Bastiaan E. de Galan

Risks of cardiovascular events and effects of routine blood pressure lowering among patients with type 2 diabetes and atrial fibrillation: results of the ADVANCE study.

AIMS The aim of this study was to investigate serious clinical outcomes associated with atrial fibrillation (AF) and the effects of routine blood pressure lowering on such outcomes in the presence or absence of AF, among individuals with type 2 diabetes. METHODS AND RESULTS About 11 140 patients with type 2 diabetes (7.6% of whom had AF at baseline) were randomized to a fixed combination of perindopril and indapamide or placebo in the Action in Diabetes and Vascular Disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study. We compared total mortality and cardiovascular disease outcomes and effects of randomized treatment for 4.3 years on such outcomes between patients with and without AF at baseline. After multiple adjustments, AF was associated with a 61% (95% confidence interval 31-96, P < 0.0001) greater risk of all-cause mortality and comparable higher risks of cardiovascular death, stroke, and heart failure (all P < 0.001). Routine treatment with a fixed combination of perindopril and indapamide produced similar relative, but greater absolute, risk reductions for all-cause and cardiovascular mortalities in patients with AF, compared with those without AF. The number of patients needed to be treated with perindopril-indapamide for 5 years to prevent one cardiovascular death was 42 for patients with AF and 120 for patients without AF at baseline. CONCLUSION Atrial fibrillation is relatively common in type 2 diabetes and is associated with substantially increased risks of death and cardiovascular events in patients with type 2 diabetes. This arrhythmia identifies individuals who are likely to obtain greater absolute benefits from blood pressure-lowering treatment. Atrial fibrillation in diabetic patients should be regarded as a marker of particularly adverse outcome and prompt aggressive management of all risk factors.

Severe Hypoglycemia and Risks of Vascular Events and Death

BACKGROUND Severe hypoglycemia may increase the risk of a poor outcome in patients with type 2 diabetes assigned to an intensive glucose-lowering intervention. We analyzed data from a large study of intensive glucose lowering to explore the relationship between severe hypoglycemia and adverse clinical outcomes. METHODS We examined the associations between severe hypoglycemia and the risks of macrovascular or microvascular events and death among 11,140 patients with type 2 diabetes, using Cox proportional-hazards models with adjustment for covariates measured at baseline and after randomization. RESULTS During a median follow-up period of 5 years, 231 patients (2.1%) had at least one severe hypoglycemic episode; 150 had been assigned to intensive glucose control (2.7% of the 5571 patients in that group), and 81 had been assigned to standard glucose control (1.5% of the 5569 patients in that group). The median times from the onset of severe hypoglycemia to the first major macrovascular event, the first major microvascular event, and death were 1.56 years (interquartile range, 0.84 to 2.41), 0.99 years (interquartile range, 0.40 to 2.17), and 1.05 years (interquartile range, 0.34 to 2.41), respectively. During follow-up, severe hypoglycemia was associated with a significant increase in the adjusted risks of major macrovascular events (hazard ratio, 2.88; 95% confidence interval [CI], 2.01 to 4.12), major microvascular events (hazard ratio, 1.81; 95% CI, 1.19 to 2.74), death from a cardiovascular cause (hazard ratio, 2.68; 95% CI, 1.72 to 4.19), and death from any cause (hazard ratio, 2.69; 95% CI, 1.97 to 3.67) (P<0.001 for all comparisons). Similar associations were apparent for a range of nonvascular outcomes, including respiratory, digestive, and skin conditions (P<0.01 for all comparisons). No relationship was found between repeated episodes of severe hypoglycemia and vascular outcomes or death. CONCLUSIONS Severe hypoglycemia was strongly associated with increased risks of a range of adverse clinical outcomes. It is possible that severe hypoglycemia contributes to adverse outcomes, but these analyses indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events. (Funded by Servier and the National Health and Medical Research Council of Australia; ClinicalTrials.gov number, NCT00145925.).

Albuminuria and Kidney Function Independently Predict Cardiovascular and Renal Outcomes in Diabetes

There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR >300 mg/g and eGFR <60 ml/min per 1.73 m(2) at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 diabetes.

Lowering Blood Pressure Reduces Renal Events in Type 2 Diabetes

BP is an important determinant of kidney disease among patients with diabetes. The recommended thresholds to initiate treatment to lower BP are 130/80 and 125/75 mmHg for people with diabetes and nephropathy, respectively. We sought to determine the effects of lowering BP below these currently recommended thresholds on renal outcomes among 11,140 patients who had type 2 diabetes and participated in the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study. Patients were randomly assigned to fixed combination perindopril-indapamide or placebo, regardless of their BP at entry. During a mean follow-up of 4.3 yr, active treatment reduced the risk for renal events by 21% (P < 0.0001), which was driven by reduced risks for developing microalbuminuria and macroalbuminuria (both P < 0.003). Effects of active treatment were consistent across subgroups defined by baseline systolic or diastolic BP. Lower systolic BP levels during follow-up, even to <110 mmHg, was associated with progressively lower rates of renal events. In conclusion, BP-lowering treatment with perindopril-indapamide administered routinely to individuals with type 2 diabetes provides important renoprotection, even among those with initial BP <120/70 mmHg. We could not identify a BP threshold below which renal benefit is lost.

