iStock
By Mary Carpenter
THE SPECTER of Joe Biden fumbling his way through the end-of-June debate has many Democrats worrying about the future presidency and others wondering about their own cognitive health. To counter the dementia of Alzheimer’s disease (AD), the two headline-grabbing, recently approved drugs Lequembi and Kisunla (donanemab) attack amyloid plaque in the brains of AD patients. But many doctors consider the results for these drugs countering AD-related dementia to be disappointing and instead place their bets on metformin and other semaglutide or GLP-1 medications, approved to treat type 2 diabetes (T2D) via glucose control and weight loss.
“Is metformin a wonder drug?” asks Senior Faculty Editor for Harvard Health publications Robert Shmerling. “Wonder drugs” earn the title, Shmerling explains, either because they provide “tremendous health benefits” for a particular condition, or “because the drug is good for many different conditions—such as aspirin, which can relieve pain, treat or prevent cardiovascular disease and even prevent cancer.” For AD, dubbed “type 3 diabetes,” tackling insulin resistance might be the key to treatment.
“Metformin does more than just help lower blood sugar in people with diabetes [it offers] cardiovascular benefits,” Shmerling writes. And he describes investigations into metformin’s ability to lower risks for dementia and stroke, as well as to “slow aging, prevent age-related disease and increase lifespan.” But Shmerling warns, because metformin research has focused on people with diabetes or prediabetes, “it’s unclear wither these potential benefits are limited to people with those conditions.”
Metformin and similar drugs aim to protect the brain by regulating insulin resistance and glucose metabolism, and their related problems, such as neuroinflammation. By contrast, the two anti-amyloid drugs—with Kisunla approved just last week—employ monoclonal antibodies in immunotherapy that reduces the plaque in the brains of AD patients that is thought to cause dementia. But according to the New York Times, in addition to these drugs’ worrisome side effects, notably brain bleeds, their success in reducing plaque has not led to clear reduction in AD symptoms.
“There’s no correlation in any of their [anti-amyloid drug] studies between the removal of amyloid plaques and the clinical response in individual subjects,” said Stanford University neurologist Michael Greicius. Noting the risk of discouraging “patients from participating in trials for treatments that could be better,” Grecius believes that the focus on these drugs is “slowing progress.”
“We are at a crossroads where GLP-1 class drugs are emerging as a new treatment strategy” for AD and PD (Parkinson’s disease), according to Florida endocrinologist Wafa Latif and colleagues. “The future looks bright…Newer drugs that have been designed to enter the brain easier already show improved effects in preclinical studies compared with the older GLP-1 class drugs…to treat diabetes.”
The link between AD and diabetes is insulin resistance—in AD, the failure of brain cells to respond to insulin—and related effects, such as neuroinflammation. Write Chengdu, China researchers studying intranasal insulin to combat dementia, “insulin, as an important neurohormone, plays a critical role in brain energy metabolism, cognitive function [while] insulin resistance has been proved to be a pathogenic mechanism of cognitive disorders.” And type 2 diabetes increases by at least two-fold the risk of cognitive disorders and dementia for those with AD and PD.
Glucose is crucial to healthy brain function—and GLP-1 drugs “may mitigate the decline in cerebral glucose metabolism and [enhance] blood-brain glucose transport capacity… [with] potential metabolic and neuroprotective benefits,” according to the Chengdu team. Among GLP-1 drugs, two top contenders for forestalling or improving symptoms of dementia are lixisenatide, in a French study of early-stage Parkinson’s patients proving effective at both improving motor activity and preventing further deterioration; and liraglutide, which has improved cognition and reduced brain shrinkage in patients with Alzheimer’s disease.
On the negative side, metformin has appeared to “trigger AD pathology and even elevate AD risk in humans,” write Korean dementia researchers So Yeon Cho and colleagues, in the journal Nature. In mice studies, long-term treatment with metformin led to “cognitive impairment in mice at old age…despite enhanced cognition observed in… mice at a young age.” As a result, the researchers argue, “drug repurposing of metformin should be carefully reconsidered…when it is intended for individuals with AD.” And while metformin therapy had appeared to increase longevity for T2D patients over the first three years of study, benefits did not last in patients examined over longer periods of more than five years, according to Cardiff researchers Joshua Stevenson-Hoare and colleagues. The Cardiff team also noted the confounding discovery of signs that “late-life diabetes can be protective against neurodegenerative disorders (as is higher body-mass index which is associated with T2D).”
The Alzheimer’s Drug Discovery Foundation considers evidence for metformin’s positive effects on brain health to be inconclusive. And Smerling writes, “While the [metformin] research so far is promising, we need more compelling evidence before endorsing its widespread use for people without diabetes. But for clinical researchers hoping to repurpose an old medicine as a new wonder drug, metformin would seem like a great place to start.”
—Mary Carpenter regularly reports on topical subjects in health and medicine.
