Diabetes & Vascular Disease Research

The disappointing results of glucose lowering studies have highlighted the ongoing need to develop new therapeutic strategies to reduce cardiovascular risk in patients with type 2 diabetes. The presence of a range of metabolic abnormalities in diabetic patients presents a number of potential targets for therapeutic intervention. While modulation of peroxisome proliferator activated receptors (PPARs) represents an attractive approach, the results of studies of pharmacological agonists have been variable. The findings of these studies and rationale for development of dual PPAR-α/γ agonists will be reviewed.

The active incretin hormone glucagon-like peptide-1(7-36)amide (GLP-1) is a 30-amino acid peptide that exerts glucoregulatory and insulinotropic actions by functioning as an agonist for the GLP-1 receptor (GLP-1R). In addition to its anti-diabetic effects, GLP-1 has demonstrated cardioprotective actions. Here we review the cardiovascular effects of the GLP-1 analogues currently approved for the treatment of type 2 diabetes, namely exenatide and liraglutide. We discuss their anti-hyperglycaemic efficacy, and offer a clinical perspective of their effects on cardiovascular risk factors such as body weight, blood pressure, heart rate and lipid profiles, as well as their potential consequences on cardiovascular events, such as arrhythmias, heart failure, myocardial infarction and death. Lastly, we briefly review additional GLP-1R agonists in clinical development.

Type 2 Diabetes continues to rise in prevalence throughout the globe, and cardiovascular diseases remain the most common cause of morbidity and mortality among patients. Dipeptidyl-peptidase-4 (DPP-4) inhibitors are a newer class of oral anti-hyperglycemic agents whose effect is mediated through the incretin hormones, GLP-1 and GIP. In this review, we discuss the incretin system, DPP-4 inhibitors and their mechanism of action and, principally, the potential impact of DPP-4 inhibition on the cardiovascular system. Some pre-clinical data, small mechanistic studies and post-hoc analyses of randomized clinical trials suggest a possible beneficial effect on cardiovascular risk. However, the relationship between DPP-4 inhibition and actual cardiovascular outcomes remains unknown. We therefore also review ongoing large, randomized clinical trials examining this very question.

Glucose in the glomerular ultrafiltrate is actively reabsorbed by sodium glucose transporters (SGLT) in the proximal tubule. The SGLT2 protein is a high capacity molecule responsible for the majority of glucose reuptake with pharmacological inhibition, resulting in the loss of about 80g of glucose in the urine each day. About a dozen inhibitors of SGLT2 have entered clinical development, and the first has recently been submitted for registration with the United States Food and Drug Administration. The rationale for the clinical evaluation of these agents is their beneficial effects on glycaemia, blood pressure and body weight. No adequately powered trial has yet determined the effects of an SGLT2 inhibitor on either macrovascular or microvascular outcomes, although a number of large-scale trials are now ongoing. Evidence that will define the overall balance of benefits and risks of this new drug class is anticipated within the next 5 years.

Gender differences in cardiovascular outcomes were compared in asymptomatic men and women with type 2 diabetes (T2DM) in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study. Of 1123 participants, 290 men and 271 women were randomised to screening with stress myocardial perfusion imaging (MPI); 311 men and 251 women were randomised to no screening. Follow-up was 4.8±0.9 years for the occurrence of cardiac events (CE; cardiac death or non-fatal myocardial infarction). The frequency of abnormal screening was similar in men (24%) and women (19%), (p=0.2), although women trended to have smaller MPI abnormalities. CE rates were lower in women than men (1.7% vs. 3.8%, p=0.04). No CEs occurred in 17 high-risk (UKPDS risk engine) women, whereas 14 (11.2%) occurred in 125 high-risk men. Asymptomatic women with T2DM have significantly better cardiac outcomes than their male counterparts and represent a subgroup for which screening for coronary artery disease does not appear warranted.

