indapamide--perindopril-drug-combination and Diabetes-Mellitus--Type-2

Much of the chronic care of patients with type 2 diabetes mellitus and hypertension involves the prevention of diabetic complications. Renin-angiotensin system inhibitors are recommended as first-line therapies because of their nephroprotective properties. Their combination with metabolically neutral diuretics is recommended to reduce blood pressure, morbidity and mortality. Our objective was to review the mechanisms by which the combination of the angiotensin-converting enzyme inhibitor, perindopril, and metabolically neutral thiazide-like diuretic, indapamide, targets the pathways involved in microvascular and macrovascular diabetic complications.. For this narrative review, extensive literature searches were performed using PubMed/Medline. Articles published in English describing clinical trials and mechanism of action studies that were relevant to the treatment of patients with perindopril and/or indapamide were included.. Perindopril/indapamide treatment has been shown to reduce blood pressure and to have significant beneficial effects on arterial distensibility, kidney structure and function, and endothelial function. Recent data also suggests that perindopril may reduce the deleterious accumulation of advanced glycation end products in diabetic tissue. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation diabetes trial, perindopril/indapamide treatment significantly reduced the relative risk of microvascular and macrovascular events by 9%, cardiovascular mortality by 18%, and all-cause mortality by 14%. Interestingly, 6 years after the end of the double-blind period, follow-up data showed that the beneficial effects on mortality continued to be significant even though differences in blood pressure and glycated hemoglobin levels had not been significant for several years. Together this data suggests that treatment with perindopril/indapamide has microvascular and macrovascular effects that extend beyond blood pressure lowering and that this treatment might confer a long-lasting beneficial vascular legacy.. Moving forward, understanding the pathophysiological bases of the effects that extend beyond those of blood pressure control will help us differentiate between anti-hypertensive choices.

Topics: Antihypertensive Agents; Blood Circulation; Diabetes Mellitus, Type 2; Drug Combinations; Humans; Hypertension; Indapamide; Perindopril

Type 2 diabetes mellitus (T2DM) accounts for 90%-95% of all diabetes cases. The overarching goal in caring for patients with T2DM is to prevent microvascular and macrovascular complications with glycemic control. Several studies such as UKPDS, DCCT, and EDIC have been performed to evaluate the effects of glucose control on tissue complications in patients with diabetes. In recent diabetes trials including ACCORD, ADVANCE, VADT, BARI 2D, and ORIGIN, intensive glucose control did not prevent macrovascular complications in older patients with long-standing diabetes with either cardiovascular disease or risk factors for cardiovascular disease. In fact, intensive therapy was associated with increased mortality in the ACCORD trial. Although no clear macrovascular benefit was seen in these trials, analyses of earlier studies in younger patients with type 1 and type 2 diabetes have suggested a significant benefit of intensive glycemic control in patients with a shorter duration of diabetes and less vasculopathy. In the UKPDS, the incidence of microvascular disease, particularly retinopathy, was reduced significantly with intensive glucose control, but in the more recent trials (ACCORD, ADVANCE, VADT, ORIGIN) the benefit was relatively modest and limited to reduced proteinuria. Perhaps the most important message from the above trials is to optimize control of cardiovascular risk factors. Although the goal HbA1c to prevent microvascular and macrovascular complications, per the American Diabetes Association, is less than 7%, hypoglycemia should be avoided as it can increase the risk for severe cardiovascular events.

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Combinations; Gliclazide; Glycated Hemoglobin; Humans; Indapamide; Perindopril; United Kingdom

Most recent meta-analyses of morbidity-mortality risk hazards brought about by the presence of diabetes as compared with non-diabetics underline the dominant risk of renal disease and cardiovascular outcomes and the relevance of blood glucose, blood pressure (BP) and cholesterol levels. The translation of this reality into therapeutic guidelines always requires interventional evidence. Evidence for combined approaches in controlling for BP and blood glucose was provided by Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation (ADVANCE), conducted in over 11 000 subjects from 20 countries. Reduction in systolic BP by 7.1 mm Hg, in diastolic BP by 2.9 mm Hg and in glycated haemoglobin A1c by 0.61% points in the combined routine BP lowering and intensive blood glucose-control group after an average 4.3 years of follow-up resulted in a relative risk reduction of 28% in renal events, 24% in cardiovascular death and 18% in all-cause mortality. While other major intervention trials performed in similar populations with analogous goals did not achieve the same level of positive therapeutic evidence and even pointed to some risk of intensified treatment of type 2 diabetes, all three major studies [Action to Control Cardiovascular Risk in Diabetes (ACCORD), Veterans Affairs Diabetes Trial (VADT) and ADVANCE] showed significant reduction in renal events, the major risk in type 2 diabetes. The divergence for other outcomes underlines the importance of considering specific therapeutic approaches for glucose control and prudent targets for BP. The current target values for glycated haemoglobin of 6.5-7% and for BP of 130/80 mmHg appear safe and beneficial. The potential long-term benefit, particularly that of initial tight blood glucose control, suggested by recent post-trial evidence is currently being evaluated in the ADVANCE-ON study.

Topics: Antihypertensive Agents; Biomarkers; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Drug Combinations; Glycated Hemoglobin; Humans; Hypertension; Hypoglycemic Agents; Incidence; Indapamide; Kidney Failure, Chronic; Multicenter Studies as Topic; Perindopril; Randomized Controlled Trials as Topic; Risk Factors

