Lifestyle and Pharmacotherapy for Weight Loss in Preventing or Delaying Diabetes

Abstract

Preventing or delaying the conversion of prediabetes to overt diabetes can reduce mortality and morbidity rates, improve health-related quality of life, and reduce other comorbid complications associated with diabetes. Studies have shown that a modest weight loss is one strategy for preventing or delaying diabetes diagnosis. First-line therapy in preventing progression of prediabetes to overt diabetes is weight loss through lifestyle modifications; however, pharmacotherapy for weight loss may be initiated if lifestyle alone is ineffective. The purpose of this article is to describe the pharmacotherapeuptic options for weight loss that can be used in conjunction with lifestyle in the prevention or delay of diabetes in patients with prediabetes.

‘Preventing or delaying the conversion of prediabetes to overt diabetes can reduce mortality and morbidity rates . . .’

According to the 2017 National Diabetes Statistics Report, there are more than 30.3 million Americans living with diabetes, and nearly 84.1 million people with prediabetes. ¹ Patients with prediabetes are at higher risk for developing type 2 diabetes and its associated complications, including myocardial infarction, nerve damage, kidney disease, stroke, amputation, and blindness.^1-3 Preventing or delaying the conversion of prediabetes to overt diabetes can reduce mortality and morbidity rates, improve health-related quality of life, and reduce other comorbid complications associated with diabetes. ⁴ Studies have shown that modest weight loss (baseline weight reductions of 5%-10%) in patients diagnosed with prediabetes is one strategy for preventing or delaying diabetes diagnosis.^4-6 Both the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) state that first-line therapy in preventing progression of prediabetes to overt diabetes is weight loss through lifestyle modifications.^2,7 The Diabetes Prevention Program (DPP) study compared the weight loss effects and incidence of diabetes of intensive lifestyle modifications, metformin therapy and placebo in 3234 patients with prediabetes. ⁴ The study found that a greater weight reduction was achieved in the lifestyle intervention group compared with metformin and placebo groups and the incidence of progression to overt diabetes was lowest in the group randomized to lifestyle change. Nearly 50% of the participants in the intensive lifestyle modification group reached and maintained the target 7% weight loss from baseline. The incidence of type 2 diabetes was reduced by 58% (95% CI = 0.48-0.66) with intensive lifestyle and 31% (95% CI = 0.17-0.43) with metformin therapy, compared with placebo. The incidence of diabetes was 39% lower (95% CI = 0.24-0.51) in the lifestyle interventions group compared with metformin. ⁴

Impressively, a study assessing the durability of outcomes in the DPP found that after 10 years of follow-up, the cumulative incidence of diabetes remained lowest in the lifestyle group compared to metformin and placebo. ⁸ The study concluded that onset of diabetes was delayed by about 4 years for the lifestyle group and 2 years by the metformin group compared to placebo.

The DPP is the only published head to head trial comparing lifestyle to pharmacotherapy for weight loss and reduced risk of incident diabetes in an American population. Lifestyle is clearly effective and should be considered first-line therapy for weight loss. However, not all patients are successful in achieving weight loss through sustained lifestyle changes. According to the AACE and the ADA, pharmacotherapy for weight loss should be initiated if lifestyle therapy alone has been ineffective.^2,7 Currently, there are no pharmacotherapy treatment options approved by the Food and Drug Administration (FDA) for the management of prediabetes or the prevention of disease progression to diabetes.^2,7 Metformin, while not indicated for weight loss, has been studied, as described above in the DPP for its effects on weight loss and incident diabetes in patients with prediabetes and is endorsed as potential therapy for prediabetes by the ADA. Other pharmacologic options approved by the FDA for weight loss include orlistat (Xenical), lorcaserin (Belviq), phentermine and topiramate extended-release (Qsymia), naltrexone and bupropion (Contrave), and liraglutide 3 mg (Saxenda). ² These medications (or combination medications) have been approved for long-term use (more than a few weeks) in patients with body mass index (BMI) >27 kg/m² with one or more obesity-associated comorbid conditions (eg, type 2 diabetes. hypertension, and dyslipidemia) and in patients with BMI >30 kg/m² who are motivated to lose weight.

The purpose of this article is to describe the pharmacotherapeutic options for weight loss that can be used in conjunction with lifestyle in the prevention or delay of the progression of prediabetes to overt diabetes. Covered medications include those approved for long-term use in weight loss and metformin (due to the prevalence of off-label use in this population). Medications will be evaluated based on weight loss, blood glucose lowering and diabetes prevention efficacy, safety, and side effect profiles.

