Agreement: I Agree Body: Dear Editor, Nong and colleagues’ living systematic review and network meta-analysis provides a timely synthesis of evidence on glucose-lowering therapies and dementia. Their finding that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may reduce dementia risk, although with low certainty (OR 0.92, 95% CI 0.83–1.02), while evidence for other drug classes remains very uncertain, highlights an important evidence gap rather than demonstrating an absence of benefit.[1] This uncertainty is particularly relevant because dementia develops over many years, whereas diabetes trials generally focus on shorter-term metabolic, cardiovascular and renal outcomes. Although the review included 23 trial comparisons involving 161,179 participants and 1,933 dementia events, the median follow-up across its 869 included trials was only six months, limiting conclusions about long-term cognitive outcomes.[1] Emerging evidence suggests that cognitive outcomes may depend on factors beyond mean HbA1c. In a cohort of 171,964 people with type 2 diabetes, greater visit-to-visit HbA1c variability was associated with increased dementia risk (adjusted HR 1.15, 95% CI 1.12–1.17), including among those with mean HbA1c below 6% or between 6% and 8%.[2] A meta-analysis involving 577,592 people with diabetes reported a similar association, although observational findings cannot establish causality.[3] Similarly, a Hong Kong cohort of 55,618 people with type 2 diabetes found that participation in a multidisciplinary diabetes-management programme was associated with lower risks of all-cause dementia, Alzheimer’s disease and vascular dementia. Risk was lowest among participants with mean HbA1c of 6.5–7.5%, with both higher and lower levels associated with greater risk.[4] While these findings do not establish an optimal HbA1c target for dementia prevention, they highlight the need to understand how glycaemic control, treatment intensity and broader care influence cognitive health. Evidence concerning individual drug classes also remains unsettled. A meta-analysis of randomised trials found no significant overall reduction in dementia or cognitive impairment with cardioprotective glucose-lowering therapies, although GLP-1RAs were associated with lower risk (OR 0.55, 95% CI 0.35–0.86); SGLT2 inhibitors showed no such association.[5] Differences in outcome definitions, follow-up duration and the inclusion of cognitive impairment alongside dementia may partly explain these contrasting estimates. The evidence gap is particularly important in low- and middle-income countries (LMICs), including India, where diabetes and other modifiable dementia risk factors are prevalent, but long-term cognitive evidence remains geographically uneven. Indian population-level estimates indicate considerable potential for dementia prevention through addressing modifiable risk factors, including diabetes and vascular risks.[7] However, potential benefits of newer therapies must be considered alongside affordability, equitable access and treatment sustainability. Future trials and real-world studies should include diverse LMIC populations, employ culturally and linguistically appropriate cognitive assessments, and account for hypoglycaemia, glycaemic variability, competing mortality and differences in healthcare access. Integrating cognitive assessments into existing diabetes and primary-care programmes could generate locally relevant evidence without requiring separate dementia surveillance infrastructure. These considerations support including cognitive decline and dementia as prespecified long-term outcomes in future diabetes trials, rather than relying primarily on post hoc analyses of administrative diagnoses. Tracking cognitive trajectories and dementia subtypes alongside hypoglycaemia, glycaemic variability and conventional metabolic and cardiovascular outcomes would help establish whether newer therapies influence dementia risk or whether observed associations reflect broader improvements in vascular and metabolic health. The 2024 Lancet Commission places diabetes, hypertension, obesity and other metabolic and vascular exposures within a life-course approach to dementia prevention.[6] Updated WHO guidance similarly addresses risk reduction for cognitive decline and dementia, although evidence for specific preventive interventions remains uncertain.[8] Ultimately, the key question is whether improved management of these risk factors translates into fewer dementia cases. The BMJ living-review approach provides a valuable framework for updating the evidence as longer-term data emerge. Dr Pradeep Paul George, Madras Diabetes Research Foundation, Gopalapuram, Chennai. Dr RM Anjana, Dr. Mohan's Diabetes Specialities Centre – Gopalapuram, Chennai, Madras Diabetes Research Foundation, Gopalapuram, Chennai. Dr Murali Krishna, Centre for Brain Research, Indian Institute of Science, Bangalore, India. Dr V Mohan, Dr. Mohan's Diabetes Specialities Centre – Gopalapuram, Chennai, Madras Diabetes Research Foundation, Gopalapuram, Chennai. References 1. Nong K, Jeppesen BT, Shi Q, et al. Medications for adults with type 2 diabetes: a living systematic review and network meta-analysis. BMJ. 2025 Aug 14;390:e083039. doi: 10.1136/bmj-2024-083039. 2. Moran C, Whitmer RA, Dove Z, et al. HbA1c variability associated with dementia risk in people with type 2 diabetes. Alzheimers Dement. 2024 Aug;20(8):5561–5569. doi: 10.1002/alz.14066. Epub 2024 Jul 3. 3. Song J, Bai H, Xu H, Xing Y, Chen S. HbA1c variability and the risk of dementia in patients with diabetes: a meta-analysis. Int J Clin Pract. 2022;2022:7706330. doi: 10.1155/2022/7706330. 4. Wang K, Zhao S, Lee EK, et al. Risk of dementia among patients with diabetes in a multidisciplinary, primary care management program. JAMA Netw Open. 2024;7(2):e2355733. doi: 10.1001/jamanetworkopen.2023.55733. 5. Seminer A, Mulihano A, O’Brien C, et al. Cardioprotective glucose-lowering agents and dementia risk: a systematic review and meta-analysis. JAMA Neurol. 2025;82(5):450–460. doi: 10.1001/jamaneurol.2025.0360. 6. Livingston G, Huntley J, Liu KY, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet. 2024;404(10452):572–628. doi: 10.1016/S0140-6736(24)01296-0. 7. Angrisani M, Nichols E, Meijer E, et al. Modifiable risk factors for dementia in India: a cross-sectional study revisiting estimates and reassessing prevention potential and priorities. BMJ Public Health. 2024;2(2):e001362. doi: 10.1136/bmjph-2024-001362. 8. World Health Organization. Risk reduction of cognitive decline and dementia: WHO guidelines. 2nd ed. Geneva: World Health Organization; 2026. ISBN: 978-92-4-012355-7. Competing Interests: No competing interests No competing Interests: Yes The following competing Interests: Electronic Publication Date: Tuesday, November 3, 2026 - 09:27 AI use: No, I have not used AI Highwire Comment Subject: Workflow State: Released Full Title: Re: Medications for adults with type 2 diabetes: a living systematic review and network meta-analysis Highwire Comment Response to: Check this box if you would like your letter to appear anonymously:: Last Name: George First name and middle initial: Pradeep Paul Email: drpradeep@mrf.in Address: No. 4, Conran Smith Road, Gopalapuram, Chennai – 600 086, Tamil Nadu, India Occupation: Epidemiologist Other Authors: Dr RM Anjana, Dr Murali Krishna, Dr V Mohan Affiliation: Madras Diabetes Research Foundation, Chennai BMJ: Additional Article Info: Rapid response
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