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Miriam E. Tucker
October 11, 2022
Thiazolidinediones (TZDs), such as pioglitazone, appear to be protective against dementia whereas sulfonylureas appear to increase the risk, a new observational study in patients with type 2 diabetes suggests.
The data, obtained from nationwide electronic medical records from the US Veterans Affairs Administration, yielded a 22% lower risk of dementia with TZD monotherapy and a 12% elevated risk with sulfonylurea monotherapy, compared with metformin monotherapy. The apparent protective effects of TZDs were greater among individuals with overweight or obesity.
“Our findings provide additional information to aid clinicians’ selection of [glucose-lowering medications] for patients with mild or moderate type 2 diabetes and [who] are at high risk of dementia,” write Xin Tang and colleagues in their article published online October 11 in BMJ Open Diabetes Research & Care.
The results, Tang and colleagues say, “add substantially to the literature concerning the effects of [glucose-lowering medications] on dementia where previous findings have been inconsistent. Studies with a follow-up time of less than 3 years have mainly reported null associations, while studies with longer a follow-up time typically yielded protective findings. With a mean follow-up time of 6.8 years, we had a sufficient duration to detect treatment differences.”
“Supplementing [a] sulfonylurea with either metformin or [a] TZD may partially offset its prodementia effects. These findings may help inform medication selection for elderly patients with T2D at high risk of dementia,” they observe.
Ivan Koychev, PhD, a senior clinical researcher in the department of psychiatry at the University of Oxford, told the UK Science Media Centre: “This is a large, well-conducted real-world data study that highlights the importance of checking whether already prescribed medications may be useful for preventing dementia.”
The findings regarding TZDs, also known as glitazones, are in line with existing literature suggesting dementia protection with other drugs prescribed for type 2 diabetes that weren’t examined in the current study, such as newer agents like glucagon-like peptide-1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, Koychev said.
“The main limitations of this study is that following the initial 2-year period the authors were interested in, the participants may have been prescribed one of the other type 2 diabetes drugs (GLP-1 agonists or SGLT2 inhibitors) that have been found to reduce dementia risk, thus potentially making the direct glitazone [TZD] effect more difficult to discern,” Koychev noted.
And, he pointed out that the study design limits attribution of causality. “It is also important to note that people with type 2 diabetes do run a higher risk of both dementia and cognitive deficits and that these medications are only prescribed in these patients, so all this data is from this patient group rather than the general population.”
James Connell, PhD, head of translational science at Alzheimer’s Research UK, agreed. “While this observational study found that those with type 2 diabetes taking thiazolidinedione had a lower dementia risk than those on the most common medication for type 2 diabetes, it only shows an association between taking the drug and dementia risk and not a causal relationship.” 
“Double-blind and placebo-controlled clinical trials are needed to see whether the drug [TDZ] could help lower dementia risk in people with and without diabetes. Anyone with any questions about what treatments they are receiving should speak to their doctor,” he told the UK Science Media Centre.
Tang, of the department of epidemiology and biostatistics at the University of Arizona Mel and Enid Zuckerman College of Public Health, Tucson, and colleagues studied 559,106 VA patients with type 2 diabetes who initiated glucose-lowering medication during 2001-2017 and took it for at least a year. They were aged 60 years or older and did not have dementia at baseline. Most were White (76.8%) and male (96.9%), two thirds (63.1%) had obesity, and mean A1c was 6.8%.
Overall, 31,125 developed all-cause dementia. The incidence rate was 8.2 cases per 1000 person-years, ranging from 6.2 cases per 1000 person-years among those taking metformin monotherapy to 13.4 cases per 1000 person-years in those taking both sulfonylurea and a TZD.
Compared with metformin monotherapy, the hazard ratio (HR) for all-cause dementia for sulfonylurea monotherapy was a significant 1.12. The increased risk was also seen for vascular dementia, with an HR of 1.14.
In contrast, TZD monotherapy was associated with a significantly lower risk for all-cause dementia (HR, 0.78), as well as for Alzheimer’s disease (HR, 0.89) and vascular dementia (HR, 0.43), compared with metformin monotherapy.
The combination of metformin and TZD also lowered the risk of all-cause dementia, while regimens including sulfonylureas raised the risks for all-cause and vascular dementia.
Most of the results didn’t change significantly when the drug exposure window was extended to 2 years.
The protective 1-year effects of TZD monotherapy and of metformin plus TZD compared to metformin alone were more significant among participants aged 75 or younger and with a body mass index (BMI) above 25 kg/m2 compared with those who were older than 75 years and with normal BMIs, respectively.
On the other hand, the greater risk for dementia incurred with sulfonylureas was further increased among those with higher BMI.
This research was partially funded by grants from the National Human Genome Research Institute, the National Science Foundation, the National Institute of Diabetes and Digestive and Kidney Disease, and the National Heart, Lung, and Blood Institute. Zhou had no further disclosures. Koychev is chief investigator for a trial, sponsored by Oxford University and funded by Novo Nordisk, testing whether the GLP-1 agonist semaglutide reduces the risk for dementia in aging adults.
BMJ Open Diab Res Care. 2022;10:e002894. Full text
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.
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Lead Image: Yee Xin Tan/Dreamstime
Medscape Medical News © 2022 WebMD, LLC

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Cite this: One Type of Older Diabetes Drug Cuts Dementia Risk, Another Ups It – Medscape – Oct 11, 2022.
Freelance writer, Medscape

Disclosure: Miriam E. Tucker has disclosed no relevant financial relationships.
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