November 2015 Issue

Weight-Loss Drugs for Diabesity
By Constance Brown-Riggs, MSEd, RD, CDE, CDN
Today's Dietitian
Vol. 17 No. 11 P. 34

Here's a review of the latest FDA-approved obesity drugs for people with diabetes and tips on how to counsel them more effectively.

The prevalence of obesity and diabetes continues to rise. In 1994, all but two states had prevalence rates of obesity less than 18%, with no state exceeding 22%. In contrast, obesity rates had soared by 2013, with no state having less than 18% and all but two states exceeding 22%.1

A similar trend was observed in diagnosed diabetes. In 1994, almost all states had a prevalence of diabetes less than 6%. In 2013, diabetes prevalence climbed, with all states exceeding 6% and 25 of them exceeding 9%.1 If obesity rates stay on their current trajectories, 44% of the US population will be obese by 2030, and the number of new type 2 diabetes cases may increase tenfold between 2010 and 2020—and double again by 2030. It's estimated that obesity could contribute to more than 6 million cases of type 2 diabetes in the next two decades.2

Because of this unprecedented parallel rise in obesity and diabetes, many experts refer to them as a single problem. In fact, Shape Up America!, an organization founded by former United States Surgeon General C. Everett Koop to raise awareness of the adverse health effects of obesity, trademarked the term diabesity to denote the causal link between obesity and type 2 diabetes.3

Diabesity is associated with the long-term complications of diabetes such as myocardial infarction, cerebrovascular stroke, end-stage renal disease, poorer health-related functioning, decreased quality of life, and reduced overall life expectancy. Chronic stress, depression, and sleep disturbances also have been linked to diabesity.4

Various treatment options for the management of diabesity are available, including several antiobesity drugs. Pharmacotherapy for weight loss isn't a new phenomenon. However, many of the medications approved by the FDA over the past decade were withdrawn due to serious adverse events such as psychiatric problems, cardiovascular risks, hemorrhagic stroke, valvular heart damage, and primary pulmonary hypertension. These problems resulted in having fewer antiobesity drugs from which to choose and skepticism about their risks vs benefits.5 Conversely, over the last two years there has been a rapid increase in approved obesity drugs; in 2012, the FDA approved lorcaserin (Belviq) and phentermine/topiramate extended-release (PHEN/TPM ER, Qsymia), followed by naltrexone and bupropion extended-release (Contrave) and liraglutide (Saxenda) in 2014.6-9

The rapid increase in approved obesity drugs for people with diabetes has produced concern among dietitians and diabetes educators over their efficacy and safety. This article will provide an overview of the mechanisms of action, indications, efficacy, safety, adverse reactions, and contraindications of incretin hormones and high-dose liraglutide, lorcaserin, phentermine/topiramate, naltrexone hydrochloride and bupropion hydrochloride. Counseling tips and considerations for advising clients and patients on the most appropriate antiobesity medications also will be discussed.

Incretin Hormones and Mimetics
Incretins are gut-derived hormones released from the intestine in response to food intake. The two most important incretins responsible for glucose regulation are glucagonlike-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).10 Both GLP-1 and GIP stimulate insulin secretion and increase peripheral insulin sensitivity. GLP-1 controls postprandial glucose levels by preventing glucagon secretion and delaying gastric emptying.10

Obesity, glucose tolerance, and insulin resistance are associated with alterations in GLP-1 and GIP responses. Studies have shown that elevated postprandial blood glucose levels in type 2 diabetes are associated with changes in incretin hormone levels.10

Incretin mimetics are a class of drugs that work by mimicking the action of the incretin hormones. GLP-1 receptor agonists are incretin mimetics that stimulate the GLP-1 receptors to increase insulin secretion, inhibit glucagon release, slow gastric emptying, and increase satiety.11,12 GLP-1 receptor agonists also are associated with a 1% to 1.5% reduction in glycosylated hemoglobin (HbA1c), a one-year average weight loss of 0.6 to 4.4 kg, and a low risk of hypoglycemia.12,13 The GLP-1 receptor agonists available include exenatide (twice daily dosing), liraglutide (once daily dosing), and albiglutide and dulaglutide (once weekly dosing).11

Liraglutide Injection for Weight Loss
Liraglutide has been available since 2010. Administered once daily at doses of 1.2 or 1.8 mg, liraglutide is FDA-approved for the treatment of type 2 diabetes and has been shown to be effective and generally well tolerated. In addition, weight loss was observed with liraglutide at these doses.13 "One of the advantages that patients and clinicians have identified with this class [GLP-1 receptor agonists] is it is well accepted and not associated with weight gain," says Todd Hobbs, MD, vice president and chief medical officer for Novo Nordisk.

