Sunil Asnani

Is weight loss possible in patients treated with thiazolidinediones? Experience with a low-calorie diet

SUMMARY Background: Weight gain is a frequent side-effect of thiazolidinediones, possibly related to fluid retention and stimulation of pre-adipocyte differentiation. Methods: We report our experience with a low-calorie diet (800cal, sodium content 1500 mmol day−1) combined with behavior modification on eight patients treated with thiazolidinediones (six pioglitazone and two rosiglitazone). Results: All patients had reported previous weight gain following treatment with thiazolidinediones. All patients lost weight over 12 weeks in the program with their mean ± SD body weight falling from 270 ± 54 lbs (123 ± 25 kg) to 244 ± 61 lbs (111 ± 28 kg) (p < 0.01). The weight loss observed was no different from that observed in 16 age- and gender-matched patients with type 2 diabetes not treated with thiazolidinediones (from 263 ± 54 lbs (120 ± 25 kg) to 239 ± 52 lbs (109 ± 24 kg); p < 0.01). Glycemic control improved while reducing insulin treatment. Blood pressure control also improved and antihypertensive medications were decreased. The degree and time course of weight loss is no different from that in patients treated with other diabetic therapies and is associated with improved glycemic and blood pressure control. Conclusions: We conclude that a program of caloric restriction and behavior modification is effective in leading to weight loss in patients treated with thiazolidinediones. This effect is reassuring, since thiazolidinediones stimulate adipogenesis.

Effects of the Thiazolidinediones on Cardiovascular Risk Factors

Rosiglitazone and pioglitazone are medications from the thiazolidinedione class of compounds currently available for the treatment of type 2 diabetes mellitus. Traditionally used to enhance insulin sensitivity and decrease plasma insulin levels, added applications have emerged beyond those involving glycemic control. Cardiovascular risk factors associated with insulin resistance such as elevated blood pressure, dyslipidemia, abnormal fibrinolysis, and endothelial and vascular dysfunction have been shown to improve after thiazolidinedione treatment. Therapy with rosiglitazone or pioglitazone has been found to modify vascular reactivity and other processes involved in atherosclerosis. There may be differences between the agents in their effects on plasma lipid characteristics and particle size. These agents serve as excellent adjuncts to oral and insulin therapy for patients with type 2 diabetes mellitus and hold promise for the prevention of cardiovascular disease associated with the insulin resistance syndrome. Clinical trials are in progress to determine whether such therapy will lead to a reduction in cardiovascular events.

Pioglitazone Restores Endothelial Function in Patients with Type 2 Diabetes Treated with Insulin

The primary aim of this study was to evaluate the effect of pioglitazone on endothelial function, as assessed by flow-mediated dilatation (FMD) nitroglycerine-induced dilatation (NID) in patients with type 2 diabetes mellitus treated with insulin. A randomized double-blind placebo-controlled trial involved 20 patients with insulin-treated type 2 diabetes. Patients received either pioglitazone 30 mg or placebo for 4 months. FMD, NID, and HbA1c were measured before and after 4 months of treatment. HbA1c decreased from 10.0 (+/- 2.3) to 8.4 (+/- 2.0) in the pioglitazone group, a statistically significant improvement in glycemic control (p = 0.018). HbA1c was unchanged in the placebo group (p = 0.477). Endothelial function as assessed by FMD significantly improved from 10.1 (+/- 4.0)% to 14.6 (+/- 6.2)% in the pioglitazone group (p = 0.036) as compared to the placebo group (p = 0.705). There was a trend towards improvement in the NID in the pioglitazone group (from 13.3 +/- 8.0% to 18.9 +/- 5.4%; p = 0.056). In insulin-treated patients with type 2 diabetes, the addition of pioglitazone improves endothelial function, as measured by FMD. Addition of pioglitazone to insulin in type 2 diabetes patients may favorably impact vascular function in diabetes, even after many years of insulin resistance and hyperglycemia.

PPARγ Agonists and Vascular Risk Factors: Potential Effects on Cardiovascular Disease

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily comprising four subtypes designated PPARalpha, PPARgamma1, PPARgamma2, and PPARdelta. These are transcription factors that regulate gene expression, thereby controlling energy metabolism. PPARgamma has widespread distribution in the adipose tissue, skeletal muscle, heart, liver, kidney, gut, macrophages, and vascular tissues. PPARgamma has a key role in adipogenesis, insulin sensitivity, and glucose and lipid metabolism, and also plays a major role in vascular biology, modulating atherosclerosis progression and vascular endothelial function. Thiazolidinediones (TZDs) are the ligands of PPARgamma, and growing evidence suggests that they might both directly and indirectly influence cardiovascular risk in type 2 diabetes patients by favorably altering several pro-atherogenic metabolic processes.

Effect of Pharmacological Treatments for Diabetes on Homocysteine

Hyperhomocysteinemia is a well-established risk factor for cardiovascular disease. The association of hyperhomocysteinemia with diabetes mellitus is complex and may explain some of the risk of CVD in diabetics not explained by traditional risk factors. Both modifiable and non-modifiable factors interact with homocysteine metabolism and determine the plasma homocysteine concentrations. These include genetic abnormalities, age, sex, and various nutritional and hormonal determinants, all of which play a role in atherosclerosis and accelerated peripheral and cardio-vascular disease (CVD). Several medications modulate homocysteine metabolism and hence may play a role in the pathogenesis of CVD. Changes in renal function and interference with the homocysteine metabolism account for some of these drug effects. While a few of these drugs raise plasma homocysteine concentrations, others are beneficial and may counter some of the deleterious effects of hyperhomocysteinemia. Treatment of hyperhomocysteinemia with vitamins lowers plasma homocysteine concentrations and also reverses many of these drug effects. Little data is available on the effect of this intervention on cardiovascular outcomes. This review briefly outlines the effect of various medications used in the management of type 2 diabetes mellitus and metabolic syndrome.