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Gadde K.M.,Duke University | Allison D.B.,University of Alabama at Birmingham | Ryan D.H.,Pennington Biomedical Research Center | Peterson C.A.,VIVUS | And 3 more authors.
The Lancet | Year: 2011

Obesity is associated with a reduction in life expectancy and an increase in mortality from cardiovascular diseases, cancer, and other causes. We therefore assessed the efficacy and safety of two doses of phentermine plus topiramate controlled-release combination as an adjunct to diet and lifestyle modification for weight loss and metabolic risk reduction in individuals who were overweight and obese, with two or more risk factors. In this 56-week phase 3 trial, we randomly assigned overweight or obese adults (aged 18-70 years), with a body-mass index of 27-45 kg/m2 and two or more comorbidities (hypertension, dyslipidaemia, diabetes or prediabetes, or abdominal obesity) to placebo, once-daily phentermine 7·5 mg plus topiramate 46·0 mg, or once-daily phentermine 15·0 mg plus topiramate 92·0 mg in a 2:1:2 ratio in 93 centres in the USA. Drugs were administered orally. Patients were randomly assigned by use of a computer-generated algorithm that was implemented through an interactive voice response system, and were stratified by sex and diabetic status. Investigators, patients, and study sponsors were masked to treatment. Primary endpoints were the percentage change in bodyweight and the proportion of patients achieving at least 5 weight loss. Analysis was by intention to treat. This study is registered with Clinical Trials.gov, number NCT00553787. Of 2487 patients, 994 were assigned to placebo, 498 to phentermine 7·5 mg plus topiramate 46·0 mg, and 995 to phentermine 15·0 mg plus topiramate 92·0 mg; 979, 488, and 981 patients, respectively, were analysed. At 56 weeks, change in bodyweight was -1·4 kg (least-squares mean -1·2, 95 CI -1·8 to -0·7), -8·1 kg (-7·8, -8·5 to -7·1; p<0·0001), and -10·2 kg (-9·8, -10·4 to -9·3; p<0·0001) in the patients assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively. 204 (21) patients achieved at least 5 weight loss with placebo, 303 (62; odds ratio 6·3, 95 CI 4·9 to 8·0; p<0·0001) with phentermine 7·5 mg plus topiramate 46·0 mg, and 687 (70; 9·0, 7·3 to 11·1; p<0·0001) with phentermine 15·0 mg plus topiramate 92·0 mg; for ≥10 weight loss, the corresponding numbers were 72 (7), 182 (37; 7·6, 5·6 to 10·2; p<0·0001), and 467 (48; 11·7, 8·9 to 15·4; p<0·0001). The most common adverse events were dry mouth (24 [2], 67 [13], and 207 [21] in the groups assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively), paraesthesia (20 [2], 68 [14], and 204 [21], respectively), constipation (59 [6], 75 [15], and 173 [17], respectively), insomnia (47 [5], 29 [6], and 102 [10], respectively), dizziness (31 [3], 36 [7], 99 [10], respectively), and dysgeusia (11 [1], 37 [7], and 103 [10], respectively). 38 (4) patients assigned to placebo, 19 (4) to phentermine 7·5 mg plus topiramate 46·0 mg, and 73 (7) to phentermine 15·0 mg plus topiramate 92·0 mg had depression-related adverse events; and 28 (3), 24 (5), and 77 (8), respectively, had anxiety-related adverse events. The combination of phentermine and topiramate, with office-based lifestyle interventions, might be a valuable treatment for obesity that can be provided by family doctors. Vivus. © 2011 Elsevier Ltd.

Riddle M.,Oregon Health And Science University | Umpierrez G.,Emory University | Digenio A.,Sanofi S.A. | Zhou R.,Medpace | Rosenstock J.,Dallas Diabetes and Endocrine Center
Diabetes Care | Year: 2011

OBJECTIVE - To determine the relative contributions of basal hyperglycemia (BHG) versus postprandial hyperglycemia (PPHG) before and after treatment intensification in patients with glycated hemoglobin A1c (A1C) >7.0% while on prior oral therapy. RESEARCH DESIGN AND METHODS - Self-measured, plasma-referenced glucose profiles and A1C values were evaluated fromparticipants in six studies comparing systematically titrated insulin glargine with an alternative regimen (adding basal, premixed, or prandial insulin, or increasing oral agents). Hyperglycemic exposure (>100 mg/dL [5.6 mmol/L]) as a result of BHG versus PPHG was calculated. RESULTS - On prior oral therapy, 1,699 participants (mean age 59 years, diabetes duration 9 years) had mean fasting plasma glucose (FPG) of 194 mg/dL (10.8mmol/L), andmean A1C was 8.7%. BHG contributed an average of 76-80% to hyperglycemia over the observed range of baseline A1C levels. Adding basal insulin for 24 or 28 weeks lowered mean FPG to 117 mg/dL (6.5 mmol/L), A1C to 7.0%, and BHG contribution to 32-41%. Alternative regimens reduced FPG to 146 mg/dL (8.1 mmol/L), A1C to 7.1%, and the contribution of BHG to 64-71%. BHG contributions for patients with A1C averaging 7.6-7.7% were 76% at baseline and 34 and 68% after adding basal insulin or other therapies, respectively. CONCLUSIONS - When A1C is >7.0% despite oral therapy, BHG routinely dominates exposure. Intensified therapy reduces A1C and changes this relationship, but BHG amenable to further intervention still accounts for one-third of total hyperglycemia after basal insulin treatment and two-thirds after alternative methods. © 2011 by the American Diabetes Association.