In fact, the weight loss benefits associated with liraglutide led Novo Nordisk to investigate its safety and efficacy as an antiobesity medication.5 "We researched liraglutide for its weight-loss benefit and then decided to pursue its efficacy at a higher dose," Hobbs says. Researchers conducted three clinical trials that included approximately 4,800 obese and overweight patients, with and without significant weight-related conditions, to evaluate the safety and efficacy of liraglutide at a 3 mg dose.9 "Two-thirds of patients in these trials lost greater than 5% of baseline body weight," Hobbs says.

Results from a clinical trial that enrolled patients without diabetes showed that patients treated with high-dose liraglutide (3 mg) experienced a 4.5% greater weight loss compared with placebo. In this trial, 62% of patients treated with high-dose liraglutide lost at least 5% of their body weight compared with 34% of patients treated with placebo.14 As a result, the Satiety and Clinical Adiposity—Liraglutide Evidence in Non-Diabetic and Diabetic Subjects (SCALE) clinical development program began.5 Results from another clinical trial in the SCALE program that enrolled patients with type 2 diabetes showed that 49% of patients treated with high-dose liraglutide lost at least 5% of their body weight compared with 16% of patients treated with placebo.9

In December 2014, the FDA approved high-dose liraglutide as a treatment option for chronic weight management, which Novo Nordisk launched under the brand name Saxenda in April 2015.9,15

Saxenda is approved for use in obese adults with a BMI of 30 or greater, or overweight adults with a BMI of 27 or greater who have at least one weight-related condition such as hypertension, type 2 diabetes, or high cholesterol.9 It shouldn't be used in combination with any other GLP-1 receptor agonist, including Victoza. Saxenda isn't indicated for the treatment of type 2 diabetes, as its safety and efficacy in this capacity hasn't been established.9 "Although it's the same molecule [liraglutide], but at a higher dose, the FDA views obesity and diabetes as two separate disease states," Hobbs says. "However, data from the SCALE trial show that Saxenda does affect glucose in a positive way with A1c reductions."

Patients using high-dose liraglutide should be evaluated after 16 weeks to determine if the treatment is working. If a patient hasn't lost at least 4% of baseline body weight, high-dose liraglutide should be discontinued, as it's unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.9

High-dose liraglutide includes a warning label stating that tumors of the thyroid gland (thyroid C-cell tumors) have been observed in rodent studies, but that it's unknown whether the drug causes thyroid C-cell tumors, including a type of thyroid cancer called medullary thyroid carcinoma, in humans.9

Serious side effects reported in patients treated with high-dose liraglutide include pancreatitis, gallbladder disease, renal impairment, suicidal thoughts, and increased heart rate.9

In clinical trials, the most common side effects observed in patients treated with Saxenda were nausea, diarrhea, constipation, vomiting, hypoglycemia, and decreased appetite.9 While nausea was noted as the chief complaint, Hobbs says, "Nausea rates were similar with Saxenda as to what was observed with Victoza. Nausea is transient and most people are able to stay on therapy. Only around 10% of patients in clinical trials had to slow down therapy due to nausea."

Oral Antiobesity Drugs
Lorcaserin, phentermine/topiramate, and naltrexone hydrochloride and bupropion hydrochloride tablets also have been FDA-approved for use in obese adults with a BMI of 30 or greater, or overweight adults with a BMI of 27 or greater who have at least one weight-related condition such as hypertension, type 2 diabetes, or high cholesterol.6-8

Approved by the FDA in June 2012, lorcaserin works by activating the serotonin 2C receptor in the brain. Activation of this receptor may help a person eat less and feel full after eating smaller amounts of food.

The safety and efficacy of lorcaserin were evaluated in three randomized, placebo-controlled trials that included nearly 8,000 obese and overweight patients, with and without type 2 diabetes, who were treated for 52 to 104 weeks. All participants received lifestyle modification that consisted of a reduced-calorie diet and exercise counseling. Compared with placebo, treatment with lorcaserin for up to one year was associated with an average weight loss ranging from 3% to 3.7%. In people with type 2 diabetes, about 38% of patients treated with lorcaserin and 16% treated with placebo lost at least 5% of their body weight.6

The approved prescribing information for lorcaserin recommends that the drug be discontinued in patients who fail to lose 5% of their body weight after 12 weeks of treatment, as these individuals are unlikely to achieve clinically meaningful weight loss with continued treatment.6

