Jeroen P.H. van Wijk

Thiazolidinediones and Blood Lipids in Type 2 Diabetes

Abstract—We evaluated study population characteristics and treatment effects on blood lipids between studies in which either rosiglitazone (RSG) or pioglitazone (PIO) was investigated in patients with type 2 diabetes. We performed a summary analysis of all published double-blind, placebo-controlled studies with RSG (4 and 8 mg/d) and PIO (15, 30, and 45 mg/d). Data were analyzed by the random-effects model. Nineteen trials met our inclusion criteria, yielding 5304 patients, 3236 in studies with RSG and 2068 in studies with PIO. Subjects treated with PIO were more obese and showed more pronounced hyperglycemia and dyslipidemia (increased triglycerides and decreased HDL cholesterol) at baseline than did subjects treated with RSG. By weighted linear-regression analysis, studies with PIO showed greater beneficial effects on triglycerides, total cholesterol, and LDL cholesterol, after adjustment for the respective lipid levels at baseline. RSG 8 mg/d showed greater increases in total cholesterol and LDL cholesterol than did RSG 4 mg/d. PIO 30 mg/d showed greater reductions in triglycerides than did PIO 15 mg/d. Studies conducted with PIO showed more beneficial effects on blood lipids, but also different study population characteristics in comparison with studies conducted with RSG. Differences in both pharmacologic properties between agents and study population characteristics are likely to have influenced the results.

Lipaemia, Inflammation and Atherosclerosis: Novel Opportunities in the Understanding and Treatment of Atherosclerosis

Atherosclerosis is the major cause of death in the world. Fasting and postprandial hyperlipidaemia are important risk factors for coronary heart disease (CHD). Recent developments have undoubtedly indicated that inflammation is pathophysiologically closely linked to atherogenesis and its clinical consequences. Inflammatory markers such as C-reactive protein (CRP), leucocyte count and complement component 3 (C3) have been linked to CHD and to hyperlipidaemia and several other CHD risk factors. Increases in these markers may result from activation of endothelial cells (CRP, leucocytes, C3), disturbances in adipose tissue fatty acid metabolism (CRP, C3), or from direct effects of CHD risk factors (leucocytes). It has been shown that lipoproteins, triglycerides, fatty acids and glucose can activate endothelial cells, most probably as a result of the production of reactive oxygen species. Similar mechanisms may also lead to leucocyte activation. Increases in triglycerides, fatty acids and glucose are common disturbances in the metabolic syndrome and are most prominent in the postprandial phase. People are in a postprandial state most of the day, and this phase is proatherogenic. Inhibition of the activation of leucocytes, endothelial cells, or both, is an interesting target for intervention, as activation is obligatory for adherence of leucocytes to the endothelium, thereby initiating atherogenesis. Potential interventions include the use of unsaturated long-chain fatty acids, polyphenols, antioxidants, angiotensin converting enzyme inhibitors and high-dose aspirin, which have direct anti-inflammatory and antiatherogenic effects. Furthermore, peroxisome proliferator activating receptor gamma (PPARγ) agonists and statins have similar properties, which are in part independent of their lipid-lowering effects.

Hypertriglyceridemia, Metabolic Syndrome, and Cardiovascular Disease in HIV-Infected Patients: Effects of Antiretroviral Therapy and Adipose Tissue Distribution

The use of combination antiretroviral therapy (CART) in HIV-infected patients has resulted in a dramatic decline in AIDS-related mortality. However, mortality due to non-AIDS conditions, particularly cardiovascular disease (CVD) seems to increase in this population. CART has been associated with several metabolic risk factors, including insulin resistance, low HDL-cholesterol, hypertriglyceridemia and postprandial hyperlipidemia. In addition, HIV itself, as well as specific antiretroviral agents, may further increase cardiovascular risk by interfering with endothelial function. As the HIV population is aging, CVD may become an increasingly growing health problem in the future. Therefore, early diagnosis and treatment of cardiovascular risk factors is warranted in this population. This paper reviews the contribution of both, HIV infection and CART, to insulin resistance, postprandial hyperlipidemia and cardiovascular risk in HIV-infected patients. Strategies to reduce cardiovascular risk are also discussed.

Rosiglitazone modulates fasting and post-prandial paraoxonase 1 activity in type 2 diabetic patients.

