Veterans Affairs Diabetes Trial Research Articles

Association of PAI-1 and fibrinogen with diabetic retinopathy in the Veterans Affairs Diabetes Trial (VADT).

OBJECTIVETo test the hypothesis that high levels of plasminogen-activating inhibitor (PAI)-1 and fibrinogen at baseline were associated with the onset or progression of diabetic retinopathy (DR) during the Veterans Affairs Diabetes Trial (VADT).RESEARCH DESIGN AND METHODSThe VADT was an open-label, prospective, randomized controlled trial to test the effect of standard glycemic control (STD) compared with intensive control (INT) on cardiovascular events in patients with advanced type 2 diabetes mellitus (T2DM). Diabetic retinopathy (DR) outcomes were also collected. Incidence and progression of DR were assessed by grading seven-field stereoscopic fundus photographs at baseline and 5 years later taken in 858 of a total of 1,791 participants who completed both eye examinations.RESULTSAssignment to INT was not independently associated with decreased risk of onset of DR. However, after adjustment for multiple covariates, baseline level of PAI-1 was an independent risk factor for the onset of DR. The risk for incidence of DR increased by 12% for each 10 ng/dL increase in baseline PAI-1 concentration (odds ratio [OR] 1.012 [95% CI 1.00–1.024], P = 0.042). Assignment to INT was not independently associated with decreased risk of progression of DR. However, there was an interaction between glycemic treatment assignment and fibrinogen level at baseline. INT was associated with decreased progression of retinopathy in those with fibrinogen <296 mg/dL (OR 0.55 [95% CI 0.31–1.00], P = 0.03).CONCLUSIONSThe results require confirmation but are consistent with greater hypercoagulabilty and inflammation, as measured by higher levels of PAI-1 and fibrinogen, being related to DR and responsiveness to INT.

Insulin as an early treatment for type 2 diabetes: ORIGIN or end of an old question?

The Emerging Risk Factors Collaboration (1) has recently confirmed that type 2 diabetes remains associated with substantial premature mortality. Compared with nondiabetic individuals, those with diabetes have a hazard ratio (HR) of 1.80 (95% CI 1.71–1.90) for death from any cause, 1.25 (1.19–1.31) for death from cancer, 2.32 (2.11–2.56) for death from vascular causes, and 1.73 (1.62–1.85) for death from other causes. As is apparent, the greater risk is owing to cardiovascular (CV) disease, which accounts for >60% of the years of life lost because of diabetes. Although this increase in CV risk is largely attributable to the coexistence of multiple metabolic and hemodynamic disorders, elevation of plasma glucose levels remains strongly associated with increased CV morbidity and mortality (2–4). In support of a potential direct effect of plasma glucose elevation is the association between fasting plasma glucose levels >100 mg/dL (5.6 mmol/L) and vascular death (1). Since this a near-linear association (1,5) it has been postulated that reduction of plasma glucose levels should exert a positive impact on CV morbidity and mortality. In the UK Prospective Diabetes Study (UKPDS), improvement of glycemic control was associated with a 16% reduction in the risk of myocardial infarction without achieving statistical significance ( P < 0.052) (6). Glycemic control in that seminal trial was, however, relatively unsuccessful. Though intensively treated patients achieved an average A1C of 7%, a progressive worsening in glycemic control occurred after the initial improvement. A more aggressive and successful approach was adopted in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) (7) and Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) (8) trials and Veterans Affairs Diabetes Trial (VADT) (9). In all these three large studies, glycemic control was achieved (A1C 6.5–7.0%) and maintained over a substantial period of …

