Scientists have a growing understanding of obesity that may lead to potentially more effective anti-obesity drugs, Angeliki M. Angelidi, MD, PhD, and colleagues, all from Harvard Medical School, Boston, Massachusetts, write in a new review published October 26 in Endocrine Reviews.
"While there are currently only five medications approved for the long-term treatment of obesity in the US," phentermine/topiramate, orlistat, naltrexone/bupropion, liraglutide, and semaglutide, "recent advances in our understanding of the pathophysiology of obesity has sparked the exploration of several promising drug targets across a wide range of systems and tissues," said coauthor Matthew J. Belanger, MD.
Of these drugs with very different targets, gut hormone analogs appear to be further along in the development pathway.
Importantly, "as more safe and effective therapies for obesity make their way from the bench to the bedside, one of the challenges and imperatives will be to ensure the equitable adoption of these therapies on a population level in order to address the obesity epidemic and its downstream health consequences," Belanger stressed in an email to Medscape Medical News.
"Ultimately, advancements in our understanding of the pathophysiological basis and the interindividual variation of obesity will hopefully lead to multimodal, personalized approaches to obesity treatment that result in safe, effective, and sustainable weight loss, which in turn, would also result in decreased prevalence of obesity comorbidities," the authors conclude.
Current Drugs Have Modest Effects
"Obesity is the epidemic crisis of our time," which leads to serious comorbidities, such as diabetes, nonalcoholic fatty liver disease (NAFLD), obstructive sleep apnea, obesity-related malignancies, and cardiovascular disease, and significantly shortens a person's length and quality of life, said another of the authors, Christos S. Mantzoros, MD, in a press release from the Endocrine Society.
Until now, the genetic and hormonal causes of obesity and how they lead to these comorbidities have been poorly understood.
"We have recently started to understand the causes of obesity in humans," Mantzoros added, "which is a big discovery that has led to designing effective therapies."
Currently available anti-obesity medications produce an average weight loss of roughly 3% to 10% of total body weight, Angelidi and colleagues explain, except for the more recently approved glucagon-like peptide-1 (GLP-1) agonist semaglutide, which produces greater weight loss approaching that of bariatric surgery.
Bariatric surgery leads to durable weight loss exceeding 25% of initial weight, "but is not without risks," they continue.
"While there are perioperative and longer-term complications that may occur with bariatric surgery, many steps have been taken to enhance the safety of weight loss surgery," Belanger clarified, "and it remains an appropriate option for patients with obesity and a body mass index (BMI) ≥ 40 kg/m2 or with a BMI ≥ 35 kg/m2 in the presence of comorbidities."
However, recent advances in noninvasive medical approaches to obesity also increase hope that sustainable reductions in body weight of 25% to 30% — similar to that seen after bariatric surgery — may one day be attainable through noninvasive therapies.
Studies have shown that a loss of 7% to 10% of initial weight is required to prevent type 2 diabetes, the authors write, while a weight loss of 10% to 15% may be needed to address concomitant cardiometabolic sequelae or other obesity-related comorbidities, such as obstructive sleep apnea or NAFLD.
"Thus, the success of these emerging approaches will need to be evaluated against the benchmark of these weight-loss thresholds, as well as in the context of long-term safety monitoring data," they add.
Anti-Obesity Drugs Infrequently Prescribed
One point the review authors stress is that the five anti-obesity drugs currently approved in the United States are not widely prescribed.
"We know that medications are not commonly prescribed for the treatment of obesity," Belanger explained, possibly due to perceived lack of efficacy, potential side effects, and patients' out-of-pocket costs.
"As obesity gains more recognition as a disease rather than a lifestyle choice, and as more effective therapies become available," he continued, "we hope that more robust systems will be in place to provide access to effective treatments for patients."
Semaglutide (Wegovy, Novo Nordisk) has a list price of $1350 for a 4-week supply, Belanger noted.
Patients with private insurance or insurance through the Affordable Care Act may be eligible to pay as little as $25 for a month's supply, but not all insurance carriers cover medications for obesity, and notably, Medicare does not cover them.
Douglas Langa, executive vice president of Novo Nordisk North America, recently noted that only about 40% of private insurers cover liraglutide (Saxenda, Novo Nordisk) for weight loss (another GLP-1 agonist approved for obesity and a predecessor of semaglutide).
"As efforts to increase insurance coverage of semaglutide are made," Belanger said, "an emphasis should also be placed on achieving 'pharmacoequity', as described by Utibe R. Essien, MD, and colleagues in a recent JAMA viewpoint."
Those viewpoint authors noted that individuals from racial and ethnic minority groups that suffer a disproportionate burden of chronic disease are less likely to have adequate insurance coverage for prescription medications and other health services.
Mantzoros said: "Insurance companies need to pay attention to data from studies, and the scientific progress we are making, and start covering the medications that are and will be approved soon, given that currently only a small minority of patients with obesity have coverage for the medications and medical care they need."
"It would be much more cost effective to cover treatments early instead of waiting for comorbidities and their complications to develop," he emphasized.
Trials of Drugs That Affect the Gut
The review also details potential weight-loss agents under investigation that affect the central nervous system, gastrointestinal system, kidney, liver, skeletal muscle, and adipose tissue. And researchers are also exploring novel drug delivery systems, vaccines, modulation of the gut microbiome, and gene therapy.
Belanger believes that "gut hormone analogs are the most promising class of obesity drugs under investigation and the [ones that are] most likely to impact clinical practice over the next decade."
Semaglutide, which was approved by the US Food and Drug Administration (FDA) in June as a once-weekly injectable drug for obesity, reduced body weight by 15% in STEP trial participants along with lifestyle modification.
"Several drugs on the horizon could potentially provide even greater weight loss by combining a GLP-1 agonist with other gut hormones in dual or triple agonist formulations," he continued.
One of the most promising dual formulations is tirzepatide (Eli Lilly), a once-weekly dual synthetic glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 agonist. The drug is being studied in the phase 3 SURMOUNT-1 trial of participants with overweight or obesity, with estimated primary completion in April 2022.
Cotadutide (MEDIO382, Medimmune/AstraZeneca), a dual GLP-1 and glucagon receptor agonist, is being investigated in a phase 2 trial in patients with obesity and NAFLD/nonalcoholic steatohepatitis. A phase 2 trial of SAR425899 (Sanofi Aventis) in patients with overweight/obesity and type 2 diabetes is ongoing.
And a once-weekly subcutaneous amylin analog (AM833, Novo Nordisk) is being investigated in a phase 2 trial in patients with overweight or obesity.
"Exciting" Preclinical Trials
Meanwhile, early research in preclinical trials is also encouraging, Belanger noted.
A peptide YY analog is being studied in a preclinical trial. Also, "some very exciting preclinical work is being done exploring gene therapy for obesity," he said.
The first report of anti-obesity gene therapy dates back to 1996 when mice with obesity due to a genetic mutation resulting in leptin deficiency were treated with a recombinant adenovirus expressing mouse leptin cDNA given intravenously, Belanger continued.
That study paved the way for more advanced gene therapy targeting obesity-related genes using viral vector delivery systems as well as nonviral gene carriers.
Gene editing using repetitive DNA sequences, called clustered regularly interspaced short palindromic repeats (CRISPR), are also being explored in animal models, he noted.
Belanger has reported no relevant financial relationships. Disclosures for the other authors are listed in the article.
Endocr Rev. Published online October 26, 2021. Abstract
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Cite this: Prescribe More Obesity Meds, Say Docs, as New Agents on Horizon - Medscape - Oct 27, 2021.