Diabetes drug linked to reduced risk for dementia, Parkinson’s disease
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Key takeaways:
- SGLT2 inhibitor use may reduce the risk for Alzheimer’s disease, Parkinson’s disease and vascular dementia.
- The drug has “neuroprotective potential,” but the study results warrant further research, the authors said.
The use of sodium-glucose cotransporter 2 inhibitors reduced the risk for multiple neurodegenerative diseases in adults with type 2 diabetes, according to study results published in Neurology.
A retrospective cohort analysis found a significantly reduced risk for vascular dementia, Alzheimer's disease and Parkinson's disease associated with the use of the type 2 diabetes treatment.
The findings align with recent research that linked sodium-glucose cotransporter 2 (SGLT2) inhibitor use to a 35% to 52% decrease in risk for several types of dementia compared with dipeptidyl peptidase-4 (DPP-4) inhibitor use.
According to Hae Kyung Kim, MD, from the Yonsei University College of Medicine in South Korea, and colleagues, SGLT2 inhibitors reduce the burden of cardiovascular disease risk factors like diabetes, obesity and hypertension, “which may have a positive impact on neurodegenerative disorders,” they wrote.
As a result, SGLT2 inhibitors could be a “promising option” to combat the risks for neurogenerative diseases, but little clinical research has been done on the inhibitors and neurologic outcomes, Kim and colleagues added.
In the analysis, the researchers used data from the Korean National Health Insurance Service database to form a sample of 1,348,362 participants aged 40 years and older with type 2 diabetes who started taking antidiabetic drugs between 2014 and 2019.
They proceeded to conduct 1:1 propensity matching between users of SGLT2 inhibitors with users of other oral antidiabetic drugs, producing a cohort of 358,862 participants (mean age, 57 years; 57.9% men).
Incidence of Alzheimer disease, vascular dementia and Parkinson’s disease served as the study’s primary outcome measurements, whereas the secondary outcomes included the incidence of all-cause dementia and a composite of all-cause dementia and Parkinson’s disease.
At a mean follow-up of 2.8 years, 6,837 incidences of dementia or Parkinson’s disease occurred in the final cohort.
Researchers reported risk reductions associated with SGLT2 inhibitor use, with a 6-month drug use lag period, of:
- 19% for Alzheimer’s disease (adjusted HR = 0.81; 95% CI, 0.76-0.87);
- 31% for vascular dementia (aHR = 0.69; 95% CI, 0.6-0.78); and
- 20% for Parkinson’s disease (aHR = 0.8; 95% CI, 0.69-0.91).
Additionally, the anaoyais found SGLT2 inhibitor use linked to a 21% reduced risk for all-cause dementia (aHR = 0.79; 95% CI, 0.69-0.9) and a 22% lower risk for all-cause dementia and Parkinson’s disease (aHR = 0.78, 95% CI 0.73–0.83) compared with the use of other oral antidiabetic drugs .
The significance for associations between SGLT2 inhibitors and reduced risk for neurogenerative disorders remained after adjusting for several factors, such as diabetes complications, medications, sex, comorbidities or bioclinical variables.
There are multiple mechanisms that contribute to SGLT2 inhibitors’ “disease-modifying potential,” according to Kim and colleagues.
For example, “fasting mimicry by [SGLT2 inhibitors] augments ketogenesis, and ketone bodies function as antioxidants and alternative energy substrates to glucose in the brain, which alleviates neuronal metabolic dysfunction,” they wrote.
The action of SGLT2 inhibitors “that mimics a fasting-like metabolic paradigm by inducing glycosuria and urinary caloric loss may partly underlie neuroprotective potential” of the drugs, they added.
The researchers noted that including users of all other oral antidiabetic drugs in the control group, instead of just users of DPP-4 inhibitors, “may have allowed an analysis of the impact of SGLT2 [inhibitor] use in a context more aligned with actual clinical practice, encompassing various severities of diabetes.”
They concluded that additional research is still needed “to validate the long-term stability of these observations.”
Perspective
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In recent years, the use of a number of medication classes— including anticholinergics, proton pump inhibitors, opioid and nonopioid pain medications and benzodiazepines — have been identified as increasing the risk for neurodegenerative disease. It is encouraging then to see a study that not only suggests a lack of increased risk but even a reduction of risk for patients taking certain medications.
SGLT2 inhibitors have become an important part of our type 2 diabetes mellitus treatment paradigm. As noted by the Kim and colleagues, this class of medication not only provides glucose lowering benefit, but has demonstrated decreased risk of cardiovascular and renal complications of type 2 diabetes mellitus.
That said, some caution in interpreting this study is warranted. First, using a homogenous population as found in the database used in this study calls into question if the results can be generalized to a more diverse population as found in the United States. Second, the relatively short duration of drug exposure of 90 days or greater and follow-up of only 5 years leaves open the questions of the duration of medication use needed to convey benefit and the duration of potential benefit or if the benefit only delays but does not prevent neurodegenerative changes. Finally, left open is the question of whether the same benefit reported in this study will be seen in a nondiabetic population.
This study is a significant first look at the question of whether SGLT-2 inhibitor use has even further risk reduction benefits beyond their cardio-renal protections. Further study is warranted to answer the important question left unanswered by this study and whether similar benefit will be gained in the nondiabetic population.
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