Guideline Approach to Therapy in Patients With Newly Diagnosed Type 2 Diabetes

Both the prevalence and incidence of type 2 diabetes are increasing worldwide in conjunction with increased Westernization of the population's lifestyle. Type 2 diabetes is still a leading cause of cardiovascular disease (CVD), amputation, renal failure, and blindness. The risk for microvascular complications is related to overall glycemic burden over time as measured by A1C (1,2). The UK Prospective Diabetes Study (UKPDS) 10-year follow-up demonstrated a possible effect on CVD as well (3). A meta-analysis of cardiovascular outcome in patients with long disease duration including Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), and Veterans Affairs Diabetes Trial (VADT) suggested that in these populations the reduction of ~1% in A1C is associated with a 15% relative reduction in nonfatal myocardial infarction (4). Most antihyperglycemic drugs besides insulin reduce A1C values to similar levels (5) but differ in their safety elements and pathophysiological effect. Thus, there is a need for recommending a drug therapy preference. While the positive effects on prevention of microvascular complications were demonstrated with the various antihyperglycemic drugs (1,2,6,7), several questions are left open regarding this therapy in newly diagnosed type 2 diabetes: 1. What is the comparative effectiveness of antihyperglycemic drugs on other long-term outcomes, i.e., β-cell function and cardiovascular morbidity and mortality? 2. What is the comparative safety of these treatments, and do they differ across subgroups of adults with type 2 diabetes? 3. Should we combine antihyperglycemic drugs at the time of diagnosis according to their pathophysiological effect to address the different pathologies leading to hyperglycemia? Most leading guidelines suggest adding one of several antihyperglycemic drugs (5,8,9) when lifestyle and metformin fail to keep A1C at target unrelated to these questions. …

The Effect of Intensive Glucose Lowering on Lipoprotein Particle Profiles and Inflammatory Markers in the Veterans Affairs Diabetes Trial (VADT)

OBJECTIVEIntensive glucose-lowering therapy (INT) did not reduce macrovascular events in the recent randomized trials, possibly because it did not improve or worsen other traditional or novel cardiovascular risk factors.RESEARCH DESIGN AND METHODSStandard plasma lipids, cholesterol content of lipoprotein subfractions, and plasma inflammatory and prothrombotic markers were determined in a subgroup of the Veterans Affairs Diabetes Trial (VADT) participants (n = 266) at baseline and after 9 months of INT or standard therapy.RESULTSINT lowered glycated hemoglobin (by a median of 2% vs. a median of 0.7% by standard treatment; P < 0.0001); increased BMI (4 vs. 1%; P < 0.001), total HDL (9 vs. 4%; P < 0.05), HDL2 (14 vs. 0%; P = 0.009), LDL2 (36 vs. 1%; P < 0.0001), and plasma adiponectin (130 vs. 80%; P < 0.01); and reduced triglycerides (−13 vs. −4%; P = 0.02) and small, dense LDL4 (−39 vs. −13%; P < 0.001), but had no effect on levels of plasma apolipoproteins B-100 and B-48, C-reactive protein, interleukin-6, lipoprotein-associated phospholipase A2, myeloperoxidase, fibrinogen, and plasminogen activator inhibitor 1. Incident macrovascular events were associated with baseline interleukin-6 (hazard ratio per each quartile increase 1.33 [95% CI 1.06–1.66]), total LDL (1.25 [1.01–1.55]), apolipoprotein B-100 (1.29 [1.01–1.65]), and fibrinogen (1.26 [1.01–1.57]) but not changes in any cardiovascular risk factors at 9 months.CONCLUSIONSINT was associated with improved adiponectin, lipid levels, and a favorable shift in LDL and HDL subfractions after 9 months. These data suggest that the failure of INT to lower cardiovascular outcomes occurred despite generally favorable changes in standard and novel risk factors early in the study.

Hypoglycaemia as predictor of cardiovascular accidents

Diabetes mellitus type 2 is not only a chronic disease, but also refers to a group of constantly progressing pathologies. Regardless of the level of development of medicine and used therapeutic approaches, mortality from cardio-vascular complications of diabetes exceeds the figures of the General population. According to the results of Veterans Affairs Diabetes Trial it was revealed that severe hypoglycemia are predictors for the development of myocardial infarction and acute disturbance of cerebral blood circulation. Pledge of successful treatment of patients with type 2 diabetes is the adequate choice of target values of glycemia and maintaining it by means of a combination of curative (observance of dietary recommendations, reception of hypoglycemic drugs, etc.) and not drug-induced (by which primarily active self-monitoring of blood glucose) activities.