Combined Effects of Routine Blood Pressure Lowering and Intensive Glucose Control on Macrovascular and Microvascular Outcomes in Patients With Type 2 Diabetes: New results from the ADVANCE trial

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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 ≤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. RESULTS There 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). CONCLUSIONS 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.

Erectile Dysfunction and Later Cardiovascular Disease in Men With Type 2 Diabetes Prospective Cohort Study Based on the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation) Trial

OBJECTIVES The aim of this study was to examine the relationship between erectile problems in men and cardiovascular disease (CVD) mortality. BACKGROUND Although there are plausible mechanisms linking erectile dysfunction (ED) with coronary heart disease (CHD) and stroke, studies are scarce. METHODS 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. RESULTS 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. CONCLUSIONS In this cohort of men with type 2 diabetes, ED was associated with a range of CVD events.

Comparison of waist-to-hip ratio and other obesity indices as predictors of cardiovascular disease risk in people with type-2 diabetes: A prospective cohort study from ADVANCE

Aims: The aim of this study was to compare the strength of associations and discrimination capability of body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) with cardiovascular disease risk in individuals with type-2 diabetes. Methods and results: Eleven thousand, one hundred and forty men and women were followed for a mean of 4.8 years. The Cox proportional hazard models were used to compute the hazard ratios and 95% confidence intervals (95% CI) for one standard deviation (SD) increase in baseline BMI (SD: 5kg/m2), WC (SD: 13cm) and WHR (SD: 0.08) with cardiovascular disease risk. After adjustment, hazard ratio (95% CI) for WC were 1.10 (1.03–1.18) for cardiovascular events, 1.13 (1.03–1.24) for coronary events, and 1.08 (0.98–1.19) for cardiovascular deaths. Estimates for WHR were 1.12 (1.05–1.19), 1.17 (1.08–1.28) and 1.19 (1.09–1.31). BMI was not related to any of these outcomes. Although the receiver operating characteristic curve could not differentiate between anthropometric variables (P values ≥ 0.24), the relative integrated discrimination improvement statistic showed an enhancement in the discrimination capabilities of models using WHR for cardiovascular outcomes, except for cerebrovascular events. Conclusion: Strengths of associations and discrimination statistics suggested that WHR was the best predictor of cardiovascular events and mortality in patients with type-2 diabetes and BMI the worst.

Glucose concentrations of less than 3.0 mmol/l (54 mg/dl) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the Europian Association for the Study of Diabetes

The International Hypoglycaemia Study Group recommends that the frequency of detection of a glucose concentration <3.0 mmol/l (<54 mg/dl), which it considers to be clinically significant biochemical hypoglycaemia, be included in reports of clinical trials of glucoselowering drugs evaluated for the treatment of diabetes mellitus. The glycaemic thresholds for symptoms of hypoglycaemia and for glucose counterregulatory (including sympathoadrenal) responses to hypoglycaemia, as plasma glucose concentrations fall, are not fixed in patients with insulin-, sulfonylureaor meglitinide(glinide)-treated diabetes. They are at higher glucose concentrations in those with poor glycaemic control and at lower glucose concentrations in those with tight glycaemic control [1–5]. The shifts in glycaemic threshold to lower glucose concentrations are largely the result of more frequent episodes of iatrogenic hypoglycaemia during intensive glycaemic therapy. Glycaemic thresholds for responses to hypoglycaemia vary, not only among individuals with diabetes but also in the same individual with diabetes as a function of their HbA1c levels and hypoglycaemic experience; it is therefore not appropriate to cite a specific glucose concentration that defines hypoglycaemia in diabetes. As a consequence, the American Diabetes Association has defined hypoglycaemia in diabetes nonnumerically as ‘all episodes of an abnormally low plasma glucose concentration that expose the individual to potential harm’ [6, 7]. Nonetheless, the International Hypoglycaemia Study Group believes that it is important to identify and record a level of hypoglycaemia that needs to be avoided because of its immediate and long-term danger to the individual. A single glucose level should be agreed to that has serious clinical and health-economic consequences. This would enable the diabetes and regulatory communities to compare the effectiveness of interventions in reducing hypoglycaemia, be they pharmacological, technological or educational. It would also permit the use of meta-analysis as a statistical tool to increase power when comparing interventions. In its discussion, the International Hypoglycaemia Study Group considered glucose concentration levels of <3.0 mmol/ l (<54 mg/dl) and <2.8 mmol/ l (<50 mg/dl) detected by self-monitoring of plasma glucose, continuous glucose monitoring (for at least 20 min) or a laboratory measurement of plasma glucose. Both of these levels are distinctly low glucose concentrations that do not occur under physiological conditions in non-diabetic individuals [8]. Thus, they are unequivocally hypoglycaemic values. They approximate the upper and lower limits, respectively, of the non-diabetic Members of the International Hypoglycaemia Study Group are listed in the Appendix.

