Antiobesity drugs in the management of type 2 diabetes: A shift in thinking?

Phentermine

Phentermine (Adipex-P, Lomaira), a sympathomimetic amine, is the most commonly prescribed antiobesity drug in the United States. A schedule IV controlled substance, it is FDA-approved for short-term use (up to 12 weeks). Its primary mechanism of action is mediated by reduction in hunger perception. It was first developed in the 1970s and is available in doses ranging from 8 mg to 37.5 mg daily.¹⁸

Benefits. In a randomized trial, at 28 weeks, weight loss was 1.5 kg with placebo and 5.3 kg with phentermine.¹⁹ No long-term (> 1 year) randomized controlled trials of the effectiveness of phentermine monotherapy in weight loss have been conducted.

Adverse effects. Dizziness, dry mouth, insomnia, constipation, and increase in heart rate were most common.¹⁹

Phentermine is contraindicated in patients with coronary artery disease, congestive heart failure, stroke, and uncontrolled hypertension. Currently, no data exist on the long-term cardiovascular effects of phentermine. We believe phentermine, used in patients at low to intermediate cardiovascular risk, is a useful “jumpstart” tool, in combination with lifestyle changes, to achieve weight loss and improve metabolic values for those with type 2 DM and obesity.

Phentermine is a controlled substance per Ohio law. Patients must be seen once a month by the prescribing provider and prescriptions are limited to a 30-day supply, which must be filled within 7 days of the date of the prescription. Phentermine can only be prescribed for a maximum of 3 months and must be discontinued for 6 months before patients are eligible for a new prescription.

Phentermine and topiramate extended-release

Obesity is a product of complex interactions between several neurohormonal pathways. Approaches simultaneously targeting more than one regulatory pathway have become popular and quite efficient strategies in treating patients with obesity.²⁰ Stemming from such approaches, antiobesity drug combinations such as phentermine and topiramate extended-release (Qsymia) have become increasingly recognized and used in clinical practice. The combination of these 2 medications has been approved for long-term use by the FDA.

Phentermine and topiramate extended-release is a fixed-dose combination that was approved for weight loss in 2012. Topiramate, an anticonvulsant, and phentermine exert their anorexigenic effects through regulating various brain neurotransmitters and result in more weight loss when used together than when either is used alone. Several clinical trials evaluated the efficacy of low doses of this combination in weight loss.

Benefits. In a randomized trial in patients with obesity and cardiometabolic diseases, at 56 weeks, the mean weight loss was:

• 1.2% in the placebo group
• 7.8% in the group receiving phentermine 7.5 mg and topiramate 46 mg
• 9.8% in the group receiving phentermine 15 mg and topiramate 92 mg.²¹

Patients in the active treatment groups also had significant improvements in cardiovascular and metabolic risk factors such as waist circumference, systolic blood pressure, and total cholesterol/high-density lipoprotein cholesterol ratio. At 56 weeks, patients with diabetes and prediabetes taking this preparation had greater reductions in HbA1c values, and fewer prediabetes patients progressed to type 2 DM.²¹

Adverse effects most commonly seen were dry mouth, paresthesia, and constipation.²¹

This combination is contraindicated in pregnancy, patients with recent stroke, uncontrolled hypertension, coronary artery disease, glaucoma, hyperthyroidism, or in patients taking monoamine oxidase inhibitors. Women of childbearing age should be tested for pregnancy before starting therapy, and monthly thereafter, and also be advised to use effective methods of contraception while taking the medication. Topiramate has been associated with the development of renal stones and thus should be used with caution in patients with a history of kidney stones.

Bupropion and naltrexone sustained-release

Bupropion and naltrexone sustained-release (Contrave) is another FDA-approved combination drug for chronic weight management. Bupropion is a dopamine and norepinephrine reuptake inhibitor approved for depression and smoking cessation, and naltrexone is an opioid receptor antagonist approved for treating alcohol and opioid dependence. The combination of these 2 medications has been approved for long-term use by the FDA.

Benefits. In a randomized trial in patients with obesity and type 2 DM, weight loss at 56 weeks was:

• 1.8% with placebo
• 5.0% with naltrexone 32 mg and bupropion 360 mg daily.

Absolute reductions in HbA1c were:

• 0.1% with placebo
• 0.6% with naltrexone-bupropion.

Improvements were also seen in other cardiometabolic risk factors such as triglyceride and high-density lipoprotein cholesterol levels.²²

Adverse effects. The most common adverse effect leading to drug discontinuation was nausea. Other adverse effects reported were constipation, headache, vomiting, and dizziness.²²

Naltrexone-bupropion is contraindicated in patients with a history of seizure disorder or a diagnosis of anorexia nervosa or bulimia, or who are on chronic opioid therapy.

Diethylpropion

Diethylpropion (Tenuate, Tenuate Dospan) is a central nervous system stimulant similar to bupropion in its structure. It was approved by the FDA for treating obesity in 1959. It should be used as part of a short-term weight-loss plan, along with a low-calorie diet. Diethylpropion is also a controlled substance and, as with phentermine therapy, patients are required to be seen once a month by their prescriber. Diethylpropion cannot be prescribed for more than 3 months.

Benefits. Weight loss in a randomized trial at 6 months:

• 3.2% with placebo
• 9.8% with diethylpropion 50 mg twice a day.²³

After 6 months, all participants received diethylpropion in an open-label extension for an additional 6 months. At 12 months, the mean weight loss produced by diethylpropion was 10.6%.²³ No differences in heart rate, blood pressure, electrocardiographic results, or psychiatric evaluations were observed.

Adverse effects. As with phentermine, common side effects of diethylpropion include insomnia, dry mouth, dizziness, headache, mild increases in blood pressure, and palpitations.²³

Lorcaserin

Lorcaserin (Belviq) was approved by the FDA for chronic weight management in June 2012. It exerts its effects through binding selectively to central 5-HT_2C serotonin receptors, with poor affinity for 5-HT_2A and 5-HT_2B receptors. Nonselective serotoninergic agents, including fenfluramine and dexfenfluramine, were withdrawn from the market in 1997 after being reported to be associated with valvular heart abnormalities.²⁴ Lorcaserin has been approved for long-term use by the FDA.

Benefits. Mean weight loss at 1 year in the Behavioral Modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus trial²⁵ was:

• 1.5% with placebo
• 5.0% with lorcaserin 10 mg once daily
• 4.5% with lorcaserin 10 mg twice daily.

Absolute reductions in HbA1c values were:

• 0.4% with placebo
• 0.9% with lorcaserin 10 mg once daily
• 1.0% with lorcaserin 10 mg twice daily.

Absolute reductions in fasting plasma glucose values were:

• 11.9 mg/dL with placebo
• 27.4 mg/dL with lorcaserin 10 mg once daily
• 28.4 mg/dL with lorcaserin 10 mg twice daily.²⁵

Adverse effects. The most common adverse effects were headache, dizziness, and fatigue. There was no significant increase in valvulopathy on echocardiography of participants receiving lorcaserin compared with placebo.²⁵