Relationship between vitamin D status and incidence of vascular events in the Veterans Affairs Diabetes Trial

ObjectiveFew studies have examined the relationship between vitamin D levels and incident cardiovascular events in large well-characterized patient cohorts. Therefore, our objective was to determine if low vitamin D levels predicted vascular complications of diabetes. MethodsProspective analysis of 936 veterans with type 2 diabetes (59.7 ± 8.4 years, 96.9% male) who participated in the Veteran Affairs Diabetes Trial (VADT) was conducted. 25(OH)-vitamin D was measured a median of two years after entry and participants were subsequently followed 3.7 years. Hazard ratios (HRs) were calculated for cardiovascular endpoints in relation to 25(OH)-vitamin D quartile. For microvascular endpoints, logistic regression was used to calculate odds ratios. ResultsAfter adjusting for age, minority status, treatment arm and history of prior event, individuals in the lowest vitamin D quartile (i.e., 1–15.9 ng/ml) were at similar risk of MI [HR = 1.13 (95% CI: 0.53, 2.42)], CHD [HR = 0.87 (95% CI: 0.49, 1.55)], congestive heart failure [HR = 1.44 (95% CI: 0.67, 3.06)], and death from any cause [HR = 1.04 (95% CI: 0.53, 2.04)] as individuals in the highest vitamin D quartile (i.e., 29.9–77.2 ng/ml). Similarly, there were no differences in the odds associated with retinopathy or renal disease onset or progression in the lowest versus highest vitamin D quartile. ConclusionsThese data indicate that vitamin D status had no significant impact on the incidence of vascular events in a cohort of high-risk veterans with diabetes in which traditional risk factors were managed according to current treatment guidelines.

Targets for Glycemic Control

Targets for Glycemic Control

Cardiovascular disease and glycemic control in type 2 diabetes: now that the dust is settling from large clinical trials

The relationship between glucose control and cardiovascular outcomes in type 2 diabetes has been a matter of controversy over the years. Although epidemiological evidence exists in favor of an adverse role of poor glucose control on cardiovascular events, intervention trials have been less conclusive. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, the Action in Diabetes and Vascular Disease (ADVANCE) study, and the Veterans Affairs Diabetes Trial (VADT) have shown no beneficial effect of intensive glucose control on primary cardiovascular endpoints in type 2 diabetes. However, subgroup analysis has provided evidence suggesting that the potential beneficial effect largely depends on patients’ characteristics, including age, diabetes duration, previous glucose control, presence of cardiovascular disease, and risk of hypoglycemia. The benefit of strict glucose control on cardiovascular outcomes and mortality may be indeed hampered by the extent and frequency of hypoglycemic events and could be enhanced if glucose-lowering medications, capable of exerting favorable effects on the cardiovascular system, were used. This review examines the relationship between intensive glucose control and cardiovascular outcomes in type 2 diabetes, addressing the need for individualization of glucose targets and careful consideration of the benefit/risk profile of antidiabetes medications.

Basic fibroblast growth factor predicts cardiovascular disease occurrence in participants from the veterans affairs diabetes trial

Aim: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in adults with type 2 diabetes mellitus. The aim of the present study was to test whether plasma basic fibroblast growth factor (bFGF) levels predict future CVD occurrence in adults from the Veterans Affairs Diabetes Trial (VADT).Methods: Nearly 400 veterans, 40 years of age or older having a mean baseline diabetes duration of 11.4 years were recruited from outpatient clinics at six geographically distributed sites in the VADT. Within the VADT, they were randomly assigned to intensive or standard glycemic treatment, with follow-up as much as seven and one-half years. CVD occurrence was examined at baseline in the patient population and during randomized treatment. Plasma bFGF was determined with a sensitive, specific two-site enzyme-linked immunoassay at the baseline study visit in all 399 subjects and repeated at the year 1 study visit in a randomly selected subset of 215 subjects.Results: One hundred and five first cardiovascular events occurred in these 399 subjects. The best fit model of risk factors associated with the time to first CVD occurrence (in the study) over a seven and one-half year period had as significant predictors: prior cardiovascular event [hazard ratio (HR) 3.378; 95% confidence intervals (CI) 3.079–3.807; P < 0.0001), baseline plasma bFGF (HR 1.008; 95% CI 1.002–1.014; P = 0.01), age (HR 1.027; 95% CI 1.004–1.051; P = 0.019), baseline plasma triglycerides (HR 1.001; 95% CI 1.000–1.002; P = 0.02), and diabetes duration-treatment interaction (P = 0.03). Intensive glucose-lowering was associated with significantly decreased hazard ratios for CVD occurrence (0.38–0.63) in patients with known diabetes duration of 0–10 years, and non-significantly increased hazard ratios for CVD occurrence (0.82–1.78) in patients with longer diabetes duration.Conclusion: High level of plasma bFGF is a predictive biomarker of future CVD occurrence in this population of adult type 2 diabetes.