Gill J.,Sanofi S.A. | Zhou R.,Medpace | Riddle M.C.,Oregon Health And Science University
Diabetes, Obesity and Metabolism | Year: 2013

Aim: Addition and titration of basal insulin is usually effective in improving glycaemic control in type 2 diabetes, but fear of hypoglycaemia remains a barrier. Ability to predict which patients might be at greatest risk of hypoglycaemia might facilitate individualization of treatment and improve safety. The aim of this study was to obtain information about clinical characteristics which might predict risk of hypoglycaemia during initiation of basal insulin. Methods: Patient-level data from 2251 participants in 11 studies in which insulin glargine was started and titrated using similar treat-to-target methods was pooled and analysed with logistic regression models. Results: Participants had mean age 58years, diabetes duration 8.9years, body mass index 31.0 and baseline A1c 8.8%. They attained mean A1c 7.1% during 6months of treatment with final mean glargine dosage 0.44units/kg. Symptomatic hypoglycaemia occurred in 52%, glucose-confirmed hypoglycaemia (blood glucose <50mg/dl) in 17%, repeated glucose-confirmed events in 7% and severe hypoglycaemia in 1.5%. Independent predictors of glucose-confirmed hypoglycaemia were younger age, lower body mass index, use of a sulphonylurea in addition to metformin, lower attained A1c and lower dosage of glargine. Conclusions: These findings confirm low rates of clinically important hypoglycaemia using this method, and suggest that higher risk of hypoglycaemia may be suspected when patients needing insulin are younger, less obese and taking metformin and a sulphonylurea, and especially when A1c levels ≤7.0% are attained with glargine dosage ≤0.4units/kg. © 2013 Blackwell Publishing Ltd.

Allison D.B.,University of Alabama at Birmingham | Gadde K.M.,Duke University | Garvey W.T.,University of Alabama at Birmingham | Peterson C.A.,VIVUS | And 5 more authors.
Obesity | Year: 2012

A 56-week randomized controlled trial was conducted to evaluate safety and efficacy of a controlled-release combination of phentermine and topiramate (PHEN/TPM CR) for weight loss (WL) and metabolic improvements. Men and women with class II and III obesity (BMI < 35 kg/m 2) were randomized to placebo, PHEN/TPM CR 3.75/23 mg, or PHEN/TPM CR 15/92 mg, added to a reduced-energy diet. Primary end points were percent WL and proportions of patients achieving 5% WL. Secondary end points included waist circumference (WC), systolic and diastolic blood pressure (BP), fasting glucose, and lipid measures. In the primary analysis (randomized patients with at least one postbaseline weight measurement who took at least one dose of assigned drug or placebo), patients in the placebo, 3.75/23, and 15/92 groups lost 1.6%, 5.1%, and 10.9% of baseline body weight (BW), respectively, at 56 weeks (P <0.0001). In categorical analysis, 17.3% of placebo patients, 44.9% of 3.75/23 patients, and 66.7% of 15/92 patients, lost at least 5% of baseline BW at 56 weeks (P <0.0001). The 15/92 group had significantly greater changes relative to placebo for WC, systolic and diastolic BP, fasting glucose, triglycerides, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). The most common adverse events were paresthesia, dry mouth, constipation, dysgeusia, and insomnia. Dropout rate from the study was 47.1% for placebo patients, 39.0% for 3.75/23 patients, and 33.6% of 15/92 patients. PHEN/TPM CR demonstrated dose-dependent effects on weight and metabolic variables in the direction expected to be beneficial with no evidence of serious adverse events induced by treatment. © 2011 The Obesity Society.

McGowan M.P.,Medpace
Current Treatment Options in Cardiovascular Medicine | Year: 2011

Opinion statement: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women of reproductive age, impacting 5-10% of premenopausal American women. During the reproductive years, women with PCOS seek medical attention related to infertility, hirsutism, and acne. About 60% of women with PCOS are obese and insulin resistant. Up to 40% of women with PCOS will develop diabetes by the age of 50 and many are dyslipidemic. In addition to treating the cosmetic and fertility issues associated with PCOS, health care providers must educate patients regarding the long-term cardiovascular consequences associated the this disorder. At menopause, a woman with PCOS is likely to have had multiple cardiac risk factors for several decades. Postmenopausal women with a history of PCOS, especially those with established diabetes and/or dyslipidemia, should be considered at high risk for the development of clinical cardiac disease. Exercise and a prudent calorie-restricted diet aimed at weight loss must be stressed early. Pharmacologic therapy for diabetes and hyperlipidemia should be used when appropriate. Bariatric surgery, known to positively impact all the aforementioned cardiac risk factors, may also be of benefit. © 2011 Springer Science+Business Media.

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