Pharmacotherapy

Metformin

Metformin is approved by the FDA to treat patients with type 2 diabetes mellitus and the ADA endorses metformin use in patients with prediabetes and additional risk factors (BMI ≥35 kg/m², age <60 years, or prior gestational diabetes mellitus), and/or those with rising HbA1C despite lifestyle intervention).^6,7 Metformin exerts its antidiabetic actions through decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving peripheral insulin sensitivity. ⁶ In the DPP, metformin and its effect on weight loss were measured for preventing diabetes. ⁹ After 1 year, patients treated with metformin (n = 1073) lost 2.7% ± 4.7% of their body weight compared with 0.43% ± 4.7% in the placebo group (n = 1082; P < .001). In this study, 29% of patients in the metformin group and 13% of patients in the placebo group achieved a ≥5% weight loss in year 1 (P < .001). In the metformin and placebo groups, 8% and 4%, respectively, lost ≥10% of their body weight in the first year (P < .001). These numbers increased for year 2, with 10% of metformin patients and 5% of placebo patients achieving ≥10% weight loss (P < .001). ⁹ The incidence of diabetes was reduced by 31% (95% CI = 0.17-0.43) in the metformin group compared with placebo. Gastrointestinal disturbances, including diarrhea, nausea, and flatulence remain the most commonly reported adverse effects with metformin use. Metformin use has been associated with renal dysfunction, metabolic acidosis, and lactic acidosis. ⁶

Orlistat

Orlistat (Xenical) is approved by the FDA for obesity management, including weight loss and management when used in conjunction with a reduced-calorie diet, and is also indicated to reduce the risk for weight regain after previous loss. ¹⁰ Orlistat reversibly inhibits gastric and pancreatic lipases, which are then unable to break down and absorb dietary fat. The Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) study, compared the effects of orlistat in combination with lifestyle modifications versus lifestyle modifications alone in the prevention of type 2 diabetes mellitus. ¹¹ The study included 3305 patients with a BMI ≥30 kg/m², 79% of whom had normal baseline blood glucose levels and 21% with impaired glucose tolerance. After 4 years of treatment, the risk of incident diabetes was reduced by 37.3% in the orlistat group compared with lifestyle alone (P = .0032). Subgroup analysis indicated that this reduction was detectable in the impaired glucose tolerance group only and not in the cohort of patients with normal baseline blood glucose levels. Weight loss at 4 years was also greater in the orlistat group, with a mean weight loss of 5.8 kg versus 3.0 kg for lifestyle modifications alone (P < .001). The most commonly observed adverse reactions include oily spotting, flatus with discharge, fecal urgency, fatty or oily stool, increased defecation, and fecal incontinence. ¹⁰ Orlistat may reduce absorption of fat soluble vitamins, and patients should be advised to supplement with a multivitamin. Patients taking orlistat are at increased risk for liver injury, kidney injury, and gallstones. ¹⁰

Lorcaserin

Lorcaserin (Belviq) is approved by the FDA for chronic weight management in adults adjunctive to diet and exercise. ¹² The exact mechanism of lorcaserin is unknown, but it is thought to selectively activate 5-HT_2c receptors on hypothalamic neurons, which decrease food consumption and increase satiety. A post hoc analysis of pooled data from phase 3 studies of lorcaserin in combination with lifestyle counseling evaluated the weight and glycemic changes of overweight/obese subjects with prediabetes at baseline. ¹³ After 52 weeks, almost twice as many patients treated with lorcaserin achieved the target ≥5% weight loss versus placebo (P < .001). In addition, fewer lorcaserin-treated patients progressed to overt diabetes versus placebo (3.2% vs 5.0%, respectively, P = .032). The most commonly observed adverse reactions include hypoglycemia, headache, dizziness, cough, dry mouth, and fatigue. ¹² Lorcaserin acts on the serotonergic system and patients taking it are at risk for developing serotonin syndrome and neuroleptic malignant syndrome–like reactions. Patients taking lorcaserin are at increased risk for attention and memory impairment, euphoria, hallucination, dissociation, hypoglycemia, decreased heart rate, hematological changes, pulmonary hypertension, and prolactin elevation. Because of its potential for euphoria, lorcaserin is a Schedule IV medication and carries warnings about abuse potential.

Phentermine and Extended-Release Topiramate

Phentermine and extended-release topiramate (Qsymia) form a combination medication approved by the FDA for chronic weight management in adults adjunctive to diet and exercise. ¹⁴ Phentermine is a sympathomimetic amine and although its primary mechanism in weight loss has not been established, it is known to cause appetite suppression and have metabolic effects. The mechanism of topiramate in weight loss is unknown. It is theorized to cause appetite suppression and enhance satiety through its effect on neurotransmitters, ion channels, and inhibition of carbonic anhydrase. Phentermine and topiramate are available in 4 strengths of oral capsules; 3.75 mg phentermine/23 mg extended-release topiramate, 7.5 mg/46 mg, 11.25 mg/69 mg, and 15 mg/92 mg. ¹⁴ A subanalysis of a phase 3 phentermine and topiramate extended release plus lifestyle modifications study evaluated weight loss and the annualized incidence rate of progression to type 2 diabetes in 475 patients with prediabetes and/or metabolic syndrome. ¹⁵ The study found that after 108 weeks, mean percentage weight loss was significantly greater in both the 7.5 mg/46 mg and 15 mg/92 mg phentermine plus topiramate extended release groups than placebo (10.9%, 12.1%, and 2.5%, respectively, P < .0001). In addition, treatment with phentermine plus topiramate was associated with reductions of 70.5% and 78.7% in the annualized incidence rate of type 2 diabetes for patients receiving the 7.5 mg/46 mg and 15 mg/92 mg strengths, respectively (P = .05), versus placebo The adverse effects associated with phentermine plus topiramate combination medications were higher than placebo. Dry mouth, paraesthesia, constipation, insomnia, dizziness, and dysgeusia were the most common adverse events in the trial. ¹⁵ Because of the phentermine component this medication is a Schedule IV drug and carries all the risks for abuse and dependence as phentermine monotherapy. ¹⁴