5thAnnual Symposium on Self-Monitoring of Blood Glucose (SMBG) Applications and Beyond, May 3–5, 2012, Dublin, Ireland

International experts in the fields of diabetes, diabetes technology, endocrinology, and pediatrics gathered for the 5th Annual Symposium on Self-Monitoring of Blood Glucose (SMBG) Applications and Beyond. The aim of this meeting was to continue setting up a global network of experts in this field and provide an international platform for exchange of ideas to improve life for people with diabetes. In line with previous editions, the 2012 meeting comprised a comprehensive scientific program, parallel interactive workshops, pros and cons debates, and a keynote. All these discussions were intended to help identifying gaps and areas where further scientific work and clinical studies are needed.

Progression of Vascular Calcification Is Increased With Statin Use in the Veterans Affairs Diabetes Trial (VADT)

OBJECTIVETo determine the effect of statin use on progression of vascular calcification in type 2 diabetes (T2DM).RESEARCH DESIGN AND METHODSProgression of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) was assessed according to the frequency of statin use in 197 participants with T2DM.RESULTSAfter adjustment for baseline CAC and other confounders, progression of CAC was significantly higher in more frequent statin users than in less frequent users (mean ± SE, 8.2 ± 0.5 mm3 vs. 4.2 ± 1.1 mm3; P < 0.01). AAC progression was in general not significantly increased with more frequent statin use; in a subgroup of participants initially not receiving statins, however, progression of both CAC and AAC was significantly increased in frequent statin users.CONCLUSIONSMore frequent statin use is associated with accelerated CAC in T2DM patients with advanced atherosclerosis.

Individualizing Targets and Tactics for High-Risk Patients With Type 2 Diabetes

Four years ago, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was stopped early as the result of increased mortality associated with intensive glycemic treatment of a population with type 2 diabetes (T2DM) and high cardiovascular (CV) risk (1). Further reports have appeared from ACCORD (2) and other studies of high-risk populations, notably the Action in Diabetes and Vascular Disease: Preterax and Diamacron MR Controlled Evaluation (ADVANCE) (3) and the Veterans Affairs Diabetes Trial (VADT) (4). These studies provide a body of evidence that intensive treatment of hyperglycemia in T2DM does not in all cases lead to an acceptable balance of benefits to risks. Although important questions remain, both the main findings and secondary and epidemiological analyses from these studies suggest possible changes of our therapeutic approach. This article summarizes the original findings of these trials, discusses recent reports from ACCORD, and describes the authors’ experiences in implementing the intensive regimen at a major ACCORD site. It will not cover all publications on CV risk in T2DM. Rather, we aim to present an updated view of challenges and opportunities in treating high-risk patients with T2DM, drawing mainly on lessons from ACCORD and including some testable hypotheses. The opinions expressed are our own and not meant to represent those of any professional or investigative group. The UK Prospective Diabetes Study (UKPDS) (5) enrolled participants soon after diagnosis of T2DM and did not require them to have other CV risk factors. At the end of randomized comparison of intensive versus standard glycemic treatment, improvements of microvascular end points were found but not a reduction of CV events or mortality. However, the numbers of participants and the rates of CV events were relatively low and thus the statistical power was limited. Later studies were designed to test the effect of intensive …