Type 2 diabetes mellitus (T2DM) is often accompanied by high blood pressure (BP) and the clustering of several cardiovascular risk factors, and is the most frequent cause of end-stage renal disease. The stages of development of overt nephropathy in T2DM patients range from an initial alteration in renal function with an increased GFR, followed by the development of microalbuminuria and macroalbuminuria or proteinuria, featuring an established diabetic nephropathy, which eventually progresses to end-stage renal disease. Early intervention is needed to prevent the development of diabetic nephropathy and requires effective control of the different risk factors, and in particular high BP. In the initial stages of the disease, strict BP control is crucial to prevent the development of initial renal and vascular damage. Adequate BP control is particularly difficult in T2DM patients and in most cases requires the use of combination therapy. Preterax, a fixed-dose combination of perindopril 2 mg and indapamide 0.625 mg, allows BP to be significantly reduced compared with conventional strategies; this combination can be uptitrated to BiPreterax when further BP control is needed. In the PREMIER study performed in T2DM over 12 months, the perindopril/indapamide combination brought about, in addition to excellent BP control, a significant reduction in urinary albumin excretion, compared with monotherapy with enalapril. In more advanced degrees of renal damage, higher doses of the fixed combination have to be considered. The pharmacological basis of the renoprotective effect of perindopril/indapamide is the demonstration that this combination prevented nephropathy as well as proteinuria in obese Zucker rats, independently of BP control. Strict BP control from the initial stages of nephropathy together with inhibition of the renin-angiotensin system is mandatory to prevent albuminuria. The fixed combination of perindopril/indapamide can greatly help clinicians in achieving the above goals, using Preterax in the early and BiPreterax in the late stages of nephropathy.

Topics: Albuminuria; Antihypertensive Agents; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Combinations; Humans; Hypertension; Indapamide; Perindopril

Pharmacological treatment of hypertension represents a cost-effective way of preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment, blood pressure should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (< 130/80 mmHg) if diabetes or renal disease co-exists. Such targets cannot usually be reached using monotherapies. This is especially true in patients who present with a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases the blood pressure control rate. Such combinations are not only efficacious, but are also well tolerated, and some fixed low-dose combinations even have a placebo-like tolerability. This is the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has been shown in controlled trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving the stiffness of large arteries. Using this combination to initiate antihypertensive therapy has been shown in a double-blind trial (Strategies of Treatment in Hypertension: Evaluation; STRATHE) to normalize blood pressure (< 140/90 mmHg) in significantly more patients (62%) than a sequential monotherapy approach based on atenolol, losartan and amlodipine (49%) and a stepped-care strategy based on valsartan and hydrochlorothiazide (47%), with no difference between the three arm groups in terms of tolerability. An ongoing randomized trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ADVANCE) is a study with a 2 x 2 factorial design assessing the effects of the fixed-dose perindopril-indapamide combination and of the intensive gliclazide modified release-based glucose control regimen in type 2 diabetic patients, with or without hypertension. A total of 11 140 patients were randomly selected. Within the first 6 weeks of treatment (run-in phase), the perindopril-indapamide combination lowered blood pressure from 145/81 +/- 22/11 mmHg (mean +/- SD) to 137/78 +/- 20/10 mmHg. Fixed-dose combinations are becoming more and more popular for the management of hypertension, and are even proposed by hypertension guidelines as a first-line option to treat hypertensive patients.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diuretics; Drug Combinations; Humans; Hypertension; Indapamide; Perindopril; Vascular Diseases

Weight loss is strongly recommended for overweight and obese adults with type 2 diabetes. Unintentional weight loss is associated with increased risk of all-cause mortality, but few studies have examined its association with cardiovascular outcomes in patients with diabetes.. To evaluate 2-year weight change and subsequent risk of cardiovascular events and mortality in established type 2 diabetes.. The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation was an international, multisite 2×2 factorial trial of intensive glucose control and blood pressure control. We examined 5 categories of 2-year weight change: >10% loss, 4% to 10% loss, stable (±<4%), 4% to 10% gain, and >10% gain. We used Cox regression with follow-up time starting at 2 years, adjusting for intervention arm, demographics, cardiovascular risk factors, and diabetes medication use from the 2-year visit.. Among 10 081 participants with valid weight measurements, average age was 66 years. By the 2-year examination, 4.3% had >10% weight loss, 18.4% had 4% to 10% weight loss, and 5.3% had >10% weight gain. Over the following 3 years of the trial, >10% weight loss was strongly associated with major macrovascular events (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.26-2.44), cardiovascular mortality (HR, 2.76; 95% CI, 1.87-4.09), all-cause mortality (HR, 2.79; 95% CI, 2.10-3.71), but not major microvascular events (HR, 0.91; 95% CI, 0.61-1.36), compared with stable weight. There was no evidence of effect modification by baseline body mass index, age, or type of diabetes medication.. In the absence of substantial lifestyle changes, weight loss may be a warning sign of poor health meriting further workup in patients with type 2 diabetes.

Topics: Adult; Aged; Body-Weight Trajectory; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Combinations; Female; Follow-Up Studies; Gliclazide; Humans; Hypertension; Indapamide; Life Style; Male; Middle Aged; Obesity; Overweight; Perindopril; Risk Factors; Weight Gain; Weight Loss

To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A. We studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models.. During 5 years' follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83-0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbA. The major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA

Topics: Aged; Blood Glucose; Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Combinations; Female; Gliclazide; Glycated Hemoglobin; Glycemic Control; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Indapamide; Male; Middle Aged; Perindopril; Prognosis; Risk Factors; Treatment Outcome

Discontinuation of angiotensin-converting enzyme (ACE) inhibitor is recommended if patients experience ≥30% acute increase in serum creatinine after starting this therapy. However, the long-term effects of its continuation or discontinuation on major clinical outcomes after increases in serum creatinine are unclear. In the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), 11 140 diabetes mellitus patients were randomly assigned to perindopril-indapamide or placebo after a 6-week active run-in period. The current study included 11 066 participants with 2 serum creatinine measurements recorded before and during the active run-in period (3 weeks apart). Acute increase in creatinine was determined using these 2 measurements and classified into 4 groups: increases in serum creatinine of <10%, 10% to 19%, 20% to 29%, and ≥30%. The primary study outcome was the composite of major macrovascular events, new or worsening nephropathy, and all-cause mortality. An acute increase in serum creatinine was associated with an elevated risk of the primary outcome ( P for trend <0.001). The hazard ratios were 1.11 (95% CI, 0.97-1.28) for those with an increase of 10% to 19%, 1.34 (1.07-1.66) for 20% to 29%, and 1.44 (1.15-1.81) for ≥30%, compared with <10%. However, there was no evidence of heterogeneity in the benefit of randomized treatment effects on the outcome across subgroups defined by acute serum creatinine increase ( P for heterogeneity=0.94). Acute increases in serum creatinine after starting perindopril-indapamide were associated with greater risks of subsequent major clinical outcomes. However, the continuation of angiotensin-converting enzyme inhibitor-based therapy reduced the long-term risk of major clinical outcomes, irrespective of acute increase in creatinine. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00145925.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cardiovascular Diseases; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Combinations; Drug Monitoring; Female; Humans; Indapamide; Male; Medication Therapy Management; Middle Aged; Perindopril; Risk Assessment; Treatment Outcome; Withholding Treatment

