Christos V. Rizos

How safe is the use of thiazolidinediones in clinical practice

Background: Thiazolidinediones (TZDs) are widely used antidiabetic drugs with proven efficacy regarding mainly surrogate markers of diabetes management. However, efficacy on surrogate markers may not always translate into benefits in clinical outcomes. Thiazolidinediones are usually well tolerated; however, their use may be associated with several adverse effects. The first TZD, troglitazone, was withdrawn from the market owing to serious hepatotoxicity. However, this does not seem to be the case with newer TZDs. Objective: The aim of the present review is to discuss the safety profile of this drug class. Methods: We searched PubMed up to July 2008 using relevant keywords. Conclusions: Common side effects associated with TZDs include edema, weight gain, macular edema and heart failure. Moreover, they may cause hypoglycemia when combined with other antidiabetic drugs as well as decrease hematocrit and hemoglobin levels. Increased bone fracture risk is another TZD-related side effect. Thiazolidinediones tend to increase serum low density lipoprotein cholesterol levels, with rosiglitazone having a more pronounced effect compared with pioglitazone. Moreover, rosiglitazone increases low density lipoprotein particle concentration in contrast to pioglitazone where a decrease is observed. Rosiglitazone has been associated with an increase in myocardial infarction incidence. On the other hand, pioglitazone may reduce cardiovascular events. Overall, TZDs are valuable drugs for diabetes management but physicians should keep in mind that they are associated with several adverse events, the most prominent of which is heart failure.

Metformin and cancer.

Type 2 diabetes mellitus is a rising cause of cardiovascular morbidity and mortality. A number of studies have also identified diabetic patients as having increased risk for the development of cancer. Metformin is a widely prescribed antidiabetic drug with an established efficacy coupled with a favorable safety profile and low cost. An increasing number of studies have associated metformin treatment with a decrease of cancer risk. Moreover, metformin has also been associated with improved outcomes in cancer patients. These possible pleiotropic effects of metformin may establish metformin as a cancer prevention and treatment option. However, any favorable effects of metformin on cancer are not always corroborated by clinical trials. Larger studies are expected to better investigate the possible antineoplastic effects of metformin.

Pleiotropic effects of thiazolidinediones

Background: Insulin resistance and hyperglycemia characterize type 2 diabetes mellitus. Type 2 diabetes mellitus is usually accompanied by concomitant disorders, such as dyslipidemia, hypertension and atherosclerosis. Thiazolidinediones are antidiabetic drugs that increase insulin sensitivity by activating the peroxisome proliferator-activated receptor γ. There is evidence that thiazolidinediones exert a number of pleiotropic effects that may play an important role in the treatment of type 2 diabetes mellitus. Objective: The purpose of the present article was to review the ‘pleiotropic’ effects of thiazolidinediones (i.e., their effects beyond glucose lowering). Methods: The study involved searching PubMed up to February 2008 using relevant keywords. Conclusions: Thiazolidinediones favorably alter fat distribution and improve cardiovascular risk factors, such as blood pressure, inflammation markers and uric acid and they may also delay the progression of atherosclerosis. The effects on the lipid profile differ between the two thiazolidinediones studied with pioglitazone having more positive effects compared with rosiglitazone. Furthermore, thiazolidinediones improve diabetic complications, such as diabetic nephropathy and non-alcoholic fatty liver disease. Thiazolidinediones may also play a role in other diseases, such as polycystic ovary syndrome. These pleiotropic effects may prove to be clinically relevant. There has been recent debate about the possible differences between the two thiazolidinediones in terms of cardiovascular disease outcome. In this context, differences in the lipid effects between the two drugs may be relevant.

Rosuvastatin treatment is associated with an increase in insulin resistance in hyperlipidaemic patients with impaired fasting glucose

Aim of the study:  The increase in physician‐reported diabetes following rosuvastatin treatment in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin study has raised concerns whether this statin exerts a detrimental effect on glucose metabolism. We assessed the effect of rosuvastatin treatment across dose range on glucose homeostasis in hyperlipidaemic patients with impaired fasting glucose (IFG), who are at high risk to develop diabetes mellitus.