This was a nested sub-study of a randomised placebo-controlled trial of the effect of 6 months of treatment with rosiglitazone added to existing therapy on myocardial triglyceride (mTG) content in patients with type 2 diabetes (T2D) and prevalent cardiovascular disease (CVD) or at least one additional risk factor. The primary endpoint, mTG content, was measured with cardiac ¹H-magnetic resonance spectroscopy. Of the 99 randomised participants selected for the imaging sub-study, 49 (48%) had complete and interpretable spectroscopy data (age = 58 years, duration of T2D = 9.5 years; 57% women and 69% non-white). There was no significant change in mTG in either group (−0.1 ± 0.6% and −0.05 ± 0.8% respectively) and the changes in mTG were not associated with changes in left ventricular structure or function. Compared with placebo, treatment with rosiglitazone for 6 months had no discernible effect on mTG or left ventricular function in this population with long-standing diabetes and CVD.

Guidelines recommend aggressive goals for lipid and blood pressure reduction for high risk patients with diabetes mellitus and atherosclerotic coronary disease. However, it remains unclear how many patients achieve treatment goals versus the number of people merely placed on treatment. We conducted an observational study in an academic cardiology clinic. A total of 926 patients with atherosclerotic cardiovascular disease and concomitant diabetes mellitus met criteria. Mean age was 68.4 ± 10.2, 65.6% were male, and 86.8% were Caucasian. By the last visit a high percentage of patients were receiving recommended medications. Mean LDL-cholesterol achieved was 80.4 mg/dl with 40.9% reaching ≤ 70 mg/dl, and 61.7% reaching SBP ≤ 130 mmHg. Many patients with diabetes mellitus and atherosclerotic cardiovascular disease are prescribed recommended medications; however, few achieve guidelines-specified therapeutic goals for LDL-cholesterol and blood pressure. Studies evaluating performance improvement should include percentage of patients reaching treatment goals. Mechanisms underlying the treatment gap need to be identified and addressed.

Background: Diabetes mellitus (DM) is often considered a risk equivalent for cardiovascular disease (CVD); however, the variation in CVD risk in adults with DM has not been described.

Methods: We studied 1114 US adults aged ≥18 years with DM from national survey data and the proportion at low (<10%), intermediate (10–20%) and high (>20%) risk, or with CVD, by age, gender, ethnicity and diabetes type and treatment, and glycaemic and risk factor control by risk group.

Results: Overall, 22.9% were low, 17.5% intermediate, 31.4% high risk and 28.2% had pre-existing CVD (total 59.6% high risk/CVD). More Hispanics (32.4%) and Blacks (30.6%) versus Whites (18.8%) were at lower risk (p<0.0001). Among type 1 versus 2 DM, 35% vs. 65% (p<0.0001) and among insulin users 68.1% were high risk or with CVD. However, among low-intermediate risk, >50% have metabolic syndrome and 7% chronic kidney disease, increasing the high risk/CVD group to 86.8%. Simultaneous achievement of HbA1c, blood pressure and low density lipoprotein-cholesterol goals was low (<15%) regardless of risk group.

Conclusions: Many DM patients are not at high 10-year CVD risk, but metabolic factors may place them at greater long-term risk. Risk assessment could help target the intensity of treatment.

Purpose: Our aim was to determine the influence of waist circumference on the repartition of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) subfractions in patients with increased waist perimeter and one or more cardiovascular risk factor.

Methods: All 117 patients without lipid-lowering therapy underwent routine clinical, biological evaluation and isolation of the following lipid subfractions: HDL2b, HDL2a, HDL3a, HDL3b, HDL3c and LDL1, LDL2, LDL3, LDL4.

Results: Mean waist circumference was 102.9 cm for women and 109.4 cm for men, and 92 patients presented with metabolic syndrome. In the highest waist circumference tertile, when compared with the lowest one, an increased HDL3c (7.7% vs. 5.7% p=0.02) and a non-significant decrease of HDL2b percentages were observed with no difference in other subfractions. In multivariate analysis, only plasma triglycerides and waist circumference remained independent predictors of HDL3c percentage.

Conclusion: In our population, waist circumference was a strong and independent determinant of a shift in the distribution of HDL toward denser particles.