Antiobesity drugs in the management of type 2 diabetes: A shift in thinking?
ABSTRACT
Antiobesity medications can improve metabolic control for patients with type 2 diabetes mellitus (DM) and obesity, but are underutilized. In this review, we describe the role of antiobesity drugs in the context of medically supervised and comprehensive weight-loss interventions and propose a pragmatic therapeutic algorithm for patients with type 2 DM and obesity that incorporates the use of antiobesity drugs early in the course of management.
KEY POINTS
- Obesity contributes to type 2 DM and worsens its control. Yet insulin therapy and most first-line diabetes drugs cause weight gain as a side effect.
- We believe that physicians should include body weight along with blood glucose levels as targets of therapy in patients with type 2 DM.
- Several drugs are approved for weight loss, and although their effect on weight tends to be moderate, some have been shown to reduce the incidence of type 2 DM and improve diabetic control.
- A stepwise approach to managing type 2 DM and obesity starts with lifestyle interventions and advances to adding (1) metformin, (2) a glucagon-like peptide-1 receptor agonist or a sodium-glucose cotransporter-2 inhibitor, and (3) one of the approved weight-loss drugs.
Liraglutide
Liraglutide (Saxenda, Victoza) is a glucagon-like peptide-1 (GLP-1) receptor agonist. Native GLP-1 is a hormone secreted by intestinal L cells in response to consumption of fat and carbohydrate-rich foods. It stimulates the release of insulin and suppresses any inappropriately elevated postprandial glucagon levels. In addition to its effect on glucose metabolism, GLP-1 also reduces appetite and delays gastric emptying in humans.26 Unlike the extremely short half-life of native GLP-1 (estimated at 1 to 2 minutes), liraglutide has a half-life of 13 hours, allowing it to be given once daily.26 Liraglutide medication has been approved for long-term use by the FDA.
Benefits. The Liraglutide Effect and Action in Diabetes 1–5 studies compared the effects of liraglutide monotherapy with antidiabetic oral medications or insulin, as well as in combination with antidiabetic oral agents. Liraglutide (Victoza) at doses approved for type 2 DM of 1.2 mg and 1.8 mg daily had significant effects in reducing HbA1c by 0.48% to 1.84% and weight by 2.5 kg to 4 kg.27,28 At a dose of 3.0 mg, liraglutide (Saxenda) is approved for chronic weight management. This dose of liraglutide has been shown to be effective and safe in patients with type 2 DM and obesity.
In the 56-week SCALE Diabetes trial,29 liraglutide at a dose of 3.0 mg resulted in 6.0% weight reduction, compared with 2.0% in the placebo group. Of participants receiving 3.0 mg of liraglutide, 54.3% achieved more than 5% weight loss at 56 weeks compared with 21.4% with placebo. Liraglutide also resulted in significant improvements in HbA1c (mean change −1.3% vs −0.3% with placebo), fasting and postprandial glucose levels, and fasting glucagon levels.29
The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial has shown liraglutide to significantly reduce rates of major cardiovascular events (first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in patients with elevated cardiovascular risk factors.30 These findings make liraglutide a favorable choice for high-risk patients with type 2 DM, obesity, and cardiovascular disease.
It is important to indicate that if a 5% weight loss is not achieved by 3 months with any of these weight-loss medications, it would be reasonable to stop the medication and consider switching to a different medication. These medications work best when combined with diet and increased physical activity. Weight-loss medications should never be used during pregnancy.
Women of childbearing age should be advised to use effective contraception methods while taking any of the above antiobesity medications.
Diabetes medications associated with weight loss: Metformin and SGLT-2 inhibitors
Although not FDA-approved for weight management, metformin has anorexigenic effects that aid in weight loss. It also inhibits hepatic glucose production and improves peripheral insulin sensitivity, making it a useful agent in patients with type 2 DM and obesity.
A meta-analysis of 31 trials showed that metformin reduced body mass index by 5.3% compared with placebo.31 Metformin should be considered as a first-line agent in obese patients with type 2 DM.
In healthy people, nearly all glucose is filtered in the glomerulus, but then 98% of it is reabsorbed in the proximal tubule by sodium-glucose cotransporter-2 (SGLT-2). Drugs that inhibit SGLT-2 increase urinary glucose excretion and, as a result, help control hyperglycemia. Another, off-label effect of excreting more glucose is weight loss: a sustained weight loss of about 3 kg to 5 kg in clinical studies.32 Although they can be used as monotherapies, SGLT-2 inhibitors are usually used as add-on therapies in patients with type 2 DM.
AN ALGORITHM FOR TREATMENT
First, we believe that lifestyle interventions by optimization of nutrition and physical activity should be the cornerstone therapy in the management plan of any patient with type 2 DM and obesity. These interventions are best implemented through a comprehensive, multidisciplinary approach that integrates the care of dietitians, physical therapists, exercise physiologists, psychologists, and social workers.33 Patients need also to be seen frequently, ie, at least once every 3 months. The possibility of seeing patients in group-shared medical appointments on a monthly basis could also be considered.
We also believe that metformin should be added early in the course of treatment for its known benefits of improving insulin sensitivity and suppressing appetite. Target HbA1c goals and body weight in patients with type 2 diabetes and obesity should be tailored to the individual based on age, general health status, risk of hypoglycemia, capacity to do physical activity, and associated comorbidities. If no improvements are seen (HbA1c > 7% and < 3 % weight loss) despite lifestyle changes and the addition of metformin, the possibility of adding a GLP-1 receptor agonist or an SGLT-2 inhibitor as a second-line therapy should be considered. Both classes of medications aid in lowering HbA1c and promote further weight loss.
If no clinical progress is achieved at 3 months, the possibility of adding an FDA-approved weight-loss medication, as discussed above, should be strongly considered. Of note, this algorithm targets different endogenous pathways for weight loss and thus minimizes weight regain through compensatory mechanisms.