1 In the present study, we have explored the effect of rosiglitazone on post‐prandial paraoxonase (PON)‐1, an enzyme with potent anti‐oxidant properties that may protect against atherosclerosis because increased post‐prandial lipaemia, although sometimes understated, is part of the diabetic dyslipidaemia. 2 A randomized, cross‐over, placebo‐controlled, double‐blind clinical trial was performed. Participants (19 type 2 diabetic patients on oral antihyperglycaemic agents) were randomly assigned to receive either placebo or rosiglitazone 4 mg twice daily for 8 weeks. After a 6 week wash‐out, the alternative treatment was implemented. Standardized 6 h oral fat‐loading tests were performed after each treatment period. 3 Patients assigned to rosiglitazone had increased fasting PON‐1 activity (from 331 ± 29 to 362 ± 32 U/L before treatment vs after treatment, respectively; P = 0.015), although the PON‐1 mass did not change (68.8 ± 21.1 vs 64.2 ± 25.4 mg/L before treatment vs after treatment, respectively). In addition, rosiglitazone significantly decreased fasting plasma peroxides compared with placebo (162 ± 25 vs 214 ± 28 mmol/L, respectively; P = 0.019). The post‐prandial fall in PON‐1 activity, expressed as area under the curve, was attenuated by rosiglitazone (−97 ± 14 vs−161 ± 24 Uh/L for rosiglitazone vs placebo, respectively; P = 0.02) and the increase in PON‐1 activity caused by rosiglitazone correlated with reductions in fasting plasma glucose (r = ‐0.42; P < 0.05), homeostatic model assessment index (r = ‐0.59; P < 0.01) and peroxides (r = ‐0.40; P = 0.07). 4 The present data indicate that rosiglitazone may convey increased protection against the oxidative modification that represents increased post‐prandial lipaemia.

Daytime triglyceride variability in men and women with different levels of triglyceridemia

BACKGROUND Triglyceride (TG) levels measured in either the fasting or non-fasting state predict the risk of cardiovascular disease (CVD). Since CVD risk assessment is affected by variability in TG, the aim of the study was to investigate intra-individual variability of non-fasting TG. METHODS Capillary triglyceride (cTG) levels were measured in 246 free-living individuals at six time-points during the day on three separate occasions. Intra-individual variability in cTG was assessed by calculating the standard deviation of three measures at each time-point. Subjects were analyzed by gender and by fasting TG level. RESULTS In the fasting state, intra-individual variability was similar in males and females (0.28 and 0.35 mmol/l, respectively), but increased significantly in male but not in female subjects during the day, i.e., 0.28 to 0.69, and 0.35 to 0.36 mmol/l, resp. Subjects with higher fasting TG levels had greater absolute variability in both fasting and non-fasting TG. CONCLUSIONS The variability in non-fasting TG is greater in males and in individuals with higher levels of TG. Since greatest variability in non-fasting TG occurs very late in the day, it is unlikely to affect the assessment of CVD risk, which is based on a blood sample taken during daylight hours.

Effects of Metformin on the Regulation of Free Fatty Acids in Insulin Resistance: A Double-Blind, Placebo-Controlled Study

Introduction. Impaired free fatty acid (FFA) metabolism is closely linked to insulin resistance. Our aim was to evaluate plasma FFA changes in insulin resistance in a physiological situation after improvement of insulin sensitivity by metformin. Methods. A double-blind, placebo-controlled intervention with metformin was carried out in patients with insulin resistance. Nineteen patients were randomized to receive metformin 850 mg b.i.d. during 6 weeks or placebo. Participants underwent a mental stress test and an oral glucose tolerance test (OGTT) before and after treatment. Results. Fasting plasma glucose, FFA, and HOMA-IR tended to decrease after metformin, suggesting improved insulin sensitivity. FFA concentrations during the mental stress test showed a similar pattern after metformin, albeit lower at all time points, in contrast to the placebo group. The decrease in fasting plasma FFAs was positively associated to the decrease in HbA1c (r = 0.70; P = 0.03) and in fasting glucose (r = 0.74; P = 0.01). The suppression of plasma FFAs during OGTT did not change by metformin or placebo. Conclusion. Metformin in insulin resistance did not lead to improved FFA dynamics despite a trend of improved insulin sensitivity. Metformin most likely decreases plasma FFAs mainly by suppressing fasting FFA concentrations and not by suppression of acute stress-induced lipolysis.