Vildagliptin: clinical trials programme in monotherapy and combination therapy for type 2 diabetes.

As part of an extensive clinical development programme in patients with type 2 diabetes (T2DM), vildagliptin 50 mg once daily and twice daily, and 100 mg once daily have been assessed in placebo-controlled and, more importantly, in head-to-head active-comparator monotherapy trials over a wide range of baseline HbA1c levels and in a large number of elderly patients. Notable findings in individual trials included: comparable HbA1c lowering over 24 weeks with 100 mg once daily or 50 mg twice daily; efficacy comparable to rosiglitazone with reduced risk of weight gain and oedema over 24 weeks; and durable glycaemic control for up to 2 years with a reduced frequency of gastrointestinal adverse events compared with metformin. Pooled monotherapy data indicate that vildagliptin 100 mg daily produces consistent and clinically meaningful reductions in HbA1c across a range of initial HbA1c levels, in patients with lower and greater body mass index, and in younger and older patients. To date, the safety/tolerability profile seems comparable to placebo with neutral effects on body weight and lipid profiles, and minimal risk of hypoglycaemia. A preliminary study in subjects with impaired glucose tolerance showed that vildagliptin 50 mg once daily enhanced islet cell function, reduced glycaemic excursions and was very well tolerated, paving the way for a future trial in diabetes prevention. Vildagliptin has also been extensively studied in multiple clinical scenarios as add-on combination therapy in patients with inadequate glycaemic control on metformin, thiazolidinedione, sulfonylurea and insulin treatment, and has consistently been shown to improve glycaemic control with good tolerability and low risk for hypoglycaemia. In a trial in patients receiving metformin, the addition of vildagliptin 50 mg twice daily resulted in a 1.1% reduction in HbA1c at 24 weeks. Compared with add-on pioglitazone 30 mg daily in patients inadequately controlled with ongoing metformin therapy, vildagliptin 50 mg twice daily reduced HbA1c by 0.9% vs. 1.0% and was not associated with weight gain (+0.3 kg vs. +1.9 kg) over 24 weeks. Most notably, vildagliptin plus pioglitazone as initial combination therapy in drug-naive patients resulted in robust HbA1c reductions of 1.9% from baseline. In patients receiving stable insulin therapy, vildagliptin 50 mg twice daily improved glycaemic control and was associated with a significant reduction in hypoglycaemic episodes over 24 weeks. Vildagliptin shows considerable promise as a partner for metformin and other commonly used oral antidiabetic agents, and may well play an important role in combination with insulin therapy to further improve glycaemic control.

Topiramate in the treatment of obese subjects with drug-naive type 2 diabetes.

AIM: The aim of this study was to examine the efficacy and safety of topiramate as an adjunct to diet and exercise in drug-naive, obese subjects with type 2 diabetes. METHODS: Drug-naive individuals with type 2 diabetes, body mass index (BMI) of > or =27 and <50 kg/m(2) and haemoglobin A(1c) (HbA(1c)) of <10.5% were enrolled into the study. All the individuals participated in a non-pharmacologic weight loss program (Pathways to Change((R)); Johnson & Johnson Healthcare Systems, Piscataway, NJ, USA) throughout the trial. After a 6-week placebo run-in, the subjects were randomized to placebo, topiramate 96 mg/day or topiramate 192 mg/day. Subjects were scheduled for 8-week titration and 52-week maintenance phases. The study was ended early; efficacy data were reported for a predefined modified intent-to-treat (MITT) population (n = 229), with 40 weeks of treatment. All the subjects who provided any safety data were included in the safety population (n = 535). RESULTS: Baseline mean weight was 103.7 kg, BMI 36 kg/m(2) and HbA(1c) 6.7% across all treatment groups. By the end of week 40, the placebo, the topiramate 96 mg/day and topiramate 192 mg/day groups lost 2.5, 6.6 and 9.1% of their baseline body weight respectively (p < 0.001 vs. placebo, MITT population using last observation carried forward). The decrease in HbA(1c) was 0.2, 0.6 and 0.7% respectively (p < 0.001 vs. placebo, MITT). Topiramate significantly reduced blood pressure and urinary albumin excretion; a weight-loss-independent HbA(1c) improving effect of topiramate was demonstrated. Adverse events were predominantly related to central nervous system (CNS). CONCLUSIONS: Topiramate as an add-on treatment to lifestyle improvements produced significant weight loss and improved glucose homeostasis in obese, drug-naive subjects with type 2 diabetes. These treatment advantages should be balanced against the occurrence of adverse events in the CNS.