Lorcaserin shouldn't be used during pregnancy. Treatment with lorcaserin may cause serious side effects, including serotonin syndrome (a potentially life-threatening drug reaction that causes high serotonin levels in the body), particularly when taken with certain medicines that increase serotonin levels or activate serotonin receptors. These include, but are not limited to, drugs commonly used to treat depression and migraine. Lorcaserin also may cause disturbances in attention or memory.6 The most common side effects of lorcaserin in patients with diabetes are hypoglycemia, headache, back pain, cough, and fatigue.6

In July 2012, the FDA approved the combination of phentermine and topiramate in an extended-release formulation known as PHEN/TPM ER. Phentermine, an anoretic, was previously approved for short-term weight loss. Topiramate is an anticonvulsant used to manage epilepsy and prevent migraine headaches.7

The safety and efficacy of PHEN/TPM ER was evaluated in two randomized, placebo-controlled trials that included approximately 3,700 obese and overweight patients, with and without significant weight-related conditions, treated for one year.7

The recommended daily dose of PHEN/TPM ER contains 7.5 mg phentermine and 46 mg topiramate extended-release. PHEN/TPM ER also is available at a higher dose (15 mg phentermine and 92 mg topiramate extended-release) for select patients. Results from the two trials show that after one year of treatment with the recommended and highest daily dose of PHEN/TPM ER, patients had a 6.7% and 8.9% greater average weight loss, respectively, than those treated with placebo. Approximately 62% and 69% of patients lost at least 5% of their body weight with the recommended dose and highest dose of PHEN/TPM ER, respectively, compared with about 20% of patients treated with placebo.7

If after 12 weeks on the higher dose of PHEN/TPM ER, a patient doesn't lose at least 5% of body weight, then PHEN/TPM ER should be discontinued, as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment.7

PHEN/TPM ER is contraindicated in pregnancy. Data show that a fetus exposed to topiramate in the first trimester has an increased risk of oral clefts. Prescribers are encouraged to undergo training, and pharmacies must be certified to dispense PHEN/TPM ER. The drug also is contraindicated in patients with glaucoma and hyperthyroidism.7,11 The most common adverse effects are dizziness, insomnia, tingling in the hands and feet, taste disturbances, and impaired cognition.11

This combination of two already FDA-approved drugs, naltrexone and extended-release bupropion, was approved in September 2014. Naltrexone is approved to treat alcohol and opioid dependence. Bupropion is approved to treat depression and seasonal affective disorder and aid in smoking cessation.8

The effectiveness of naltrexone/bupropion was evaluated in multiple clinical trials that included approximately 4,500 obese and overweight patients, with and without significant weight-related conditions, treated for one year.

Results from a clinical trial that enrolled patients with type 2 diabetes showed that patients had an average weight loss of 2% more than those treated with placebo at one year. In this trial, 36% of patients treated with naltrexone/bupropion lost at least 5% of their body weight compared with 18% of patients treated with placebo.8

Patients using naltrexone/bupropion at the maintenance dose should be evaluated after 12 weeks to determine if the treatment is working. If a patient hasn't lost at least 5% of baseline body weight, naltrexone/bupropion should be discontinued.8

Because naltrexone/bupropion contains bupropion, it includes a warning label to alert health care professionals and patients to the increased risk of suicidal thoughts and behaviors associated with antidepressant drugs. The warning also notes that serious neuropsychiatric events have been reported in patients taking bupropion for smoking cessation.8

Naltrexone/bupropion is contraindicated in patients who have seizure disorders, women who are pregnant or who are trying to become pregnant, patients using opioids, or individuals with eating disorders. Naltrexone/bupropion also can raise blood pressure and heart rate and must not be used in patients with uncontrolled high blood pressure. The most common adverse reactions reported with naltrexone/bupropion include nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and diarrhea.8

Counseling Clients and Patients
When advising clients and patients on the most appropriate antiobesity medication, consider the following counseling tips and strategies.

• Suggest intensive lifestyle therapy first. Pharmacotherapy is a treatment option that should be considered only if a patient hasn't lost one pound per week after six months of combined lifestyle therapy, which includes a low-calorie diet, increased physical activity, and behavior therapy.16 "A patient that has demonstrated the effort to attempt to lose weight with healthful dietary modifications and exercise but hasn't been successful could be considered for pharmacotherapy for weight loss," says Alyssa Gallagher, RD, LD, CDE, of St. Luke's Humphreys Diabetes Center in Boise, Idaho. "In addition, the patient should have other health conditions in which their obesity puts them at higher risk. These might include hypertension, dyslipidemia, diabetes, or sleep apnea."