Editorial: Thematic Issue-Topic–Diabetic Cardiovascular Disease–An Unmet Medical Need: Emerging Targets and Therapies-Introduction to the Special Issue

The major cause of death and complications in patients with type 2 diabetes is cardiovascular disease. Cardiovascular complications that are often associated with diabetes include heart failure, acute myocardial infarction (MI), peripheral vascular disease, and cerebrovascular disease. More than 60% of all patients with type 2 diabetes die of cardiovascular disease, and an even greater percentage have serious complications. The impact of glucose lowering on cardiovascular complications is a hotly debated issue and recent large clinical trials, the Action in Diabetes and Vascular Disease (ADVANCE), Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Veterans Affairs Diabetes Trial (VADT) reported no significant decrease in cardiovascular events with intensive glucose control. Risk remains high even after correcting diabetes-associated dyslipidemia (high triglycerides and low HDL). Several mechanisms are likely to contribute to the accelerated atherosclerosis and increased cardiovascular disease risk seen in type 2 diabetics. Of these, postprandial hyperglycemia/lipemia, insulin resistance and inflammation may be the most important and under controlled contributing factors to vascular disease. The goal of this thematic issue is to address limitations of current therapies and review emerging research and therapeutic approaches that target inflammation, insulin resistance and other pathological mechanisms that contribute to cardiovascular disease in diabetes.

How much glycemic control is needed to prevent progression of diabetic nephropathy?

How much glycemic control is needed to prevent progression of diabetic nephropathy?

Nerve growth factor: Does this have the potential to become a miraculous treatment for diabetic heart?

Nerve growth factor: Does this have the potential to become a miraculous treatment for diabetic heart?

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

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

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

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

What matters in ADVANCE and ADVANCE‐ON

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.

Treating diabetes today with gliclazide MR: a matter of numbers

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by worsening hyperglycaemia. Lowering haemoglobin A1c to below or around 7% has been shown to reduce microvascular and neuropathic complications of diabetes. The ongoing uncertainty regarding whether intensive glycaemic control can reduce the increased risk of cardiovascular disease (CVD) in people with T2DM stirred the launch of the recent long-term megatrials. These trials compared the effects of intensive vs. standard control on vascular complications in relatively high CV risk participants with T2DM. While in Veterans Affairs Diabetes Trial, and Action to Control Cardiovascular Risk in Diabetes, the effect of glucose optimization resulted either in no protection or in an excessive CVD death, the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial showed that intensive glycaemic control reduced the risk of combined major macrovascular and microvascular events. In this trial, the glucose control strategy was based on gliclazide MR at randomization in all patients and then further sequential addition of other glucose-lowering drugs. Several studies showed that gliclazide has antioxidant properties, reduces markers of endothelial inflammation, and prevents glucose-induced apoptosis of endothelial cells. These positive antioxidant effects are not confined to the vascular wall but they are effective also in the β cells. These properties are important because (i) in patients with atherosclerotic process, microvascular abnormalities may hasten disease progression and (ii) slowing the microvascular complications may have a potentially remarkable effect on the natural history of macrovascular disease.

Intensive Glycemic Control and Cardiovascular Disease: Are There Patients Who May Benefit?

Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Recent major publications, such as the Action to Control Cardiovascular Risk in Diabetes trial, the Advance in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation trial, and the Veterans Affairs Diabetes Trial, found that intensive glucose control in patients with T2DM did not reduce CVD outcomes. However, in this article, we review observational studies and clinical trials that, on aggregate, indicate how glucose lowering appears to reduce risks of CVD in certain subgroups, but can be harmful in other individuals. Based on available evidence, we suggest that younger patients with a shorter duration of T2DM, without CVD, and with few comorbid conditions may experience the greatest cardiovascular beneft from intensive glucose control. In contrast, more aggressive glucose lowering in older patients with a longer duration of T2DM, a history of CVD, and/or multiple comorbidities does not translate to reduced cardiovascular events, and may cause harm. The target goal and therapeutic strategy for intensive glucose control should be established for each individual after a careful review of his or her medical and psychosocial history, and should not refect a “one-size-fts-all” approach.