SGLT-2 inhibitors and dementia
BMJ 2024; 386 doi: https://doi.org/10.1136/bmj.q1841 (Published 28 August 2024) Cite this as: BMJ 2024;386:q1841Linked Research
Risk of dementia after initiation of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in adults aged 40-69 years with type 2 diabetes
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Dear Editor
The study by Shin and colleagues (doi:10.1136/bmj-2024-079475)(1) on the neuroprotective benefits of SGLT-2 inhibitors in relation to dementia makes for an encouraging read.
In addition to welcome findings in a limited field of dementia prevention treatments, the study design and use of rigorous pharmacoepidemiological methods demonstrates significant potential to be able to draw stronger conclusions from observational data. This would be of great help in expediting access to new treatments in populations that have previously been underserved due to exclusion from randomised control trials (RCTs), including those with chronic and end-stage kidney disease, pregnancy, rarer genetic conditions, and our increasingly older patients(2). The use of target trial emulation(3) and propensity scoring methods(4) can lend weight to the efficacy of treatments in these populations through more robust analysis of observational data.
Active comparators (5) could be used to compare the benefits and risk profiles of different treatments where direct comparison in head-to-head trials has not yet happened. For example, where drugs have been produced by different pharmaceutical companies, including different forms of SGLT-2 inhibitors, direct oral anticoagulants (DOACS) and in comparing the advances in new immunosuppressive treatments in conditions like lupus nephritis.
While RCTs will rightly remain necessary as the gold standard of assessing treatment efficacy, this fresh approach to observational studies can help improve access to new treatments and reduce non-equity amongst patient groups.
1. Shin A, Koo BK, Lee JY, Kang EH. Risk of dementia after initiation of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in adults aged 40-69 years with type 2 diabetes: population based cohort study. BMJ. 2024 Aug 28;386:e079475.
2. GOV.UK [Internet]. 2023 [cited 2024 Sep 14]. Chief Medical Officer’s annual report 2023: health in an ageing society. Available from: https://www.gov.uk/government/publications/chief-medical-officers-annual...
3. Matthews AA, Danaei G, Islam N, Kurth T. Target trial emulation: applying principles of randomised trials to observational studies. BMJ. 2022 Aug 30;378:e071108.
4. Austin PC. An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. Multivariate Behav Res. 2011 May;46(3):399–424.
5. Sendor R, Stürmer T. Core concepts in pharmacoepidemiology: Confounding by indication and the role of active comparators. Pharmacoepidemiol Drug Saf. 2022 Mar;31(3):261–9.
Competing interests: No competing interests
From Diabetes to Cognition: The Pleiotropic Promise of SGLT-2 Inhibitors
Dear Editor,
In a recent humorous article on social media, users were asked to share their theoretical “Personal Preventative Cocktail” of medications. This would be a combination of medications that they would choose to optimize their own long-term health outcomes. I noted common themes including statins, metformin, angiotensin-receptor blockers, as well as, unsurprisingly, SGLT-2 inhibitors.
Primarily known for their ability to improve glycaemic control through the prevention of glucose reabsorption in the kidneys, their utility has expanded into the management of cardiovascular and renal disease, following evidence demonstrating its benefit in cardiovascular disease (1,2), and its ability to slow the progression of chronic kidney disease (3,4) respectively.
Through your findings which have linked SGLT-2 inhibitors to a lower risk of dementia, there has been added yet another dimension to their pleiotropic effects. This growing body of evidence underscores the importance of further randomized controlled trials to confirm these promising results and solidify the neuroprotective role of these drugs.
Recognizing the strengths and limitations of your study as you have already outlined, I would like to see two more variables to be considered in future research.
Cognitive function at baseline - if SGLT-2 inhibitor users had higher cognitive function at baseline compared to DPP-4 inhibitor users, it could explain the observed association rather than the drug itself having a protective effect. To better isolate the effects of SGLT-2 inhibitors, future studies should integrate cognitive assessments in their methodology. Validated tools such as the Montreal Cognitive Assessment or the Mini-Mental State Examination could be used to better appreciate the cognitive trajectory of patients over time.
Adherence to medications - future studies should address patient adherence to SGLT-2 inhibitors or comparator medications used in the trial. As non-adherence could be linked to a higher risk for dementia (5), this issue could be tackled by including measures of medication adherence, such as pharmacy refill data. If future studies were to adjust for adherence levels, that could give us a clearer understanding of the link between actual drug exposure and dementia risk.
As it stands, SGLT-2 inhibitors are making a strong case to be included as my top choice in a “Personal Preventative Cocktail” of medications, and your research has further reinforced this position.
1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine. 2015 Nov 26;373(22):2117–28.
2. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. New England Journal of Medicine [Internet]. 2017 Aug 17;377(7):644–57. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa1611925
3. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in Patients with Chronic Kidney Disease. New England Journal of Medicine [Internet]. 2020 Sep 24;383(15). Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2024816
4. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. New England Journal of Medicine [Internet]. 2019 Jun 13;380(24):2295–306. Available from: https://mycourses.purdue.edu/bbcswebdav/pid-13899303-dt-content-rid-1065...
5. Smith D, Lovell J, Weller C, Kennedy B, Winbolt M, Young C, et al. A Systematic Review of Medication non-adherence in Persons with Dementia or Cognitive Impairment. Chen K, editor. PLOS ONE [Internet]. 2017 Feb 6;12(2):e0170651. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293218/
Competing interests: No competing interests