Efficacy and safety of topiramate in combination with metformin in the treatment of obese subjects with type 2 diabetes: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To investigate the efficacy and safety of topiramate in obese subjects with type 2 diabetes treated with metformin. DESIGN: This was a multicenter, double-blind, placebo-controlled trial. All subjects received a non-pharmacological program of diet, exercise and behavioral modification throughout the study; the assigned diet was 600 kcal/day less than the subject's individually calculated energy expenditure. After a 6-week single-blind placebo run-in, subjects were randomized to placebo, topiramate 96 mg/day or topiramate 192 mg/day. Following an 8-week titration period, subjects remained on their assigned dose for 52 weeks. However, the sponsor ended the study early in order to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population. A total of 646 obese men and women (age: 18-75 years, body mass index: 27-50 kg/m(2)) with an established history of type 2 diabetes mellitus controlled by metformin monotherapy were randomized. Efficacy was assessed in a pre-determined modified intent-to-treat (MITT) population of 307 subjects whose randomization date would have allowed them to complete 24 weeks on study medication before the announcement of study termination. MEASUREMENTS: Joint primary efficacy parameters were mean percent change in weight and change in glycosylated hemoglobin (HbA(1c)) from baseline to week 24. RESULTS: Subjects in the placebo, topiramate 96 mg/day and topiramate 192 mg/day groups lost 1.7%, 4.5% (P<0.001) and 6.5% (P<0.001), respectively, of their baseline body weight and had absolute decreases in HbA(1c) of 0.1%, 0.4% (P<0.001) and 0.6% (P<0.001) (MITT, last observation carried forward). Topiramate-treated subjects also experienced statistically significant decreases in systolic blood pressure. Most common adverse events were paresthesia and events related to the central nervous system. CONCLUSIONS: Topiramate was effective for weight reduction and improvement in glycemic control in obese subjects with type 2 diabetes treated with metformin monotherapy. Further study in obese diabetics is warranted.

The benefits of modest weight loss in type II diabetes.

Obesity increases the risk of developing type II diabetes. However, the link between the two remains unclear, although insulin resistance and visceral adiposity are dominant risk factors. A study with CT scanning confirmed that the degree of visceral adiposity had a significant positive correlation with insulinaemia, and was negatively associated with insulin sensitivity. A 48 month retrospective study in patients with type II diabetes, who had received dietary therapy, identified a 'responder' group in whom metabolic improvements accompanied weight loss. Preferential loss of visceral fat may be an important factor in these 'responders'. Patients losing > 6.9 kg (or at least 10% mean baseline body weight) have demonstrated significant improvements in their glucose, HbA1 and lipid profiles. Modest weight loss by patients with type II diabetes therefore improves glycaemic control, insulin sensitivity and cardiovascular risk factors; and the risk of developing long-term diabetes-related complications may also be reduced by such metabolic improvements.

A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects.

BACKGROUND: Treatment of obese subjects with topiramate has recently been associated with significant weight loss in a 6-month dose-ranging study. OBJECTIVE: To investigate the long-term efficacy and safety of topiramate in obese subjects. DESIGN: Randomised, double-blind, placebo-controlled study investigating three doses of topiramate: 96, 192, and 256 mg/day. All subjects also participated in a nonpharmacological weight-loss programme. SUBJECTS: The study included 1289 subjects 18-75 y with a body mass index >/=30 kg/m(2) and <50 kg/m(2) in the absence of comorbidities, or >/=27 kg/m(2) and <50 kg/m(2) in the presence of controlled hypertension and/or dyslipidaemia. DURATION: The original study design was for a 6-week, single-blind, placebo run-in phase followed by an 8-week titration phase and 2 y of maintenance at the assigned dose. Sponsor ended study early in order to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population. Therefore, none of the subjects completed the full 2 y of treatment. Efficacy results are based on subjects who were enrolled early enough to have had an opportunity to complete 1 y at their assigned dose (modified intent-to-treat population, MITT) before learning of the decision to terminate the study. Safety results are based on all subjects who took at least one dose of study medication. RESULTS: The safety population consisted of 1282 subjects, and the MITT efficacy population was 854 subjects. At 60 weeks, subjects in the placebo group lost 1.7% of their baseline body weight, while subjects in the topiramate 96, 192, and 256 mg/day treatment groups lost 7.0, 9.1, and 9.7%, respectively (P<0.001, MITT, last observation carried forward). Weight loss >/=5% of baseline weight was achieved by 18% of subjects in the placebo arm vs 54, 61, and 67% of subjects receiving topiramate 96, 192, and 256 mg/day, respectively; weight loss >/=10% was achieved by 6 vs 29, 40, and 44%, respectively (P<0.001). Weight loss was accompanied by significant improvements in blood pressure (systolic/diastolic changes of +0.4/+1.0, -3.1/-1.3, -5.7/-3.4, and -4.6/-2.4 mmHg were observed for placebo, topiramate 96 mg/day, 192 mg/day, and 256 mg/day, respectively, P<0.001) and glucose and insulin. The most common adverse events more frequently observed in topiramate-treated subjects occurred mostly during the titration phase and were related to the central or peripheral nervous system and included paresthesia, difficulty with concentration/attention, depression, difficulty with memory, language problems, nervousness, and psychomotor slowing. CONCLUSION: Topiramate treatment of obese subjects over the course of 1 y resulted in clinically significant weight loss. Improvements were also observed in blood pressure and glucose tolerance.