Chapter 50
Obesity and Diabetes — 9
In two randomized trials of a certain type of heart failure (preserved ejection fraction) that accounts for approximately half of all cases of heart failure, there was a marked reduction of symptoms and improvement in how much exercise people were able to do. One of the trials was in patients with diabetes and obesity; the other was obesity alone. Once again, the weight loss was substantially less—nearly half as much—in people with diabetes. Notably, GLP-1 led to a substantial decrease of hs-CRP that emerged before the effect on weight loss. That, along with weight loss, may account for the marked reduction of atrial fibrillation in multiple randomized trials of GLP-1 drugs.
The benefit of GLP-1 for kidney function was assessed in over thirty-five hundred people with diabetes and obesity with impaired renal function. The effect of the drug was so beneficial that the trial was discontinued early. A dose of 1 milligram of semaglutide dramatically reduced kidney failure, the need for dialysis or kidney transplant, and even death from cardiovascular causes.
While not as common as obesity, nonalcoholic steatohepatitis causes one in four people worldwide to develop fatty liver disease (NAFLD) and 10 percent of these progressing to the severe form (NASH), with marked scarring (fibrosis), cirrhosis, and liver cancer. Ten to 20 percent of cases are in lean, nonobese individuals. These conditions have been renamed to MASH and MALFD, with the M standing for metabolic dysfunction to separate them from obesity and alcohol-related ailments. The first approved drug for MASH is resmetirom (Rezdiffra), approved in 2024, which improves mitochondrial function in liver cells. Multiple GLP-1 drugs are showing benefit, including semaglutide in patients with human immunodeficiency virus (HIV) and MALFD, as well as randomized trials of tirzepatide and survodutide for patients with MASH. Prevention of the fibrosis and its progression is the key determinant of outcomes. By achieving improved glucose control and some weight loss in people with type 2 diabetes, there are studies in people that suggest GLP-1 drugs may help fix this specific metabolic dysfunction.
The GLP-1 anti-inflammatory effect in the brain has led to ongoing clinical trials for prevention of both Parkinson’s disease and Alzheimer’s disease. For Parkinson’s, there have been three small randomized trials of GLP-1 drugs versus placebo, with a consistent benefit of stopping or reducing progression of motor symptoms. A real-world study of nearly ninety thousand Medicare beneficiaries over four years who were new users of a GLP-1 drug compared with dipeptidyl peptidase 4 (DPP-4) inhibitors drugs found a 23 percent lower risk of developing Parkinson’s disease. To put this in context, we have never had a drug that is disease modifying for Parkinson’s disease; the only medications available treat symptoms such as tremor and rigidity.