The optimal blood pressure (BP) goal in patients with diabetes mellitus remains controversial. We examined whether benefits and risks of intensified antihypertensive therapy in diabetes mellitus are influenced by either baseline BP or cardiovascular disease (CVD) risk. We studied 10 948 people with diabetes mellitus, at moderate-to-high risk, in the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation). Cox models were used to determine whether baseline BP category or CVD risk modified the outcomes of combination perindopril-indapamide treatment, compared with placebo. During 4.3 years of follow-up, treatment with perindopril-indapamide versus placebo reduced mortality and major vascular (macrovascular or microvascular) events. There was no evidence of differences in these effects, regardless of baseline systolic BP (evaluated down to <120 mm Hg; P for heterogeneity, 0.85), diastolic BP (evaluated down to <70 mm Hg; P=0.49), or whether 10-year CVD risk was ≥20% or <20% ( P=0.08). The effects of randomized treatment on discontinuation of treatment because of cough or hypotension/dizziness were also statistically consistent across subgroups defined by baseline BP and CVD risk (all P ≥0.08). Adults with diabetes mellitus appear to benefit from more intensive BP treatment even at levels of BP and CVD risk that some guidelines do not currently recommend for intervention. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00751972.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Combinations; Female; Follow-Up Studies; Global Health; Humans; Incidence; Indapamide; Male; Middle Aged; Perindopril; Risk Factors; Survival Rate; Treatment Outcome

Poor blood pressure (BP) control contributes to complications in sub-Saharan African (SSA) type 2 diabetic individuals. Experts have advocated the use of combination therapies for effective BP control in these patients. The suggested combinations should include a RAAS antagonist and either a CCB or a thiazide diuretic; however, their efficacy is yet to be established in SSA. We investigated the short-term effects of two combination therapies on BP control in SSA type 2 diabetic individuals. This was a double-blinded randomized controlled trial conducted at the Yaoundé Central Hospital (Cameroon) from October 2016 to May 2017. We included type 2 diabetic patients, newly diagnosed for hypertension. After baseline assessment and 24-hour ABPM, participants were allocated to receive either a fixed combination of perindopril + amlodipine or perindopril + indapamide for 42 days. Data analyses followed the intention-to-treat principle. We included fifteen participants (8 being females) in each group. Both combinations provided good circadian BP control after 6 weeks with similar efficacy. Twenty-four-hour SBP dropped from 144 to 145 mm Hg vs 128 to 126 mm Hg with perindopril-amlodipine and perindopril-indapamide, respectively (P = 0.003 for both groups). Twenty-four-hour DBP dropped from 85 to 78 mm Hg (P = 0.013) vs 89 to 79 mm Hg (P = 0.006) in the same respective groups. No significant adverse effect was reported. A fixed initial combination of perindopril-amlodipine or perindopril-indapamide achieved similar effective BP control after 6 weeks in SSA type 2 diabetic individuals with newly diagnosed hypertension. Therefore, these combinations can be used interchangeably in this indication.

Topics: Africa South of the Sahara; Amlodipine; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Comorbidity; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Combinations; Drug Monitoring; Female; Humans; Hypertension; Indapamide; Male; Middle Aged; Perindopril; Treatment Outcome

Previous studies have suggested that the haemoglobin glycation index (HGI) can be used as a predictor of diabetes-related complications in individuals with type 1 and type 2 diabetes. We investigated whether HGI was a predictor of adverse outcomes of intensive glucose lowering and of diabetes-related complications in general, using data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.. We studied participants in the ADVANCE trial with data available for baseline HbA. Intensive glucose control lowered mortality risk in individuals with high HGI only (HR 0.74 [95% CI 0.61, 0.91]; p = 0.003), while there was no difference in the effect of intensive treatment on mortality in those with high HbA. HGI predicts risk for complications in ADVANCE participants, irrespective of treatment allocation, but no better than HbA

Topics: Aged; Antihypertensive Agents; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Combinations; Female; Gliclazide; Glycosylation; Hemoglobins; Humans; Hypoglycemic Agents; Indapamide; Male; Microcirculation; Middle Aged; Perindopril; Proportional Hazards Models; Risk; Treatment Outcome; Vascular Diseases

We aimed to evaluate the relationship between BMI and the risk of renal disease in patients with type 2 diabetes in the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) study.. Participants were divided into six baseline BMI categories: <18.5 (underweight, n = 58); ≥18.5 to <25 (normal, n = 2894); ≥25 to <30 (overweight, n = 4340); ≥30 to <35 (obesity grade 1, n = 2265); ≥35 to <40 (obesity grade 2, n = 744); and ≥40 kg/m. During 5-years of follow-up, major renal events occurred in 487 (4.6%) patients. The risk increased with higher BMI. Multivariable-adjusted HRs (95% CIs), compared to normal weight, were: 0.91 (0.72-1.15) for overweight; 1.03 (0.77-1.37) for obesity grade 1; 1.42 (0.98-2.07) for grade 2; and 2.16 (1.34-3.48) for grade 3 (p for trend = 0.006). These findings were similar across subgroups by randomised interventions (intensive versus standard glucose control and perindopril-indapamide versus placebo). Every additional unit of BMI over 25 kg/m. Higher BMI is an independent predictor of major renal events in patients with type 2 diabetes. Our findings encourage weight loss to improve nephroprotection in these patients.

