Effect of liraglutide on estimates of lipolysis and lipid oxidation in obese patients with stable coronary artery disease and newly diagnosed type 2 diabetes: A randomized trial.

Elevated levels of non-esterified fatty acids (NEFA) play a role in insulin resistance, impaired beta-cell function and they are a denominator of the abnormal atherogenic lipid profile that characterizes obese patients with type 2 diabetes (T2DM). We hypothesized that the GLP-1 receptor agonist liraglutide, in combination with metformin, would reduce lipolysis. In a randomized, double-blind, placebo-controlled, cross-over trial, 41 T2DM patients with coronary artery disease were randomized and treated with liraglutide-metformin vs placebo-metformin during 12- + 12-week periods with a wash-out period of at least 2 weeks before and between the intervention periods. NEFA kinetics were estimated using the Boston Minimal Model of NEFA metabolism, with plasma NEFA and glucose levels measured during a standard 180-minute frequently sampled intravenous glucose tolerance test. Liraglutide-metformin reduced estimates of lipolysis. Furthermore, placebo-metformin increased estimates of lipid oxidation, while treatment with liraglutide eliminated this effect. We conclude that liraglutide exerts a clinically relevant reduction in estimates of lipolysis and lipid oxidation which is explained, in part, by improved insulin secretion, as revealed by an intravenous glucose tolerance test.

Liraglutide effects on beta-cell, insulin sensitivity and glucose effectiveness in patients with stable coronary artery disease and newly diagnosed type 2 diabetes.

AIMS: The aims of the study were to investigate the effects of the GLP-1 receptor agonist liraglutide as add-on to metformin on insulin sensitivity (Si) and glucose effectiveness (Sg) in addition to its positive effects on beta-cell function in overweight/obese patients with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). METHODS: The design of the study was a randomized, double-blind, placebo-controlled, cross-over trial in patients with stable CAD and newly diagnosed well-controlled T2DM. Patients were treated with liraglutide/metformin vs placebo/metformin for a 12 + 12-week period with ≥2-week wash-out. First phase insulin secretion (AIRg), Si and Sg were estimated by the Bergman Minimal Model, enabling calculation of beta-cell function; Disposition Index (DI) = AIRg × Si. A total of 30 patients from among 41 randomized were available for paired analysis. RESULTS: Baseline characteristics were: HbA1c 47 mmol/mol (SD 6), BMI 31.6 kg/m2 (SD 4.8), fasting plasma-glucose 6.9 mmol/L (IQR 6.1; 7.4) and HOMA-IR 4.9 (IQR 3.0; 7.5). Liraglutide treatment improved AIRg by 3-fold, 497 mU × L-1 × min (IQR 342; 626, P < .0001) and DI by 1-fold, 766 (SD 824, P < .0001). Despite a significant weight loss of -2.7 kg (-6.7; -0.6) during liraglutide treatment, we found no improvement in HOMA-IR, Si or Sg. Weight loss during liraglutide therapy did not result in a carry-over effect. CONCLUSION: Liraglutide as add-on to metformin induces a clinically significant improvement in beta-cell function in overweight/obese, high cardiovascular risk patients with newly diagnosed well-controlled T2DM and CAD. The effect of liraglutide on DI is mediated entirely by improved AIRg whereas the effects on Si and Sg are neutral.

Resting, night-time, and 24 h heart rate as markers of cardiovascular risk in middle-aged and elderly men and women with no apparent heart disease.

AIMS: Increased heart rate (HR) is a predictor of all-cause and cardiovascular (CV) mortality. We tested which measure of HR had the strongest prognostic value in a population with no apparent heart disease. METHODS AND RESULTS: Six hundred and fifty-three men and women between the age of 55 and 75 years were included in the Copenhagen Holter Study and underwent 48 h ambulatory electrocardiographic (ECG) monitoring. Resting HR was measured after at least 10 min of rest. Twenty-four-hour HR was derived from the mean time between normal-to-normal RR intervals (MEANNN). Night-time HR was derived from a 15 min sequence between 2:00 and 2:15 a.m. The median follow-up time was 76 months, and an adverse outcome was defined as all-cause mortality and the combined endpoint of CV death, acute myocardial infarction (AMI), and revascularization. All three measures of HR were significantly associated with all-cause mortality, also after adjustment for conventional risk factors. We found an association between all three measures of HR and CV events in analyses adjusted for sex and age. However, when adjusting for CV risk factors, the association with resting HR and 24 h HR disappeared. In a fully adjusted model, only night-time HR remained in the model, hazard ratio = 1.17 (1.05-1.30), P = 0.005. CONCLUSION: In middle-aged subjects with no apparent heart disease, all measures of increased HR were associated with increased mortality and CV risk. However, night-time HR was the only parameter with prognostic importance after multivariable adjustment.

A randomised trial comparing weight loss with aerobic exercise in overweight individuals with coronary artery disease: The CUT-IT trial.

BACKGROUND: We aimed to compare the effect of aerobic interval training (AIT) versus a low energy diet (LED) on physical fitness, body composition, cardiovascular risk factors and symptoms in overweight individuals with coronary artery disease (CAD). METHODS AND DESIGN: Seventy non-diabetic participants with CAD, a BMI>28 kg/m(2) and aged 45 to 75 years were randomised to 12 weeks' AIT at 90% peak heart rate three times a week or LED (800-1000 kcal/day) for 8-10 weeks followed by 2-4 weeks' weight maintenance diet. RESULTS: Twenty-six (74%) AIT and 29 (83%) LED participants completed intervention per protocol. VO2peak (mL/kg fat free mass(0.67)/min) increased by 10.4% (p = 0.002) following AIT, whereas no change was observed after LED (-3.0%, p = 0.095). The LED group lost 10.6% body weight and 26.6% body fat mass (p < 0.001) compared to 1.6% (p = 0.002) and 5.5% (p < 0.001) following AIT. Waist circumference and visceral abdominal fat were reduced by both interventions but were most pronounced following LED (between-group, p < 0.001). Total cholesterol, non-HDL-C and triglycerides decreased significantly in both groups whereas HDL-C and blood pressure were unchanged. Six participants had their antihypertensive treatment reduced following LED (between-group, p = 0.032). Canadian Cardiovascular Society (CCS), New York Heart Association (NYHA) and anxiety scores were improved, while depressive symptoms remained unchanged. Intention-to-treat analyses including 65 participants (93%) were similar to per protocol analysis. CONCLUSION: Both interventions were feasible and effective in achieving the desired effects. LED was superior in improving body composition and blood pressure, whereas effects on lipids and symptoms were similar in the two groups. Thus, both AIT and LED improve the cardiovascular risk profile in overweight individuals with contemporarily treated CAD.