Treating Obesity as a Disease
A review and assessment of recent literature for the clinical applications of new research in treating obesity as a disease. Plus: Extra commentary with our new podcast, After Hours.
March 2021
Volume 10, Issue 1

Chapter 1: Treatments for Type 2 Diabetes Open Door for Treatment of Adiposopathy

Updates in pharmacotherapy for the treatment of adiposity and adiposopathy

Lancet. 2019;7:776–85

Man opening door

The first glucagon-like peptide-1 (GLP-1) receptor analogue to be introduced into medical practice in the United States was exenatide. The initial approval in 2005 was for treatment of type 2 diabetes mellitus (DM-2) for patients who had not achieved adequate control on metformin and/or a sulfonylurea. In 2009, it was approved as monotherapy for DM-2 for patients not achieving their glycemic treatment goal with nutrition and physical activity interventions alone. The dramatic improvements in glycemia noted with early use of exenatide placed patients at risk for hypoglycemia. This mandated the concomitant decrease of sulfonylurea dosing, to avoid the hypoglycemia. The ultimate risk for hypoglycemia has always been treatment with insulin. In October 2011, exenatide received approval to be added to insulin glargine, with or without metformin and/or a TZD, with ongoing nutrition and physical activity interventions, for patients not treated to goal on insulin therapy.

Exenatide requires a twice-daily dose, timed within 60 minutes prior to morning and evening meals. It increases insulin secretion and restores the first phase of insulin release in patients with DM-2. It inhibits glucagon release both through a receptor mediated effect on the alpha cells of the pancreas, and through the indirect inhibition of release by increased insulin. The increased insulin and decreased glucagon lead to decreased hepatic glucose production. In addition to improved glycemia, exenatide causes dose-dependent CNS-mediated fullness, delayed gastric emptying, and weight loss.

There are now 6 GLP-1 receptor agonists approved for treatment of DM-2. Two are available in combination with insulin, and one is now available in oral form (Table 1). They all gained approval for marketing because compared to placebo they achieved significant reductions in plasma glucose and hemoglobin A1c. They all convey a weight benefit as well.

In 2019, Kristensen and colleagues published a meta-analysis of cardiovascular, mortality and kidney outcomes with GLP-1 receptor agonist treatment in people with DM-2, compared to placebo.

  • All-cause mortality was reduced 12% (0·88, 0·83–0·95; p=0·001).
  • Hospital admission for heart failure was reduced 9% (0·91, 0·83–0·99; p=0·028).
  • A broad composite kidney outcome (development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate (or increase in creatinine), progression to end-stage kidney disease, or death attributable to kidney causes) was reduced 17% (0·83, 0·78–0·89; p<0·001), mainly due to a reduction in urinary albumin excretion.
  • There was no increase in risk of severe hypoglycemia, pancreatitis, or pancreatic cancer.

The potential market for successful weight loss treatments still merits an effort by pharmaceutical companies to develop them. Overweight and obesity are still treated differently than other chronic diseases. The very low prescription rates for obesity medications are an example of this. The threshold for discontinuation of medications is very low, and recently lorcaserin was removed from the US market because in a subanalysis of cancer rates, some were higher with treatment than with placebo. The fact that some were higher with placebo than with treatment was ignored. And the fact that for the study as a whole there was no statistically significant difference in cancer incidence rates between treatment and placebo was not allowed to weigh into the decision to withdraw lorcaserin. In the last decade, rimonabant was not approved in the US due to reports of serious psychiatric problems, including suicide, in the registration trials. With an ongoing track record of introductions and withdrawals, or failure to reach the market, the obesity medications in development are under increased scrutiny.

Two developments have given us strong reason to hope that new treatments for adiposopathy, overweight and obesity are in the horizon. Three-year data of liraglutide, 3 mg, vs placebo, became available in 2017. Compared to placebo, where at 3 years there was 2.7 % loss from baseline, ongoing treatment with daily liraglutide, 3 mg, led to 7.1% loss from baseline. The biggest obstacle to the deployment of liraglutide, 3 mg, is cost, when not covered by insurance. And like the formulation for diabetes, the 3 mg liraglutide option is a daily injection.

Higher doses of dulaglutide are now available (the initial doses were 0.75 and 1.5 mg weekly). This is already a treatment for diabetes at doses of 3 and 4.5 mg. As opposed to other meds, which were developed strictly as an obesity treatment, it remains indicated for treatment of DM-2. The use of dulaglutide in people who have overweight, obesity, or adiposopathy in the absence of DM-2 is not approved. However, there is a weight benefit, and it is being used off-label, when coverage is available.

The most recent development in this area of treatment is the Semaglutide Treatment Effect in People with obesity (STEP) program, which includes once weekly semaglutide at a higher dose (0.25, 0.5, or 1 mg weekly). In the STEP program, semaglutide is being dosed at a dose of 2.4 mg weekly, with changes in weight from baseline of:

  • Down 14.9% in STEP 1
  • Down 9.6% in STEP 2
  • Down 16.0% in STEP 3
  • Down 17.4% and 7.9% in STEP4

The second development in this field is the introduction of GLP-1 agonists in combination with other molecules to achieve a more pronounced effect on weight loss. Prior treatments needed to meet a benchmark of 5-10% weight loss from baseline to be considered effective, and for the FDA to approve them for weight management. With bariatric surgery there is over 25% weight loss from baseline consistently. In the obsolete model of starting with one medication for weight loss, and substituting it for a different one over time, there has not been an escalation of treatment. The progression from monotherapy to combination therapy that is the norm for every other chronic disease is difficult to accomplish in the management of overweight or obesity. When combination therapy is instituted with the medications available, the difference between monotherapy and surgery is obliterated. Yet, the discontinuation rules in play for obesity medications make it almost impossible to accomplish the progression of pharmacotherapy with FDA-approved treatments for weight loss. Rather, we are relegated to off-label use of medications for other conditions which have a weight benefit.

Not only is there looming approval for the 2.4 mg semaglutide dose as treatment for obesity, but also in development is a combination of semaglutide with an amylin analogue. A parallel program is the combination of gastric inhibitory polypeptide (GIP) with a GLP-1 agonist. Tirzepatide promises to become another GLP-1 related product that will have therapeutic applications beyond glycemic control, with weight loss approaching that achieved by bariatric surgery.

Other candidate molecules for treatment of overweight, obesity and adiposopathy include setmelanotide, a melanocortin-4 (MC4) receptor agonist which has already been shown to cause significant weight loss in patients with proopiomelanocortin deficiency. Stimulation of MC4 receptors in neurons in the hypothalamus leads to decreased hunger and decreased weight.

And in clinical trials for people with DM-2, the sodium-glucose transporter-2 (SGLT-2) inhibitors are effective for glycemic control, while in addition they are being found to:

  • Control blood pressure because of osmotic diuresis from glucosuria
  • Elicit weight loss due to renal calorie leak
  • Help “rest the pancreas” as there is not as much glucose returning to the circulation after renal filtration
  • Decrease the risk of hospitalization for heart failure in CV outcome trials
  • Decrease mortality from cardiovascular events (except for ertugliflozin – which was not statistically significant vs placebo)
  • SGLT-2 inhibitors are now first line or close to first line therapy in the clinical practice guidelines for diabetes. Although none are indicated for weight management, this is certainly the case for most patients who are treated with them for their DM-2. 

Commentary

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