Improved Pharmacokinetic and Pharmacodynamic Profile of Rapid-Acting Insulin Using Needle-Free Jet Injection Technology

OBJECTIVE Insulin administered by jet injectors is dispensed over a larger subcutaneous area than insulin injected with a syringe, which may facilitate a more rapid absorption. This study compared the pharmacologic profile of administration of insulin aspart by jet injection to that by conventional insulin pen. RESEARCH DESIGN AND METHODS Euglycemic glucose clamp tests were performed in 18 healthy volunteers after subcutaneous administration of 0.2 units/kg body wt of aspart, either administered by jet injection or by conventional pen, using a randomized, double-blind, double-dummy, cross over study design. Pharmacodynamic and pharmacokinetic profiles were derived from the glucose infusion rate (GIR) needed to maintain euglycemia and from plasma insulin levels, respectively. RESULTS The time to maximal GIR was significantly shorter when insulin was injected with the jet injector compared with conventional pen administration (51 ± 3 vs. 105 ± 11 min, P < 0.0001). The time to peak insulin concentration was similarly reduced (31 ± 3 vs. 64 ± 6 min, P < 0.0001) and peak insulin concentrations were increased (108 ± 13 vs. 79 ± 7 mU/L, P = 0.01) when insulin was injected by jet injection compared with conventional pen injection. Jet injector insulin administration reduced the time to 50% glucose disposal by ∼40 min (P < 0.0001). There were no differences in maximal GIR, total insulin absorption, or total insulin action between the two devices. CONCLUSIONS Administration of insulin aspart by jet injection enhances insulin absorption and reduces the duration of glucose-lowering action. This profile resembles more closely the pattern of endogenous insulin secretion and may help to achieve better meal insulin coverage and correction of postprandial glucose excursions.

Randomized Forced Titration to Different Doses of Technosphere® Insulin Demonstrates Reduction in Postprandial Glucose Excursions and Hemoglobin A1c in Patients with Type 2 Diabetes

Background: Individuals with type 2 diabetes mellitus have impairments in early insulin release, resulting in increased postprandial glucose excursions and suboptimal glycemic control. Studies with Technosphere® Insulin (TI) indicate that it has rapid systemic absorption and a short duration of glucose-lowering activity, making it well suited for controlling postprandial glucose levels. Methods: The goal of this phase 2b, prospective, multicenter, double-blind, placebo-controlled study was to characterize the dose response of four different doses (equivalent to 3.6, 7.3, 10.9, and 14.6 U subcutaneous regular human insulin) of prandial TI or Technosphere powder alone administered before each of three meals daily, in combination with insulin glargine over an 11-week treatment period, in patients with type 2 diabetes and suboptimal glycemic control. Conclusions: This study demonstrated that, over 11 weeks, TI plus basal insulin glargine is well tolerated and results in dose-dependent reductions in postprandial glucose and HbA1c levels. Results: The study enrolled 227 patients. In all dose groups, TI demonstrated statistically significant dose-dependent reductions in hemoglobin A1c (HbAlc) versus baseline (−0.4, −0.5, −0.5, and −0.6 for 3.6, 7.3, 10.9, and 14.6 U equivalents, respectively; p < 0.05 in all groups), as well as versus placebo or Technosphere powder alone (−0.40, −0.67, −0.70, and −0.78 for 3.6, 7.3, 10.9, and 14.6 U equivalents, respectively; p < 0.04 in all groups). It reduced the postprandial maximum glucose concentration within each treatment group (statistically significant in all but the TI 3.6 U-equivalent group) and reduced the postprandial area under the glucose curve (statistically significant for the TI 10.9 and 14.6 U-equivalent groups) versus placebo. There were no cases of severe hypoglycemia, while mild/moderate hypoglycemia was observed most frequently in the highest dosage groups, as expected. Rates of cough were low and comparable among all groups. No clinically relevant changes in pulmonary function tests, body weight, or high-resolution computerized axial tomography and magnetic resonance imaging were observed.