• Calculate BMI. Jessica Crandall, RDN, CDE, spokesperson for the Academy of Nutrition and Dietetics, says when determining who's appropriate for pharmacotherapy, the first step is to calculate BMI. "A potential candidate for weight loss pharmacotherapy is someone who's obese and is currently working on exercise and dietary modification, or someone who's overweight with comorbidities."

• Realize there are no magic bullets. Because there's no single weight-loss drug that works for everyone, dietitians and diabetes educators will need to counsel clients and patients in accordance with their individual lifestyles, and preferred approach to weight loss. "It's important to highlight the need for lifestyle changes," Hobbs says. "All participants in the SCALE trial received specific dietary counseling to reduce caloric intake by 500 calories daily. No single weight loss medication is a magic bullet. For best outcomes, Saxenda should be used in conjunction with lifestyle management."

Crandall agrees: "I try to incorporate nutrition modifications, behavior changes, and exercise guidelines they can participate in. It's important for these three areas to be addressed and individualized in order to achieve optimal results with any weight-loss drug."

• Educate providers. Gallagher says some of the biggest barriers facing health care professionals when working with pharmacotherapy for weight loss include cost and provider buy-in. "Many providers may not be familiar with a drug. It's good to familiarize yourself with different drugs available and provide suggestions and information, if needed, to the providers," Gallagher says.

• Assess the patient's relationship with food. Patients should be working on the behavioral and emotional issues they have with food in conjunction with diet and nutrition, according to Gallagher. "I discuss meeting with our onsite psychologist with every patient that sees me for weight loss." Gallagher also considers the patient's eating habits. "Orlistat is best for the person who's already following a fairly low-fat diet, rather than a high-protein, high-fat diet because the side effects could be unbearable. Patients who struggle with hunger and fullness cues might benefit from Saxenda, as this drug works on a hormonal level as well as delays gastric emptying," Gallagher says.

• Provide patient-centered counseling. Motivational interviewing, a patient-centered approach to counseling, helps resolve a person's ambivalence towards changing behavior. "Motivational interviewing is a great technique for nutrition professionals to use in assessing the patient's readiness to change, and helping them come to their own solutions on their journey with weight loss," Gallagher says. Crandall believes her role as a dietitian is to meet clients where they are and further educate them about their options on ways to improve and achieve optimal results.

— Constance Brown-Riggs, MSEd, RD, CDE, CDN, is the past national spokesperson for the Academy of Nutrition and Dietetics, specializing in African-American nutrition, and author of The African American Guide to Living Well With Diabetes and Eating Soulfully and Healthfully With Diabetes.

1. Centers for Disease Control and Prevention. Maps of trends in diagnosed diabetes and obesity. Published January 2015. Accessed August 31, 2015.

2. Trust for America's Health. F as in fat: how obesity threatens America's future 2012. Published September 2012. Accessed September 8, 2015.

3. Shape Up America! historical highlights. Shape Up America! Website. Accessed August 31, 2015.

4. Farag YM, Gaballa MR. Diabesity: an overview of a rising epidemic. Nephrol Dial Transplant. 2011;26(1):28-35.

5. The role of anti-obesity drugs in patients with type 2 diabetes. Touch Endocrinology website. Accessed September 8, 2015.

6. FDA approves Belviq to treat some overweight or obese adults. US Food and Drug Administration website. Updated June 27, 2012. Accessed September 8, 2015.

7. FDA approves weight-management drug Qsymia. US Food and Drug Administration website. Updated July 17, 2012. Accessed September 8, 2015.

8. FDA approves weight-management drug Contrave. US Food and Drug Administration website. Updated September 10, 2014. Accessed September 8, 2015.

9. FDA approves weight-management drug Saxenda. US Food and Drug Administration website. Updated December 23, 2014. Accessed September 8, 2015.

10. Opinto G, Natalicchio A, Marchetti P. Physiology of incretins and loss of incretin effect in type 2 diabetes and obesity. Arch Physiol Biochem. 2013;119(4):170-178.

11. Diabetes Care and Education. There's a pill (or injection) for that: a diabetes pharmacotherapy update. Published 2015. Accessed August 31, 2015.

12. Drug for diabetes. Medscape website. Accessed August 31, 2015.

13. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA. 2015;314(7):687-699.

14. Astrup A, Rössner S, Van Gaal L, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374(9701):1606-1616.

15. United States first country to launch Saxenda. Novo Nordisk website. Updated April 22, 2015. Accessed September 8, 2015.

16. National Heart Lung and Blood Institute. The practical guide: identification, evaluation, and treatment of overweight and obesity in adults. Published October 2000. Accessed September 8, 2015.