Topics: Aged; Albuminuria; Blood Glucose; Body Mass Index; Creatinine; Diabetes Mellitus, Type 2; Drug Combinations; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Indapamide; Kidney; Kidney Diseases; Male; Middle Aged; Obesity; Overweight; Perindopril; Reference Values; Renal Insufficiency

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial reported that intensive glucose control prevents end-stage kidney disease (ESKD) in patients with type 2 diabetes, but uncertainty about the balance between risks and benefits exists. Here, we examine the long-term effects of intensive glucose control on risk of ESKD and other outcomes.. Survivors, previously randomized to intensive or standard glucose control, were invited to participate in post-trial follow-up. ESKD, defined as the need for dialysis or kidney transplantation, or death due to kidney disease, was documented overall and by baseline CKD stage, along with hypoglycemic episodes, major cardiovascular events, and death from other causes.. A total of 8,494 ADVANCE participants were followed for a median of 5.4 additional years. In-trial HbA1c differences disappeared by the first post-trial visit. The in-trial reductions in the risk of ESKD (7 vs. 20 events, hazard ratio [HR] 0.35, P = 0.02) persisted after 9.9 years of overall follow-up (29 vs. 53 events, HR 0.54, P < 0.01). These effects were greater in earlier-stage CKD (P = 0.04) and at lower baseline systolic blood pressure levels (P = 0.01). The effects of glucose lowering on the risks of death, cardiovascular death, or major cardiovascular events did not differ by levels of kidney function (P > 0.26).. Intensive glucose control was associated with a long-term reduction in ESKD, without evidence of any increased risk of cardiovascular events or death. These benefits were greater with preserved kidney function and with well-controlled blood pressure.

Topics: Aged; Antihypertensive Agents; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Drug Combinations; Female; Follow-Up Studies; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Indapamide; Kidney Failure, Chronic; Male; Middle Aged; Perindopril; Treatment Outcome

Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis in type 2 diabetes, but the relationship between other vascular diseases and PAD has been poorly investigated. We examined the impact of previous microvascular and macrovascular disease on the risk of major PAD in patients with type 2 diabetes.. We analyzed 10,624 patients with type 2 diabetes free from baseline major PAD in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) clinical trial. The primary composite outcome was major PAD defined as PAD-induced death, peripheral revascularization, lower-limb amputation, or chronic ulceration. The secondary end points were the PAD components considered separately.. Major PAD occurred in 620 (5.8%) participants during 5 years of follow-up. Baseline microvascular and macrovascular disease were both associated with subsequent risk of major PAD after adjustment for age, sex, region of origin, and randomized treatments. However, only microvascular disease remained significantly associated with PAD after further adjustment for established risk factors. The highest risk was observed in participants with a history of macroalbuminuria (hazard ratio 1.91 [95% CI 1.38-2.64], P < 0.0001) and retinal photocoagulation therapy (1.60 [1.11-2.32], P = 0.01). Baseline microvascular disease was also associated with a higher risk of chronic lower-limb ulceration (2.07 [1.56-2.75], P < 0.0001) and amputation (1.59 [1.15-2.22], P = 0.006), whereas baseline macrovascular disease was associated with a higher rate of angioplasty procedures (1.75 [1.13-2.73], P = 0.01).. Microvascular disease, particularly macroalbuminuria and retinal photocoagulation therapy, strongly predicts major PAD in patients with type 2 diabetes, but macrovascular disease does not.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Drug Combinations; Endpoint Determination; Female; Follow-Up Studies; Gliclazide; Glycated Hemoglobin; Humans; Indapamide; Male; Middle Aged; Perindopril; Peripheral Arterial Disease; Proportional Hazards Models; Risk Factors

The burden of vascular diseases remains substantial in patients with type 2 diabetes, requiring identification of further risk markers. We tested the absence of dorsalis pedis and posterior tibial pulses as predictors of major macrovascular and microvascular events, death, and cognitive decline in this population.. Data were derived from 11,120 patients with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) study. Absent peripheral pulses at baseline were defined as absence of at least one dorsalis pedis or posterior tibial pulse.. Absent compared with present peripheral pulses (n = 2,218) were associated with increased 5-year risks for major macrovascular events (hazard ratio 1.47 [95% CI 1.28-1.69], P < 0.0001), myocardial infarction (1.45 [1.13-1.87], P = 0.003), stroke (1.57 [1.23-2.00], P = 0.0003), cardiovascular death (1.61 [1.33-1.95], P < 0.0001), heart failure (1.49 [1.21-1.84], P = 0.0002), all-cause mortality (1.48 [1.29-1.71], P < 0.0001), major microvascular events (1.17 [1.00-1.36], P = 0.04), nephropathy (1.24 [1.00-1.54], P = 0.04), end-stage renal disease or renal death (2.04 [1.12-3.70], P = 0.02), and peripheral neuropathy (1.13 [1.05-1.21], P = 0.0008) after multiple adjustment. Participants with absent dorsalis pedis or posterior tibial pulses had comparable hazard ratios. Risks increased proportionally with the number of absent peripheral pulses, with the highest risks observed in patients with three or four absent pulses. Every additional absent pulse increases the risk of all outcomes.. Absent dorsalis pedis and/or posterior tibial pulses are independent predictors of major vascular outcomes in patients with type 2 diabetes. These simple clinical indicators should be used to improve risk stratification and treatment of these patients.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diagnostic Techniques, Cardiovascular; Disease Progression; Drug Combinations; Female; Gliclazide; Humans; Hypoglycemic Agents; Indapamide; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Perindopril; Pulse; Risk Factors; Stroke