Effects of rosuvastatin combined with olmesartan, irbesartan, or telmisartan on indices of glucose metabolism in Greek adults with impaired fasting glucose, hypertension, and mixed hyperlipidemia: a 24-week, randomized, open-label, prospective study.

BACKGROUND Statin therapy has been reported to be associated with new-onset diabetes. Angiotensin II-receptor blockers (ARBs) are effective antihypertensive drugs that have been reported to activate peroxisome proliferator-activated receptor gamma (PPARgamma) to differing extents, with favorable effects on glucose metabolism and the incidence of new-onset diabetes. Among the ARBs, telmisartan is a partial activator of PPARgamma, irbesartan is a weak partial activator, and olmesartan has no effect on PPARgamma activation. OBJECTIVE The goal of this study was to evaluate the effects on glucose homeostasis of combining rosuvastatin with ARBs of varying PPARgamma-activating potency in Greek adults with impaired fasting glucose, mixed dyslipidemia, and stage 1 hypertension. METHODS This was a 24-week, randomized, open-label study. Inclusion criteria were impaired fasting plasma glucose (FPG) (100-125 mg/dL [5.6-6.9 mmol/L]), mixed dyslipidemia (LDL-C >160 mg/dL [4.14 mmol/L] and triglycerides >150 mg/dL [1.69 mmol/L]), and stage 1 hypertension (systolic blood pressure 140-159 mm Hg and/or diastolic blood pressure 90-99 mm Hg). After 12 weeks of dietary intervention, patients were randomly allocated to receive rosuvastatin 10 mg/d plus telmisartan 80 mg/d (RT group), irbesartan 300 mg/d (RI group), or olmesartan 20 mg/d (RO group) for 24 weeks. The primary end point was change in the following indices of glucose metabolism after 6 months of treatment: FPG, homeostasis model assessment of insulin resistance (HOMA-IR), HOMA of beta-cell function (HOMA-B), and glycosylated hemoglobin (HbA(1c)). Secondary end points included changes in anthropometric variables, blood pressure, serum lipids, and high-sensitivity C-reactive protein (hs-CRP). Tolerability was monitored throughout the study. RESULTS After the 12-week dietary intervention, 151 white patients (78 female, 73 male) met the inclusion criteria and were randomized to receive RT (n = 52), RI (n = 48), or RO (n = 51). The mean (SD) age of the 3 groups was 60 (10), 60 (10), and 58 (12) years, respectively; their mean weight was 79 (11), 81 (12), and 78 (11) kg. At 6 months, the RT group had a 29% decrease in HOMA-IR (from a median [range] of 2.6 [0.6-6.6] to 1.8 [0.5-5.1]), the RI group had a 16% increase (from 2.5 [0.5-6.2] to 2.9 [0.5-8.1]), and the RO group had a 14% increase (from 2.4 [0.5-7.9] to 2.7 [0.5-5.2]) (all, P < 0.05 vs baseline). The improvement in the RT group was statistically significant compared with the RI group (P < 0.01) and the RO group (P < 0.05). The changes from baseline in FPG and HbA(1c) were not significant in any group. Fasting serum insulin decreased by 21% in the RT group (from 10.4 [2.4-28.1] to 8.2 [2.4-18.8] microU/mL), whereas it increased by 12% in the RI group (from 9.1 [2.0-26.5] to 10.2 [2.0-25.2] microU/mL) and by 8% in the RO group (from 10.1 [2.0-29.6] to 10.9 [2.0-19.1] microU/mL) (all, P < 0.05 vs baseline). Again, there was a significant difference between the RT group and the RI group (P < 0.01) and RO group (P < 0.05). Levels of hs-CRP decreased by 44% in the RT group (from 2.2 [0.3-7.9] to 1.2 [0.4-7.0] mg/L), by 12% in the RI group (from 2.2 [0.3-12.3] to 1.9 [0.2-11.4] mg/L), and by 22% in the RO group (from 2.1 [0.7-4.0] to 1.7 [0.7-6.2] mg/L). The difference was statistically significant for the RT group compared with baseline and with the RI and RO groups (all comparisons, P < 0.05). Blood pressure was significantly reduced from baseline in all 3 groups, with no significant differences between groups. No serious adverse events were reported during the study, nor were there any clinically significant elevations in aminotransferases or creatine kinase. CONCLUSION In this small, randomized, open-label study, the RT combination had favorable effects on HOMA-IR, fasting serum insulin, and hs-CRP compared with the RI and RO combinations in Greek adults with impaired fasting glucose, mixed hyperlipidemia, and stage 1 hypertension.

