Bariatric Endocrinology: Obesity, Adiposity and Adiposopathy
October 2021
Volume 10, Issue 3

Chapter 2: Pharmacotherapy as a First-Line Treatment

N Engl J Med. 2021;384:989-1002

Adipose tissue.

FDA-Approved Treatments

The first pharmacological intervention in the management of overweight, obesity and adiposopathy is to identify medications that a patient is currently taking that promote weight gain, and to exchange them for alternative treatments known to promote weight maintenance or weight loss. Recent articles in EndocrineWeb have covered GLP-1 agonists and SGLT-2 inhibitors, which are now preferred agents for hyperglycemia given their association with weight loss and decreased cardiovascular events.

Needless to say, care must be individualized for each patient. The benefits and risks of each medication should be carefully weighed before proceeding. For example, a woman with severe endometriosis needs suppression of endometrial shedding, and continuous progestins are indicated. Their effect to trigger hunger and fluid retention needs to be overcome as part of treatment. However, a woman who is using progesterone-only contraception has other choices that minimize exposure to progestins. Similarly, a patient with established coronary disease benefits from beta-blockade. Nonetheless, if beta-blockers are being used for hypertension only, then there are better choices. Beta-blockers have a negative chronotropic effect that prevents the heart from speeding up with physical activity. They may contribute to asthma and depression, and cause sexual dysfunction and hyperglycemia. These qualities may cause beta-blockers to promote weight gain.

It is important to provide a structured cycle of visits for patients with overweight, obesity and adiposopathy. A quarterly cycle of visits allows for interventions should treatment goals not be met. At each visit, pharmacotherapy and weight loss procedures should be offered.

What all pharmacological interventions for weight management have in common is that:

  • Compared to placebo, pharmacotherapy helps patients lose more weight from baseline.
  • Compared to placebo, maintenance of lost weight is better with pharmacotherapy.
  • All weight loss medications should be discontinued during pregnancy and lactation.
  • All weight loss medications will have a finite effect on weight loss, reaching a plateau 36 to 52 weeks from onset of treatment and necessitating additions to treatment for ongoing weight loss.
  • With weight loss there are improvements in metabolism, and the magnitude of which is dependent on the population studied.
  • None of the treatments are approved for patients under age 12 years.
  • Combination pills need the consideration of potential side effects and drug-drug interactions of the individual components.
  • None of the medications is recommended for patients with severe hepatic impairment.
  • All weight loss agents are appropriate for patients with hyperglycemic derangements with normal renal and hepatic function.
  • None of these weight loss agents has been studied in patients with congestive heart failure, so use in this patient population must be done with caution.
  • As is the case for every other chronic disease, success with these medications mandates ongoing use. Withdrawal of treatment would be expected to result in the disease marching unabated, with weight regain and metabolic deterioration.
  • For the newer medications with discontinuation rules, failure to meet the expected benchmarks for weight loss (response of adiposity) merits very careful review of each case to exclude factors that may have interfered with the medication’s success.  Only after all other confounders are excluded can one conclude the medication truly is not effective for a patient.
  • All of these medications have limited effects by themselves.  Therefore, off-label use in combination with other weight loss medications or procedures is appropriate.
  • Universally, with effective weight loss, patients with hyperglycemic diseases have improvements in the level of glycemia.
  • Universally, with effective weight loss, triglycerides levels decrease, and HDL levels rise.

It is important to understand the historical context in which these medications came to market. The agents introduced in the late 1950s and early 1960s are all adrenergic agonists. The amphetamines had been recognized as being habit-forming, tolerance-building and addictive. Obesity was not recognized as a chronic disease. This led to labeling for these weight loss medications in the 1950s that recommended limiting their use to a few months and raised concerns that they may behave like amphetamines.

Over 60 years later, we now understand that obesity is a chronic disease. We have data that phentermine is not like amphetamines, and may be started or stopped without concern for withdrawal symptoms. Because of trial data of phentermine in combination with topiramate, phentermine is now approved for indefinite treatment for overweight and obesity. Off-label use of generic phentermine is therefore considered safe long-term. This is an important consideration given the cost differential of medications, especially when third party payers do not cover them.

In addition to the FDA-approved medications for weight loss, the components of combination medications are available individually and in generic form. Generic topiramate can be added to phentermine off-label for weight management. It may also be prescribed on-label for patients with migraine headaches or seizure disorder, with expected additional benefits to the weight. The same holds true for generic bupropion and generic naltrexone. Each individual agent may be used off-label for weight loss.

Of the currently available medications, lisdexamphetamine dimesylate stands apart because it is approved for treatment of binge-eating disorder. It is an amphetamine. The dose may be titrated from 30 mg to 70 mg daily.

The FDA-approved list of medications includes setmelanotide, the first-in-class melanocortin 4 receptor (MC4R) agonist. MC4R is activated by alpha-melanocyte stimulating hormone (MSH) produced in the hypothalamus. Stimulation of the receptor causes satiety or fullness.  The release of MSH from proopiomelanocortin (POMC) cells in the hypothalamus is stimulated by leptin. Individuals with leptin receptor mutations in the POMC cells of the hypothalamus cannot activate this pathway and develop obesity. The same holds true for individuals with POMC deficiency. Proprotein subtilisin/kexin type 1 (PCSK1) deficiency impairs POMC processing in addition to other prohormones to mature hormone processes. Setmelanotide bypasses all the pathway and directly stimulates MC4R. It is indicated for very rare individuals with obesity recognized to be due to POMC deficiency, PCSK1 deficiency or leptin receptor deficiency. Setmelanotide holds potential for development in the treatment of other forms of obesity.

Emerging Treatments

The development of agents that modulate the entero-cerebral axis has been fruitful in bringing about new treatments for diabetes mellitus. The glucagon-like peptide 1 (GLP-1) agonists are now in the mainstream of medical practice because they are effective to control hyperglycemia while at the same time promoting weight loss. Two of these agents, liraglutide and semaglutide, have already been approved for treatment of obesity at doses higher than those used for diabetes.

Tirzepatide is a molecule with GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) activities in the same molecule. Preliminary data is promising that there is a dose-dependent reduction in A1c in people with diabetes, while there is concomitant weight loss of up to 14% from baseline.

A long-acting amylin analogue is under development, co-administered with semaglutide, 2.4 mg. The phase 1B trial was published in April, 2021, and the change in weight from baseline reached up to 17%.

Glucagon agonists, peptide YY agonists, CNS ghrelin agonists, neuropeptide Y antagonists, zonisamide-bupropion, new generation cannabinoid type-1 receptor blockers and combinations of these compounds, have all been under investigation recently, and may result in viable treatment options in the near future.

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