Blood pressure-lowering treatment reduces cardiovascular risk in patients with diabetes mellitus, but the effect varies between individuals. We sought to identify which patients benefit most from such treatment in a large clinical trial in type 2 diabetes mellitus. In Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) participants (n=11 140), we estimated the individual patient 5-year absolute risk of major adverse cardiovascular events with and without treatment by perindopril-indapamide (4/1.25 mg). The difference between treated and untreated risk is the estimated individual patient's absolute risk reduction (ARR). Predictions were based on a Cox proportional hazards model inclusive of demographic and clinical characteristics together with the observed relative treatment effect. The group-level effect of selectively treating patients with an estimated ARR above a range of decision thresholds was compared with treating everyone or those with a blood pressure >140/90 mm Hg using net benefit analysis. In ADVANCE, there was wide variation in treatment effects across individual patients. According to the algorithm, 43% of patients had a large predicted 5-year ARR of ≥1% (number-needed-to-treat [NNT5] ≤100) and 40% had an intermediate predicted ARR of 0.5% to 1% (NNT5=100-`200). The proportion of patients with a small ARR of ≤0.5% (NNT5≥200) was 17%. Provided that one is prepared to treat at most 200 patients for 5 years to prevent 1 adverse outcome, prediction-based treatment yielded the highest net benefit. In conclusion, a multivariable treatment algorithm can identify those individuals who benefit most from blood pressure-lowering therapy in terms of ARR of major adverse cardiovascular events and may be used to guide treatment decisions in individual patients with diabetes.. http://www.clinicaltrials.gov. Unique identifier: NCT00145925.

Topics: Aged; Antihypertensive Agents; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Combinations; Female; Follow-Up Studies; Gliclazide; Humans; Hypoglycemic Agents; Indapamide; Male; Perindopril; Risk Factors; Time Factors; Treatment Outcome

The objective of the present analysis was to determine the effects of a fixed combination of perindopril and indapamide in combination with calcium channel blockers (CCBs) in patients with type 2 diabetes mellitus. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Controlled Evaluation (ADVANCE) trial was a factorial randomized controlled trial. A total of 11 140 patients with type 2 diabetes mellitus were randomly assigned to fixed combination of perindopril-indapamide (4/1.25 mg) or placebo. Effects of randomized treatment on mortality and major cardiovascular outcomes were examined in subgroups defined by baseline use of CCBs. Patients on CCB at baseline (n=3427) constituted a higher risk group compared with those not on CCB (n=7713), with more extensive use of antihypertensive and other protective therapies. Active treatment reduced the relative risk of death by 28% (95% confidence interval, 10%-43%) among patients with CCB at baseline compared with 5% (-12% to 20%) among those without CCB (P homogeneity=0.02) and 14% (2%-25%) for the whole population. Similarly, the relative risk reduction for major cardiovascular events was 12% (-8% to 28%) versus 6% (-10% to 19%) for those with and without CCB at baseline although the difference was not statistically significant (P homogeneity=0.38). There was no detectable increase in adverse effects in those receiving CCB. The combination of perindopril and indapamide with CCBs seems to provide further protection against mortality in patients with type 2 diabetes mellitus.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Combinations; Drug Therapy, Combination; Female; Gliclazide; Humans; Hypertension; Hypoglycemic Agents; Indapamide; Male; Middle Aged; Perindopril; Proportional Hazards Models

Moderate alcohol consumption has been associated with a reduced risk of mortality and coronary artery disease. The relationship between cardiovascular health and alcohol use in type 2 diabetes is less clear. The current study assesses the effects of alcohol use among participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial.. The effects of alcohol use were explored using Cox regression models, adjusted for potential confounders. The study end points were cardiovascular events (cardiovascular death, myocardial infarction, and stroke), microvascular complications (new or worsening nephropathy or retinopathy), and all-cause mortality.. During a median of 5 years of follow-up, 1,031 (9%) patients died, 1,147 (10%) experienced a cardiovascular event, and 1,136 (10%) experienced a microvascular complication. Compared with patients who reported no alcohol consumption, those who reported moderate consumption had fewer cardiovascular events (adjusted hazard ratio [aHR] 0.83; 95% CI 0.72-0.95; P = 0.008), less microvascular complications (aHR 0.85; 95% CI 0.73-0.99; P = 0.03), and lower all-cause mortality (aHR 0.87; 96% CI 0.75-1.00; P = 0.05). The benefits were particularly evident in participants who drank predominantly wine (cardiovascular events aHR 0.78, 95% CI 0.63-0.95, P = 0.01; all-cause mortality aHR 0.77, 95% CI 0.62-0.95, P = 0.02). Compared with patients who reported no alcohol consumption, those who reported heavy consumption had dose-dependent higher risks of cardiovascular events and all-cause mortality.. In patients with type 2 diabetes, moderate alcohol use, particularly wine consumption, is associated with reduced risks of cardiovascular events and all-cause mortality.

Topics: Aged; Alcohol Drinking; Antihypertensive Agents; Coronary Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Retinopathy; Drug Combinations; Female; Gliclazide; Humans; Hypertension; Hypoglycemic Agents; Indapamide; Male; Myocardial Infarction; Perindopril; Retrospective Studies; Risk Reduction Behavior; Stroke

There is no consensus on the importance of visit-to-visit glycemic variability in diabetes. Therefore, we assessed the effects of visit-to-visit variability (VVV) in HbA1c and fasting glucose on major outcomes in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial.. ADVANCE was a factorial randomized controlled trial of intensive glucose control and blood pressure lowering in patients with type 2 diabetes. VVV in the intensive glucose treatment group was defined using the SD of five measurements of HbA1c and glucose taken 3-24 months after randomization. Outcomes were combined macro- and microvascular events and all-cause mortality occurring post 24 months. Sensitivity analyses were performed using other indices of variability and in the standard glucose treatment group.. Among 4,399 patients in the intensive group, an increase in VVV of HbA1c was associated with an increased risk of vascular events (P = 0.01) and with mortality (P < 0.001): highest versus lowest tenth hazard ratio (95% CI) 1.64 (1.05-2.55) and 3.31 (1.57-6.98), respectively, after multivariable adjustment. A clear association was also observed between VVV of fasting glucose and increased risk of vascular events (P < 0.001; 2.70 [1.65-4.42]). HbA1c variability was positively associated with the risk of macrovascular events (P = 0.02 for trend), whereas glucose variability was associated with both macro- and microvascular events (P = 0.005 and P < 0.001 for trend, respectively). Sensitivity analyses using other indices, and patients in the standard glucose treatment group, were broadly consistent with these results.. Consistency of glycemic control is important to reduce the risks of vascular events and death in type 2 diabetes.