Antihypertensive drugs and glucose metabolism

Hypertension plays a major role in the development and progression of micro- and macrovascular disease. Moreover, increased blood pressure often coexists with additional cardiovascular risk factors such as insulin resistance. As a result the need for a comprehensive management of hypertensive patients is critical. However, the various antihypertensive drug categories have different effects on glucose metabolism. Indeed, angiotensin receptor blockers as well as angiotensin converting enzyme inhibitors have been associated with beneficial effects on glucose homeostasis. Calcium channel blockers (CCBs) have an overall neutral effect on glucose metabolism. However, some members of the CCBs class such as azelnidipine and manidipine have been shown to have advantageous effects on glucose homeostasis. On the other hand, diuretics and β-blockers have an overall disadvantageous effect on glucose metabolism. Of note, carvedilol as well as nebivolol seem to differentiate themselves from the rest of the β-blockers class, being more attractive options regarding their effect on glucose homeostasis. The adverse effects of some blood pressure lowering drugs on glucose metabolism may, to an extent, compromise their cardiovascular protective role. As a result the effects on glucose homeostasis of the various blood pressure lowering drugs should be taken into account when selecting an antihypertensive treatment, especially in patients which are at high risk for developing diabetes.

Effect of Non-Statin Lipid Lowering and Anti-Obesity Drugs on LDL Subfractions in Patients with Mixed Dyslipidaemia

Small, dense low density lipoprotein (sdLDL) particles are considered an emerging cardiovascular risk factor. Obese patients with mixed dyslipidaemia frequently have elevated sdLDL cholesterol (sdLDL-C) levels. Therefore, agents that favourably modulate the LDL phenotype may be of clinical value in these patients. We review the efficacy of anti-obesity and lipid lowering drugs other than statins on LDL subfractions in patients with mixed dyslipidaemia primarily focusing on those who are overweight/obese. The literature search was based on PubMed listings up to 26 November 2009. In most studies ezetimibe decreases the large and medium LDL subclasses and, to a lesser extent, the sdLDL particles, while it does not substantially influence LDL size. Fibrates and niacin reduce sdLDL particles and shift LDL size towards large, buoyant LDL particles. More studies are needed to elucidate the effects of fish oils and resins on LDL phenotype. Orlistat and rimonabant have been associated with reductions in sdLDL-C levels along with an increase in LDL particle size. We did not find any literature describing the effect of sibutramine on sdLDL profile. Treatment with fibrates and niacin seems to be beneficial in patients with mixed dyslipidaemia. The addition of orlistat may further improve LDL phenotype in overweight/obese patients.

