 diabetes

Perindopril plus indapamide reduced death and major macrovascular and microvascular events in type 2 diabetes

The prevention of the hypertension related damage in type-2 diabetes: the first step of the ADVANCE trial

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. After a mean of 4.3 years of follow-up, 73% of those assigned to active treatment (fix combination of 4/1.25 mg perindopril/indapamide) and 74% of those assigned to control remained on randomised treatment. Compared with patients assigned to placebo, those assigned to active therapy had a mean reduction in blood pressure of 5.6/2.2 mm Hg. The relative risk of a major macrovascular or microvascular event was reduced by 9% (861 [15.5%] active vs 938 [16.8%] placebo; hazard ratio 0.91, 95% CI 0.83-1.00, p = 0.04). The fix combination of perindopril and indapamide could be the best possible protector against hypertension-related consequences for patients with type 2 diabetes mellitus.

Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial

Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes, and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension. We assessed the effects of the routine administration of an angiotensin converting enzyme (ACE) inhibitor-diuretic combination on serious vascular events in patients with diabetes, irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs. The trial was done by 215 collaborating centres in 20 countries. After a 6-week active run-in period, 11 140 patients with type 2 diabetes were randomised to treatment with a fixed combination of perindopril and indapamide or matching placebo, in addition to current therapy. The primary endpoints were composites of major macrovascular and microvascular events, defined as death from cardiovascular disease, non-fatal stroke or non-fatal myocardial infarction, and new or worsening renal or diabetic eye disease, and analysis was by intention-to-treat. The macrovascular and microvascular composites were analysed jointly and separately. This trial is registered with ClinicalTrials.gov, number NCT00145925. After a mean of 4.3 years of follow-up, 73% of those assigned active treatment and 74% of those assigned control remained on randomised treatment. Compared with patients assigned placebo, those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg. The relative risk of a major macrovascular or microvascular event was reduced by 9% (861 [15.5%] active vs 938 [16.8%] placebo; hazard ratio 0.91, 95% CI 0.83-1.00, p=0.04). The separate reductions in macrovascular and microvascular events were similar but were not independently significant (macrovascular 0.92; 0.81-1.04, p=0.16; microvascular 0.91; 0.80-1.04, p=0.16). The relative risk of death from cardiovascular disease was reduced by 18% (211 [3.8%] active vs 257 [4.6%] placebo; 0.82, 0.68-0.98, p=0.03) and death from any cause was reduced by 14% (408 [7.3%] active vs 471 [8.5%] placebo; 0.86, 0.75-0.98, p=0.03). There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline. Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events, including death. Although the confidence limits were wide, the results suggest that over 5 years, one death due to any cause would be averted among every 79 patients assigned active therapy.

Effect of intensive diabetes management on macrovascular events and risk factors in the diabetes control and complications trial

The Diabetes Control and Complications Trial (DCCT), a multicenter, randomized, controlled clinical trial, demonstrated that intensive diabetes therapy delays the onset and slows the progression of retinopathy, nephropathy, and neuropathy in patients with insulin-dependent diabetes mellitus. This study presents the effect of intensive therapy on atherosclerosis-related events and associated risk factors. Patients (n = 1,441) between the ages of 13 and 39 years with insulin-dependent diabetes mellitus were randomly assigned to conventional or intensive diabetes treatment. The patients were free of cardiovascular disease at baseline. Patients with hypertension, hypercholesterolemia, or obesity were excluded. Average length of follow-up was 6.5 years (range 3.5 to 9). The study used standardized definitions of macrovascular events, verification of such events, and central laboratories for determination of lipids and the grading of electrocardiograms. The number of combined major macrovascular events was almost twice as high in the conventionally treated group (40 events) as in the intensive-treatment group (23 events), although the differences were not statistically significant (p = 0.08). There were no differences in the cumulative incidence of hypertension. Mean total serum cholesterol, calculated low-density lipoprotein cholesterol, and triglycerides were significantly reduced in the intensive-treatment group (p < or = 0.01), as was the development of low-density lipoprotein cholesterol levels > 160 mg/dl. Weight gain was significantly increased in the intensive-treatment group (p < 0.001). There were no differences in cigarette smoking habits, consumption of alcohol, or aspirin use between treatment groups. The reduction in some, but not all, cardiovascular risk factors suggests a potential beneficial effect of intensive therapy on macrovascular disease in insulin-dependent diabetes mellitus.