Topics: Aged; Aged, 80 and over; Blood Glucose; Cause of Death; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Combinations; Female; Follow-Up Studies; Gliclazide; Humans; Hypoglycemic Agents; Indapamide; Male; Middle Aged; Office Visits; Perindopril; Risk Factors

In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial, the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes, but intensive glucose control, targeting a glycated hemoglobin level of less than 6.5%, did not. We now report results of the 6-year post-trial follow-up.. We invited surviving participants, who had previously been assigned to perindopril-indapamide or placebo and to intensive or standard glucose control (with the glucose-control comparison extending for an additional 6 months), to participate in a post-trial follow-up evaluation. The primary end points were death from any cause and major macrovascular events.. The baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood-pressure-lowering comparison) or 5.4 years (glucose-control comparison). Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit. The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure-lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval [CI], 0.84 to 0.99; P=0.03) and 0.88 (95% CI, 0.77 to 0.99; P=0.04), respectively. No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucose-control group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively.. The benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure-lowering therapy were attenuated but still evident at the end of follow-up. There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events. (Funded by the National Health and Medical Research Council of Australia and others; ADVANCE-ON ClinicalTrials.gov number, NCT00949286.).

Topics: Antihypertensive Agents; Blood Glucose; Diabetes Mellitus, Type 2; Drug Combinations; Female; Follow-Up Studies; Gliclazide; Glycated Hemoglobin; Humans; Hypertension; Hypoglycemic Agents; Indapamide; Male; Middle Aged; Perindopril; Risk Factors

To asses differences in treatment effects of a fixed combination of perindopril-indapamide on major clinical outcomes in patients with type 2 diabetes across subgroups of cardiovascular risk.. 11,140 participants with type 2 diabetes, from the ADVANCE trial, were randomized to perindopril-indapamide or matching placebo. The Framingham equation was used to calculate 5-year CVD risk and to divide participants into two risk groups, moderate-high risk (<25% and no history of macrovascular disease), very high risk (>25% and/or history of macrovascular disease). Endpoints were macrovascular and microvascular events.. The mean age of participants was 66 years (42.5% female). 1000 macrovascular and 916 microvascular events were recorded over follow-up of 4.3 years. Relative treatment effects were similar across risk groups, (all P-values for heterogeneity ≥0.38). Hazard ratios for combined macro- and microvascular events were 0.89 (0.77-1.03) for the moderate-high risk and 0.92 (0.81-1.03) for the very high risk. Absolute treatment effects tended to be greater in the high risk groups although differences were not statistically significant (P>0.05).. Relative effects of blood pressure lowering with perindopril-indapamide on cardiovascular outcomes were similar across risk groups whilst absolute effects trended to be greater in the high risk group.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Combinations; Female; Humans; Hypertension; Indapamide; Male; Odds Ratio; Perindopril; Risk Factors; Treatment Outcome

The aim of this study was to examine the relationship between erectile problems in men and cardiovascular disease (CVD) mortality.. Although there are plausible mechanisms linking erectile dysfunction (ED) with coronary heart disease (CHD) and stroke, studies are scarce.. In a cohort analysis of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation) trial population, 6,304 men age 55 to 88 years with type 2 diabetes participated in a baseline medical examination when inquiries were made about ED. Over 5 years of follow-up, during which study members attended repeat clinical examinations, the presence of fatal and nonfatal CVD outcomes, cognitive decline, and dementia was ascertained.. After adjusting for a range of covariates, including existing illness, psychological health, and classic CVD risk factors, relative to those who were free of the condition, baseline ED was associated with an elevated risk of all CVD events (hazard ratio: 1.19; 95% confidence interval: 1.08 to 1.32), CHD (hazard ratio: 1.35; 95% confidence interval: 1.16 to 1.56), and cerebrovascular disease (hazard ratio: 1.36; 95% confidence interval: 1.11 to 1.67). Men who experienced ED at baseline and at 2-year follow-up had the highest risk for these outcomes.. In this cohort of men with type 2 diabetes, ED was associated with a range of CVD events.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Combinations; Drug Therapy, Combination; Erectile Dysfunction; Follow-Up Studies; Gliclazide; Humans; Hypoglycemic Agents; Indapamide; Male; Middle Aged; Perindopril; Prospective Studies; Risk Factors; Time Factors; Treatment Outcome

To 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.. This 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 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).. The 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.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Combinations; Drug Therapy, Combination; Female; Gliclazide; Humans; Hypertension; Hypoglycemic Agents; Indapamide; Male; Microcirculation; Middle Aged; Perindopril; Placebos

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.

Topics: Aged; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Combinations; Female; Follow-Up Studies; Humans; Hypertension, Renal; Indapamide; Male; Middle Aged; Perindopril; Placebos; Treatment Outcome

