By Annette M. Boyle
BIRMINGHAM, AL — Two recently available drugs for long-term treatment of obesity helped patients lose 5% or more of their body weight over the course of a year, according to their VA criteria for use statements. The medications, a phentermine and topiramate extended-release combination (P/T) and lorcaserin, are the first new weight loss drugs to be launched in 13 years.
P/T also slowed progression to type 2 diabetes in more than 70% of patients with prediabetes or metabolic syndrome, according to research recently published in Diabetes Care. 1
For the nearly 40% of veterans receiving care through the VA who are obese (body mass index of 30 or more), the effectiveness of the new drugs provide new options and new hope.
“Overweight and obese patients have had limited choices,” according to W. Timothy Garvey, MD, of the Birmingham VA Medical Center and lead researcher for the Diabetes Care article. “They had the lifestyle interventions of diet and exercise, which often do not produce the weight loss needed to significantly reduce health risks. At the other extreme, they had bariatric surgery, which poses significant risks itself and is not an approved option for most patients.”
Being overweight or obese significantly increases the risk of type 2 diabetes, hypertension, sleep apnea, hyperlipidemia, stroke and other chronic diseases. Increased awareness of the role of obesity in diabetes led to this year’s revision of the American Association of Clinical Endocrinologists (AACE) Comprehensive Diabetes Management Algorithm to include medically assisted weight loss as a first-line treatment for prediabetes. 2
Garvey and his colleagues conducted a subset analysis of 475 high-risk overweight or obese patients with prediabetes or metabolic syndrome who participated in a two-year multi-center study of the phentermine/topiramate combination plus lifestyle intervention. Participants were randomly assigned to placebo, a low dose of P/T (phentermine 7.5mg/topiramate 46 mg) or a higher dose (phentermine 15 mg/topiramate 92) for 108 weeks. The researchers evaluated the rate of progression to type 2 diabetes and changes in glycemia, lipid measures, blood pressure and waist circumference.
“We clearly saw a dose-dependent relationship for both weight loss and risk reduction,” Garvey told U.S. Medicine.
Participants on the 7.5/46 dose had a mean weight loss of 10.9%, while those on the higher dose lost an average of 12.1% of their starting weight. Participants in the placebo arm averaged a 2.5% weight loss.
The participants in both P/T arms also profoundly reduced their risk for diabetes. The annualized incidence rate for type 2 diabetes among those receiving the lower dose dropped 70.5%, while those on the 15/92 dose experienced a 78.7% reduction. Study subjects who had prediabetes at initiation saw a 48.6% reduction in the annualized incidence of type 2 diabetes on the 7.5/46 dose and an 88.6% reduction at the higher dose, compared to placebo.
Cardiometabolic measures also improved in patients on the medication, with improvements seen in waist size, blood pressure, insulin resistance, triglycerides and HDL-C levels. About a quarter of participants taking P/T achieved remission of metabolic syndrome.
“While losing more weight provided greater benefit, losing just 5% significantly improved outcomes,” Garvey said.
Participants with less than 5% weight loss had an annualized type 2 diabetes incidence rate of 6.3, while those with 5% to 10% or 10% to 15% weight loss had an incidence rate of 1.3. Losing 15% or more of baseline body weight conferred the greatest benefit. The incidence rate in this group was just 0.9.
In a study of lorcaserin presented at Obesity Week, patients taking 10 mg twice a day for a year lost 9.9% of their body fat, while those taking 10 mg once a day lost 6.1%. They lost about 2% of lean body mass. Overall, participants averaged weight loss of 7.1% and 4.8% for the twice and once daily doses, respectively. The placebo group lost 3.4% 3
Effective, long-term medications to facilitate and maintain weight loss “enable a comprehensive medical approach to obesity that allows physicians to tailor treatment based on complications and risk factors,” Garvey noted.
Physicians have been reluctant to prescribe weight loss medications because of their side effects or ineffectiveness, particularly over the long term. “So many patients need continued support to achieve meaningful weight loss and keep it off,” Garvey said.
The new drugs are not listed on the VA national formulary but are available through the non-formulary request process.
The older weight loss drugs (phentermine, diethylpropion, phendimetrazine and benzphetamine) had Food and Drug Administration approval for use for 12 weeks or less and showed only modest effectiveness. (As a monotherapy, phentermine is typically prescribed at higher doses than in the P/T combination.) The only other long-term weight loss medication, the gastrointestinal lipase inhibitor orlistat, causes gastrointestinal side effects for many patients, which leads to high rates of discontinuation. Less than 10% of patients continue to take orlistat for a year, and less than 2% take it for two or more years. 4
The phenteramine/topiramate combination has a risk evaluation and mitigation strategy (REMS) because of topiramate’s known association with increased risk of oral clefts in infants born to mothers taking the drug.
The FDA has required post-marketing studies for lorcaserin because of its similarities to fenfluramine, which was associated with heart valve issues. The new drug selectively targets the 5HT2C receptor, which is not found in the heart muscle, rather than the 5HT2B receptor fenfluramine affected.
1 Garvey WT, Ryan DH, Henry R, Bohannon NJ, Toplak H, Schwiers M, Troupin B, Day WW. Prevention of Type 2 Diabetes in Subjects With Prediabetes and Metabolic Syndrome Treated With Phentermine and Topiramate Extended-Release. Diabetes Care. 2013 Oct 8. Epub ahead of print.
2 Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, et al. AACE Consensus Statement: American Association of Clinical Endocrinologists’ Comprehensive Diabetes Management Algorithm 2013 Consensus Statement. Endocrine Practice. 19(2); May/June 2013.
3 Rubino D, et al. Effects of Lorcaserin on Lean and Fat Mass Loss in the BLOSSOM Study of Obese and Overweight Patients. Obesity Week 2013; Abstract 739.
4 Hampp C, Kang EM, Borders-Hemphill V. Use of Prescription Antiobesity Drugs in the United States [epub ahead of print] Sept 9, 2013]. Pharmacotherapy. 2013.