Nov. 6, 2023 – It’s new, it’s exciting, and it’s a topic that has many diabetes researchers and doctors cautiously optimistic, while others are taking a wait-and-see approach until more evidence arrives.
But for older people with type 2 diabetes, as well as for those who are starting treatment, the news may be a clear win: New research has shown that common diabetes medications may lower the risk of dementia and, perhaps, other potentially life-threatening disorders.
If proven, the link might provide a path toward mindful aging in every sense of the word.
Diabetes affects roughly 37 million people in the U.S. and almost half a billion people worldwide, figures that are projected to significantly increase in the next 2 decades. At the same time, “we have some 47 million people living with dementia, and we expect this number to be almost doubled in 2030, and again by 2050,” said Stella Daskalopoulou, MD, a professor and internist in the Department of Medicine at McGill University Health Centre in Montreal.
The two conditions are related, with a growing body of research that suggests that diabetes, as well as metabolic syndrome and obesity, increases the risk for dementia. This raises the question of whether better control of diabetes and conditions that happen with it can help preserve mental skills throughout life.
“Over the past decade, there’s been a lot of work using existing data to understand the association between different diabetes medications and the risk of either mild cognitive impairment or dementia,” said Rozalina G. McCoy, MD, an associate professor of medicine and associate division chief for clinical research in the Division of Endocrinology, Diabetes, and Nutrition at the University of Maryland School of Medicine in Baltimore.
“They’ve been really consistent in what they’ve found,” she said. What they’ve found is that continued use of metformin, a very common drug to treat blood sugar issues in people with diabetes, appears to lower the risk for cognitive impairment or dementia. On the other hand, another diabetes drug known as sulfonylureas is tied with a higher risk.
A recently published review and analysis Daskalopoulou co-authored appears to confirm this protective effect of metformin against cognitive decline. But metformin is not the only medication that appears to support the brain; the researchers learned that studies of newer agents like Jardiance, Ozempic, and Trulicity also appear to significantly reduce dementia risk, perhaps even more so than metformin.
Importantly, there have not been any studies comparing metformin to these newer agents, so it’s impossible to draw definitive conclusions, but the data looks promising.
Even more compelling is a recent study that analyzed data from the health records of over 40,000 people with type 2 diabetes who either routinely used metformin or, for various reasons, stopped taking their medication but remained on at least one other diabetes drug.
“We found that staying on metformin prevented or delayed dementia onset,” said senior author Sarah Ackley, PhD, an epidemiologist at Boston University, and first author Scott C. Zimmerman, MPH, a research data analyst in the Department of Epidemiology and Biostatistics at the University of California San Francisco.
On the flip side, people who stopped metformin appeared to have a 1.2 times higher rate of dementia, again suggesting the protective role of metformin.
“Since initiating treatment with metformin and remaining on it both seems beneficial, it seems likely that any exposure – even limited exposure – to metformin is good,” they said.
But Absalon Gutierrez, MD, an associate professor at McGovern Medical School at the University of Texas Health Science Center in Houston, and medical director for endocrinology at Lyndon B. Johnson Hospital, said these studies come with an important caveat:
The study does not prove that metformin lowers dementia risk. In other words, he said, “it cannot establish causality. There might have been other factors leading to dementia as well. Larger, high-quality studies are needed.”
Diabetes and the Brain
A number of things appear to connect diabetes and brain health. Arman Fesharaki-Zadeh, MD, PhD, a behavioral neurologist and neuropsychiatrist at Yale School of Medicine in New Haven, CT, said magnetic resonance imaging (MRI) of patients with uncontrolled diabetes shows blood vessel changes that greatly affect how the body delivers oxygen.
“It’s essentially vascular damage to the brain that happens over time, usually due to diabetes, high blood pressure, and high cholesterol, (i.e., metabolic syndrome),” he said. “And studies are showing that the rate of this progression tends to be significantly faster in diabetic patients with Alzheimer's.”
Another important key is blood sugar, or glucose, a primary energy source for the brain.
“If you have a condition that essentially alters the way that your body processes blood glucose, it can significantly affect your cognition by proxy,” Fesharaki-Zadeh said.
But “if someone is already on that process to develop full-blown either vascular dementia or Alzheimer’s or a combination, having rigorous control of their diabetes can slow this decline,” he said.
The Path to Better Cognition Starts With Better Health
Research has yet to show if certain diabetes drugs are better than others at slowing progression to poor mental skills, dementia, and/or Alzheimer’s. But what is clear is that better diabetes control leads to a variety of better health outcomes.
McCoy points to several important things to cover when discussing diabetes with your doctor, whether you’re newly diagnosed or a veteran.
“Most of my patients see me for lowering their blood sugar levels, but lowering blood sugar is not the only consideration,” she said. Doctors also have to think about overall health and maybe heart outcomes; for example, which medication is going to decrease the risk of heart attack or stroke or fatty liver disease, or cancer, or dementia. They must also take into account “how difficult is it going to be for them to get on this medication, and what is going to be the impact of this medication on their lives.”
“I usually start with metformin because of the overwhelming evidence showing that it is basically beneficial not just in diabetes outcomes, but for things like heart attacks and strokes, as well as microvascular disease like retinopathy or neuropathy,” said Daskalopoulou.
Still, like other diabetes medications, metformin is not without side effects, and she said she sees them often.
“Sometimes you have to reduce [dosage] because they have a lot of gastrointestinal side effects like diarrhea or nausea, and then you have to add another agent to compensate,” she explained.
Sometimes, Daskalopoulou said, if a patient can’t tolerate metformin, another drug might work better.
At the same time, none of these medications are the be-all and end-all, and they should be considered a supplement, not a replacement, for lifestyle changes.
In addition to weight loss and diet, Fesharaki-Zadeh mentioned a key intervention that not only helps improve diabetes outcomes and, ideally, reverse the course of diabetes, but also has a significant effect on brain health: exercise.
“I cannot emphasize the importance of exercise enough. When you have a healthy cardiovascular system, especially through working out the muscles, that can go a long way toward managing the way your body processes blood sugar levels. But there’s also a phenomenon that happens in the brains of people who exercise called neurogenesis; they literally form new connections in the memory regions of their brains.”
“Why wait until the crisis is already in the process of happening?” he said.