Microvascular disease is associated with a high risk of macrovascular events in patients with type 2 diabetes, but the impact of macrovascular disease on the risk of microvascular events remains unknown. We sought to evaluate the respective effects of prior microvascular and macrovascular disease on the risk of major outcomes, including microvascular events, in these patients.. Participants in the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) trial (n = 11,140) and the ADVANCE-ON post-trial study (n = 8494) were categorized into 4 groups at baseline: dual absence of microvascular or macrovascular disease (n = 6789), presence of microvascular disease alone (n = 761), macrovascular disease alone (n = 3196), and both (n = 394). Outcomes were all-cause mortality, major macrovascular events (MACE), and major clinical microvascular events.. All-cause mortality, MACE, and major clinical microvascular events occurred in 2265 (20%), 2166 (19%), and 807 (7%) participants respectively, during a median follow-up of 9.9 (inter-quartile interval 5.6-10.9) years. The adjusted hazard ratios [95% CI] of death, MACE, and major clinical microvascular events were each greater in patients with baseline microvascular disease (1.43 [1.20-1.71], 1.64 [1.37-1.97], and 4.74 [3.86-5.82], respectively), macrovascular disease (1.43 [1.30-1.57], 2.04 [1.86-2.25], and 1.26 [1.06-1.51]) or both (2.01 [1.65-2.45], 2.92 [2.40-3.55], and 6.30 [4.93-8.06]) compared with those without these conditions. No interaction was observed between baseline microvascular and macrovascular disease for these events. The addition of microvascular disease (change in c-statistic [95% CI] 0.005 [0.002-0.008], p = 0.02) or macrovascular disease (0.005 [0.002-0.007], p < 0.0001) considered separately or together (0.011 [0.007-0.014], p < 0.0001) improved the discrimination and the classification (integrated discrimination improvement (IDI): 0.013 [0.010-0.016], p < 0.001; net reclassification improvement (NRI): 0.021 [0.011-0.032], p < 0.001) of the risk of all-cause mortality. Microvascular disease improved discrimination (0.009 [0.003-0.014]) and classification (IDI: 0.008 [0.006-0.010]; NRI: 0.011 [0.001-0.020]) of MACE. Baseline macrovascular disease modestly enhanced IDI (0.002 [0.001-0.002]) and NRI (0.041 [0.002-0.087]), but not discrimination, of major clinical microvascular events.. Microvascular and macrovascular disease are independently associated with the 10-year risk of death, MACE, and major clinical microvascular events in patients with type 2 diabetes. The coexistence of these conditions was associated with the highest risks.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Combinations; Female; Gliclazide; Humans; Hypoglycemic Agents; Indapamide; Male; Microvessels; Middle Aged; Perindopril; Risk Factors; Treatment Outcome

Blood pressure (BP) control in hypertensive patients remains poor worldwide, particularly in high-risk patients with hypertension and diabetes. Guidelines recommend that such patients receive prompt pharmacological therapy at maximal doses to rapidly control BP. We aimed to evaluate efficacy and safety of single-pill combination (SPC) perindopril/indapamide (PER/IND) at full dose (10/2.5 mg) in hypertensive patients, including diabetics, with BP uncontrolled by previous medication.. Twelve-week prospective, observational study in patients with uncontrolled hypertension (≥160-200 mmHg systolic BP [SBP] and <110 mmHg diastolic BP [DBP]) on a previous SPC or free-dose combination of renin-angiotensin system blocker plus thiazide diuretic, substituted with PER/IND 10/2.5 mg. Office BP, quality of life, and blood parameters were evaluated in the whole cohort and patients with type 2 diabetes mellitus.. 2120 ambulatory hypertensive patients were enrolled, including 307 with type 2 diabetes. Two weeks after substitution, SBP significantly decreased from 171.0 ± 13.3 to 148.6 ± 13.4 mmHg, and DBP from 98.6 ± 8.3 to 88.8 ± 7.9 mmHg (both p < 0.00001). A similar rapid decrease was noted in the diabetes subgroup. After 12 weeks, BP had reduced by 42/19 mmHg in the whole cohort (diabetes subgroup: 41/18 mmHg). Most (84%; diabetes subgroup: 77%) patients reached BP target (<140/90 mmHg). Laboratory tests and quality of life improved in the whole cohort and the diabetic subgroup.. Switching to PER/IND at full dose (10/2.5 mg) was well tolerated, leading to fast BP reduction and control in the majority of patients with uncontrolled hypertension, including difficult-to-treat patients with diabetes.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Diuretics; Drug Combinations; Drug Resistance; Female; Humans; Hypertension; Indapamide; Male; Middle Aged; Perindopril; Prospective Studies; Treatment Outcome

To measure the placebo-controlled effects of combination therapy on hypotension, treatment discontinuation, and major renal outcomes, according to baseline blood pressure.. We conducted an analysis of the action in diabetes and vascular disease: preterax and diamicron-MR controlled evaluation ADVANCE and perindopril protection against recurrent stroke study PROGRESS trials, including 14 684 participants allocated combination therapy or placebo. The mean age was 65 years, 61% were men, and 64% were receiving background blood pressure lowering (BPL) therapy. Participants were stratified into five subgroups by baseline SBP less than 120, 120-129, 130-139, 140-159, and at least 160 mmHg. Discontinuation of study treatment during the active run-in phase and postrandomization follow-up was assessed for hypotension/dizziness and other causes. Major renal outcomes (sustained doubling in creatinine or renal death) were also assessed.. Discontinuation during the 4-6-week active run-in phase due to hypotension/dizziness ranged from 3.6% in those with SBP less than 120 mmHg to 1.3% in those with SBP at least 160 mmHg. Median follow-up in the randomized phase was 5.6 years, and discontinuation for hypotension was higher with combination therapy compared with placebo in the less than 120 mmHg group (4.7 vs. 1.2%). However, for each subgroup with baseline SBP 120-129, 130-139, and 140-159 mmHg, the absolute excess of discontinuation due to hypotension with combination therapy was 0.7%. Total discontinuations were only increased in the less than 120 mmHg group (18.4 vs. 12.5%) and the 120-129-mmHg subgroup (17.6 vs. 14.2%). There were no clear differences across the SBP subgroups for the combined renal outcome (overall, 0.8 vs. 0.6%).. Compared with those with baseline SBP 140-159 mmHg, side effects of dual combination BPL are essentially the same for people with SBP 130-139 mmHg and only modestly increased among patients with SBP 120-129 mmHg. During long-term therapy, side effects sufficient to stop treatment that are treatment related (i.e. occur in excess of rates seen with placebo) occur at less than 0.5%/year in patients with baseline SBP 120-139 mmHg. These results have important implications in assessing the likely balance of benefits and side effects of BPL with combination therapy among those with SBP 120-139 mmHg.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Drug Combinations; Female; Humans; Hypertension; Hypotension; Indapamide; Male; Medication Adherence; Middle Aged; Multicenter Studies as Topic; Perindopril; Placebos; Proportional Hazards Models; Randomized Controlled Trials as Topic; Stroke

