Semaglutide and tirzepatide work by mimicking the action of GLP-1, a hormone that occurs naturally in the body. They act on GLP-1 receptors in the pancreas to stimulate the release of insulin after meals, helping people with diabetes to control blood sugar levels. They also bind to GLP-1 receptors in the brain, making people feel fuller and helping them eat less.
Scientists are still trying to figure out other knock-on effects of these drugs, such as their effects on the cardiovascular system. One explanation is that GLP-1 receptors are also present on cells in the heart, blood vessels, liver, and kidneys, so these drugs may act directly on those organs. “It turns out these receptors are present in many parts of the body,” says Katherine Tuttle, clinical professor of nephrology at the Washington University School of Medicine.
A recent clinical trial led by Dr. Tuttle was stopped early because overwhelming evidence showed that semaglutide has a kidney-protecting effect. The study involved more than 3,500 subjects with both type 2 diabetes and kidney disease. About half of the subjects received weekly semaglutide injections, and the other half received placebo injections. After an average of three and a half years, those in the semaglutide group were 24 percent less likely to experience a major kidney disease event, such as the need for dialysis or a kidney transplant.
Clinical trials aren’t typically designed to determine how a drug works — in fact, the mechanisms of action of many drugs on the market aren’t fully understood — but Tuttle has his own theory about how semaglutide protects the kidneys: by reducing inflammation.
GLP-1 drugs may also quell inflammation in the brain, raising hopes that they could be used to treat conditions such as dementia and Parkinson’s disease, both of which are thought to play a role in the development of the condition.
In a UK trial of 200 people with mild Alzheimer’s, an older GLP-1 drug called liraglutide appeared to slow the shrinkage of parts of the brain that control memory, learning, language and decision-making by up to 50 percent. Patients who received weekly injections of liraglutide for 52 weeks saw their cognitive decline slow by 18 percent after a year, compared with those who received a placebo. Obesity is a known risk factor for developing Alzheimer’s, but the study did not specifically include obese people, so the drug may be working in another way.
The authors, who presented their findings last month at the Alzheimer’s Association annual conference, believe liraglutide may work in a few different ways, including reducing brain inflammation and lowering insulin resistance.
Heather Snyder, vice president of medical and scientific affairs at the Alzheimer’s Association, said the results are intriguing, but larger trials are needed to confirm the preventative effect. “This is the first study to show any indication of this benefit for individuals,” she said.
And the neuroprotective effects may even extend to Parkinson’s disease. Lixisenatide, an older diabetes drug from the GLP-1 family, appears to help slow the progression of Parkinson’s symptoms in a small French study of 156 patients. Results published in April showed that participants with early Parkinson’s disease who took the drug for a year saw no worsening of motor symptoms such as tremors, balance problems, slow movements and stiffness. Meanwhile, participants who received a placebo saw their symptoms worsen over the same period.