The effect of simvastatin alone versus simvastatin plus ezetimibe on the concentration of small dense low-density lipoprotein cholesterol in subjects with primary hypercholesterolemia

Abstract Objective: To compare the effects of simvastatin alone versus simvastatin plus ezetimibe on small dense low-density lipoprotein cholesterol (sdLDL-C) concentration in subjects with primary hypercholesterolemia. Research design and methods: Patients with LDL-C levels above those recommended by the National Cholesterol Education Program Adult Treatment Panel III were randomized to open-label simvastatin 40 mg (n = 50) or simvastatin/ezetimibe 10/10 mg as a fixed combination (n = 50) daily. LDL particle size (estimated by electrophoresis), sdLDL-C levels, and lipid profile were blindly assessed at baseline and 3 months. Clinical trial registration: clinicaltrials.gov NCT00932620. Results: Both simvastatin 40 mg and simvastatin/ezetimibe 10/10 mg decreased total cholesterol (−31% and −36%, respectively), LDL-C (−43% and −49%, respectively), triglycerides (−17% and −19%, respectively), non-high-density lipoprotein cholesterol (non-HDL-C; −40% and −46%, respectively), large LDL-C (−40 and −44%, respectively) and sdLDL-C levels (−42% and −46%, respectively, all p < 0.000 vs baseline) and increased LDL particle size (+0.5% and +0.7%, respectively, both p < 0.05 vs baseline). The changes in total cholesterol, LDL-C and non‐HDL-C were greater in the simvastatin/ezetimibe group (all p < 0.05). Changes in triglycerides, large LDL-C, sdLDL-C levels and LDL particle size were similar in the two groups. In multivariate analysis, baseline sdLDL-C and triglyceride levels, but not the choice of treatment, were significantly and independently correlated with the changes in sdLDL-C levels. Conclusion: The combination of simvastatin 10 mg plus ezetimibe 10 mg is similarly effective to simvastatin 40 mg in improving sdLDL-C concentration and LDL particle size in subjects with primary hypercholesterolemia.

The current role of thiazolidinediones in diabetes management.

Among the epidemics of modern time, type 2 diabetes mellitus (T2DM) is one of the main contributors to overall morbidity as well as mortality. A number of different treatment options are available for the management of diabetes. Among them thiazolidinediones (TZDs) is an interesting drug class since it does not target the result of T2DM, i.e., hyperglycemia but rather some of the core mechanisms of the disease. Indeed, glitazones increase insulin sensitivity by activating the peroxisome proliferator-activated receptor γ, which plays an important role in regulating various metabolic parameters. Although TZDs have an established efficacy in T2DM treatment, their usage during the past years was questioned following the emergence of some alarming data regarding their safety and especially the cardiovascular safety of rosiglitazone. As a result, there is often some skepticism about the current role of TZDs in T2DM management. This mainly affects rosiglitazone even leading to its withdrawal from several markets in contrast to pioglitazone, which has shown a beneficial cardiovascular profile. A comprehensive assessment of the benefit-to-risk ratio of TZDs is required in order to better understand the place of these drugs in T2DM management.

Does combination therapy with statins and fibrates prevent cardiovascular disease in diabetic patients with atherogenic mixed dyslipidemia

Type 2 diabetes mellitus (T2DM) is associated with the development and progression of cardiovascular disease (CVD). Statins have an established efficacy in the management of dyslipidemia primarily by decreasing the levels of low-density lipoprotein cholesterol and thus decreasing CVD risk. They also have a favorable safety profile. Despite the statin-mediated benefit of CVD risk reduction a residual CVD risk remains, especially in T2DM patients with high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) values. Fibrates decrease TG levels, increase HDL-C concentrations, and improve many other atherosclerosis-related variables. Fibrate/statin co-administration improves the overall lipoprotein profile in patients with mixed dyslipidemia and may reduce the residual CVD risk during statin therapy. However, limited data exists regarding the effects of statin/fibrate combination on CVD outcomes in patients with T2DM. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study the statin/fibrate combination did not significantly reduce the rate of CVD events compared with simvastatin/placebo in patients with T2DM. However, it did show a possible benefit in a pre-specified analysis in the subgroup of patients with high TG and low HDL-C levels. Furthermore, in the ACCORD study the simvastatin/fenofibrate combination significantly reduced the rate of progression of retinopathy compared with statin/placebo administration in patients with T2DM. The present review presents the available data regarding the effects of statin/fibrate combination in patients with T2DM and atherogenic mixed dyslipidemia.