To formulate a combined cardiovascular risk score in diabetes that could be useful both to physicians and healthcare funders.. Data were derived from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational (ADVANCE-ON) study, a randomized controlled trial (mean duration 5 years) with a post-randomization follow-up (mean 4.9 years), that included 11 140 high-risk patients with diabetes. The outcome analysed was the occurrence of either fatal or non-fatal macrovascular or renal disease. A Cox regression model was used to determine weightings in the risk score. The resultant score was recalibrated to each of three major global regions, as covered by the ADVANCE-ON study.. Over a median of 9.9 years, 1145 patients experienced at least one component of the combined outcome event. The resultant score, the AD-ON risk score, incorporated 13 demographic or clinical variables. Its discrimination was modest [c-statistic = 0.668 (95% confidence interval 0.651, 0.685)] but its calibration was excellent (predicted and observed risks coincided well, within disparate global regions). In terms of the integrated discrimination improvement index, its performance was marginally superior, over a 10-year risk horizon, to existing risk scores in clinical use, from a restricted version of the same data, for macrovascular and renal disease separately.. The AD-ON risk score has advantages over the existing vascular risk scores in diabetes that used data from the original ADVANCE trial, which treat macrovascular and renal diseases separately. These advantages include its simplicity of use and global application.

Topics: Aged; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Combinations; Drug Therapy, Combination; Female; Gliclazide; Health Status Indicators; Humans; Hypoglycemic Agents; Indapamide; Male; Middle Aged; Perindopril; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors

Intensive glucose control reduces the risk of vascular complications while increasing the risk of severe hypoglycaemia at a group level. We sought to estimate individual beneficial and adverse effects of intensive glucose control in patients with type 2 diabetes.. Based on these models, 76% of patients had a substantial estimated 5 year ARR for major vascular events (>1%, 5 year number-needed-to-benefit [NNTB. Taking account of the effects of intensive glucose control on major micro- and macrovascular events and severe hypoglycaemia for individual patients, the estimated net benefit was positive in the majority of the participants in the ADVANCE trial. The estimated individual effects can inform treatment decisions once individual weights assigned to positive and adverse effects have been specified.. ClinicalTrials.gov NCT00145925.

Topics: Aged; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Combinations; Female; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Indapamide; Male; Middle Aged; Perindopril; Precision Medicine; Risk Factors; Risk Reduction Behavior

Topics: Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Combinations; Female; Gliclazide; Humans; Hypertension; Indapamide; Male; Perindopril

Hypertension and type 2 diabetes mellitus (T2DM) synergistically deteriorate the vascular environment, making blood pressure reduction challenging, and substantially increasing cardiovascular risk.. In the real-life, open-label, observational, PICASSO study, 9,257 hypertensive patients unsuccessfully treated with antihypertensives were switched to fixed-dose combination of perindopril 10 mg/indapamide 2.5 mg. In this subgroup analysis, we analyzed changes in blood pressure and laboratory parameters of 2,762 hypertensive patients with T2DM or pre-diabetes.. After 3 months of treatment, significant decreases in office blood pressure were noted in the whole cohort (-27.0±14.8/-12.7±9.8 mmHg; p<0.001). Significant decreases were also recorded in patients with grade 1 hypertension (19.2±10.0/-9.4±7.9 mmHg), grade 2 (29.2±10.9/-13.3±8.7 mmHg) and grade 3 (-45.1±15.4/-21.5±11.2 mmHg). Significant decreases in ambulatory blood pressure were also noted (n=93). In patients previously treated with angiotensin-converting enzyme inhibitor±hydrochlorothiazide or angiotensin receptor blocker±hydrochlorothiazide, mean 24-h blood pressure decreased by 23.4±13.9/11.5±9.7 and 22.3±8.7/10.4±13.2 mmHg, respectively (p<0.001). Treatment was well tolerated and the switch to treatment with perindopril/indapamide was associated with improvements in laboratory parameters.. Data from this diabetes subgroup analysis suggest that fixed combination of perindopril 10 mg/indapamide 2.5 mg should be routinely considered for the treatment of hypertension in diabetic patients who are unsuccessfully managed with other antihypertensive medications.

Topics: Aged; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Diabetes Mellitus, Type 2; Drug Combinations; Female; Humans; Hypertension; Indapamide; Male; Middle Aged; Perindopril; Prediabetic State; Retrospective Studies; Severity of Illness Index; Treatment Outcome

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.

Topics: Aged; Antihypertensive Agents; Blood Glucose; Blood Pressure; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Combinations; Female; Gliclazide; Humans; Hypoglycemic Agents; Indapamide; Male; Middle Aged; Perindopril; Randomized Controlled Trials as Topic

The relationship between cognitive function, cardiovascular disease and premature death is not well established in patients with type 2 diabetes. We assessed the effects of cognitive function in 11,140 patients with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Furthermore, we tested whether level of cognitive function altered the beneficial effects of the BP-lowering and glycaemic-control regimens in the trial.. Cognitive function was assessed using the Mini Mental State Examination at baseline, and defined by scores 28-30 ('normal', n = 8,689), 24-27 ('mild dysfunction', n = 2,231) and <24 ('severe dysfunction', n = 212). Risks of major cardiovascular events, death and hypoglycaemia and interactions with treatment were assessed using Cox proportional hazards analysis.. Relative to normal function, both mild and severe cognitive dysfunction significantly increased the multiple-adjusted risks of major cardiovascular events (HR 1.27, 95% CI 1.11-1.46 and 1.42, 95% CI 1.01-1.99; both p < 0.05), cardiovascular death (1.41, 95% CI 1.16-1.71 and 1.56, 95% CI 0.99-2.46; both p

Topics: Aged; Antihypertensive Agents; Cognition; Cognition Disorders; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Combinations; Drug Therapy, Combination; Educational Status; Female; Gliclazide; Humans; Hypoglycemia; Hypoglycemic Agents; Indapamide; Male; Mental Status Schedule; Myocardial Infarction; Perindopril; Risk Factors; Stroke

Topics: Cardiovascular Diseases; Congresses as Topic; Diabetes Mellitus, Type 2; Drug Combinations; Europe; Humans; Indapamide; Microcirculation; Multicenter Studies as Topic; Perindopril; Randomized Controlled Trials as Topic; Societies, Medical; Survival Rate