Naltrexone and Bupropion

Naltrexone and bupropion (Contrave) form a sustained-release combination medication approved by the FDA for chronic weight management in adults adjunctive to a reduced-calorie diet and exercise. ¹⁶ Naltrexone is an opioid antagonist, while bupropion weakly inhibits dopamine and norepinephrine reuptake. The exact mechanism of this combination in weight loss is not fully understood, but it is thought to be in part due to the effects in the hypothalamus and dopamine circuit, which control the appetite and reward system, respectively. The effects of naltrexone plus bupropion sustained-release plus standardized lifestyle intervention in overweight and obese patients with type 2 diabetes showed a significant body weight reduction and improved glycemic control compared with placebo. ¹⁷ More patients in the treatment group than placebo achieved ≥5% (44.5% vs 18.9%) and ≥10% (18.5% vs 5.7%) body weight reduction at week 56 (P < .001). In addition, there were more patients in the naltrexone/bupropion group achieving an HbA1C of <7 % (44.1%) than placebo (26.3%) (P < .001) and HbA1C <6.5% (20.7 vs 10.2%; P = .004). The most commonly reported adverse events with naltrexone and bupropion was nausea (42.3% vs 7.1%), vomiting (18.3% vs 3.6%), and constipation (17.7% vs 7.1%). ¹⁷ Patients taking this agent for weight loss are at an increased risk for suicidal behavior and ideation, increases in blood pressure and heart rate, hepatotoxicity, angle-closure glaucoma, and hypoglycemia. ¹⁶

Liraglutide

Liraglutide (Saxenda) is approved by the FDA for chronic weight management in adults adjunctive to diet and exercise. ¹⁸ A lower dose of this medication is also marketed under the brand name Victoza, which is approved for treatment of diabetes. Liraglutide agonizes the glucagon-like peptide 1 (GLP-1) receptor, which regulates appetite. It is given by daily subcutaneous injections, starting with 0.6 mg for 1 week and increasing by 0.6 mg weekly to reach a 3 mg dose. ¹⁸ In the SCALE Obesity and Prediabetes trial, participants in the liraglutide group achieved a mean weight reduction of 8.4 ± 7.3 kg, while participants in the placebo group had a mean weight reduction of 2.8 ± 6.5 kg after 56 weeks (P < .001). ¹⁹ In addition to weight loss, change in HbA1C and fasting blood glucose (FBG) were assessed. The results showed that there was a greater reduction in HbA1C and FBG in the liraglutide group compared with placebo (HbA1c, 0.32% vs 0.07%, P < .001; FBG, 8.2 vs 0.11 mg/dL, P < .001). At week 56, the prevalence of prediabetes was significantly lower in the liraglutide group than in placebo (30.8% vs 67.3%, P < .001). ¹⁹ Generally, liraglutide was well tolerated with the most common adverse reactions reported were gastrointestinal upset, fatigue, and increased lipase. Liraglutide does have an increased risk for acute pancreatitis, acute gallbladder disease, thyroid c-cell tumors, heart rate, with reported jaundice, hepatitis, and suicidal behavior and ideation. ¹⁷

Conclusion

Weight loss plays a significant role in preventing the progression of prediabetes to diabetes in overweight and obese patients. The AACE and the ADA recommend lifestyle interventions as the first line option for achieving weight loss goals in prediabetic patients. In a head to head trial, lifestyle intervention was superior to pharmacotherapy in preventing type 2 diabetes in patients at high risk for the condition. ⁴ This study was extended and had durable effects after 10 years of follow-up. In general, pharmacological treatment of obesity has been limited by low adherence, modest efficacy, adverse effects, and weight regain after medication cessation. ²⁰ The longest duration of follow-up in the studies described above was 4 years in the XENDOS study. Therefore, pharmacotherapy should be considered only in patients in whom lifestyle modifications alone have been ineffective, and always in conjunction with intensive lifestyle therapy. No one medication has proven to be the most effective for weight loss and diabetes prevention in obese and overweight patients. Pharmacotherapy should be initiated based on patient goals, comorbidities, and side effect profiles.