Anti-obesity therapies go beyond weight loss

Weight loss strategies do not only provide therapeutic alternatives for obesity but may also hold promise in the management of type 2 diabetes (T2D) and NAFLD*.

“Obesity, T2D, and NAFLD are interrelated,” said Dr Raluca Pais from the Pitié Salpêtrière Hospital, Paris, France, during her presentation at EASL 2023. “Targeting obesity might result in additional improvement in obesity-related comorbidities, including T2D and NAFLD.”

A 13-percent weight loss was tied to additional health benefits in T2D patients with BMI >30 kg/m². [Int J Obes (Lond) 2021;45:1249-1258] “[Weight loss had] a real additional benefit … The risk after the weight loss was lower than the risk in an individual with corresponding stable BMI,” Pais said.

 

Lifestyle changes

The Mediterranean diet (MED) is one of the most prevalent dietary patterns today that has been evaluated in patients with obesity or NAFLD.

In a study comparing MED against a low-fat diet, a modest reduction in weight was achieved with both dietary patterns. Despite the lack of significant difference between groups, the weight loss was slightly better with MED than its comparator. MRI scans also revealed marked reductions in liver fat content, visceral adipose tissue, and cardiac and intramuscular fat with MED than low-fat diet. [Circulation 2018;137:1143-1157]

“The addition of physical activity did not result in additional weight loss, but it prevented and slowed down weight regain,” Pais added.

 

Pharmacologic therapy

Pais noted that the EASO** advises pharmacologic therapy for obese individuals as an adjunct to lifestyle changes.

The GLP1-RA semaglutide has shown efficacy against overweight or obesity in multiple trials. In the STEP-4 trial, overweight/obese patients experienced rapid weight loss with semaglutide. Almost 10 percent weight loss was achieved at 20 weeks of treatment. Those who continued with semaglutide continued to lose weight that by the end of the trial, about 17 percent of weight loss was achieved. Patients who switched to placebo regained some weight but did not spring back to baseline. [JAMA 2021;325:1414-1425]

In another study on NASH* patients, 60 percent of participants on semaglutide achieved NASH resolution without worsening of fibrosis. Semaglutide also prevented fibrosis progression. [N Engl J Med 2021;384:1113-1124]

Tirzepatide, a GIP and GLP-1 RA***, was associated with significant reductions in visceral adipose tissue, liver enzymes, and liver fat content in a phase III trial on T2D patients. [Lancet Diabetes Endocrinol 2022;10:393-406]

Another player in the anti-obesity drug pipeline is cagrilintide, a long-acting amylin analogue that has also shown promise for weight management. [Lancet 2021;398:2160-2172] A combination regimen comprising cagrilintide and semaglutide led to nearly 20-percent weight loss. [Lancet 2021;397:1736-1748] “Based on the safety results of this preliminary phase Ib trial, the combination of semaglutide and cagrilintide 2.4 mg is being developed for patients with obesity and NASH,” said Pais.

 

Surgery

“Bariatric surgery is a promising therapeutic option for NASH patients,” noted Pais. Apart from its potential to deliver histological improvements, it can also improve NASH-related comorbidities.

In a study on patients with histologically proven NASH, recipients of sleeve or gastric bypass lost up to 30 percent of their weight. There was also a high rate of T2D remission (up to 68 percent) in the intention-to-treat (ITT) population. Almost 60 percent of patients in the ITT cohort had NASH resolution without worsening of fibrosis following bariatric surgery, while ~40 percent had improvement of fibrosis by at least one stage without NASH worsening. [Lancet 2023;401:1786-1797]

“What is important in this trial is that the histologic improvement – particularly the NASH resolution – was tightly correlated with the amount of weight loss. It became significant and much higher in patients who lost >20 percent of their initial weight,” Pais noted. Of note, 11 percent of participants had advanced fibrosis (F3).

In an analysis on patients with severe liver fibrosis at baseline, the advanced fibrosis persisted in almost half of patients following treatment. [Hepatology 2022;76:456-468] “This occurred despite a significant weight loss and amelioration of the metabolic condition, which was secondary to the bariatric surgery,” Pais said.

“[These suggest that] the effect of bariatric surgery might be less prominent for those with more advanced fibrosis,” she noted.

 

Key takeaways

In sum, these data demonstrate the benefits of anti-obesity therapies beyond weight loss. “GLP1-RAs promote significant weight loss and offers promising therapeutic options for NAFLD. These could be the backbone of future NASH/combination therapies,” said Pais.

Bariatric surgery also offers significant cardiometabolic benefits and histologic improvements consistent with the amount of weight loss. For patients with advanced NASH however, advanced fibrosis may persist even after bariatric surgery.