9th November 2024, A/Prof Chee L Khoo
Metformin has been the first line treatment for patients with type diabetes for many years. It has many mechanisms of action with many more that we have yet to uncover. We know that it improves glucose control by improving insulin resistance. These days we have many other glucose lowering agents that are a lot more potent than metformin. It is sometimes tempting to wonder whether we still need metformin anymore. In patients who has well controlled T2D, should we bother with metformin anymore?
Metformin may reduce dementia risk by improved glucose control or by mechanisms unrelated to diabetes, including activation of adenosine monophosphate–activated protein kinase, which may mimic starvation or by inhibition of aromatase, which may be associated with lower blood pressure (1-3). The data from clinical trials is conflicting. Most of the trials were looking at the cognitive benefit from the degree of glucose improvement rather than metformin use per se.
Observational studies found that initiating metformin treatment was associated with a benefit in dementia risk, including a benefit compared with other anti-diabetes drugs but confounding factors including severity and duration of diabetes may have affected the results (4,5).
There is another way of looking at the potential benefit of metformin beyond glucose control. In the real world, metformin may be ceased because of gastrointestinal side effects or because of declining renal function. What if we look at what happens when patients stop metformin and compared them with those who continue their metformin and see whether there is any difference in their health benefits. This is exactly what Zimmerman S. et al did in his recent study ().
Zimmerman et al posed the question: “Is cessation of metformin therapy associated with dementia incidence, and is the association mediated by hemoglobin A1c (HbA1c) level or insulin use?” They obtained data from the large Kaiser Permanente Northern California integrated health care delivery system and examine a cohort of metformin users born prior to 1955 without history of diagnosed kidney disease at metformin initiation. Dementia follow-up began with the implementation of electronic health records in 1996 and continued to 2020.
Individuals who stopped metformin with normal eGFR were termed as early terminators. They were compared with routine metformin users who had not yet terminated metformin treatment or had terminated (with or without restarting) after their first abnormal eGFR measurement. Early terminators were matched with routine users of the same age and gender who had diabetes for the same duration. The outcome of interest was all-cause incident dementia.
There were 12,220 early terminators and 29,126 routine metformin users. Mean age was 59.4 years old. Early terminators had 1.21 times the hazard of dementia diagnosis compared with routine users. Contributions to this association by changes in HbA1c level or insulin use ranged from no contribution for insulin use at 5 years after termination to 0.07 years for HbA1c level at 1 year after termination, suggesting that the association was largely independent of changes in HbA1c level and insulin usage.
The conclusion from this study is not that unexpected. Previously meta-analysis indicated that people with diabetes who receive metformin had 0.76 times the hazard of Alzheimer disease compared with people with diabetes not receiving metformin (4). This meta-analysis included control groups of patients with diabetes receiving sulphonylurea therapy or no drug therapy or any patients with diabetes not receiving metformin. A prior study (4,7) found an HR of 0.82 comparing metformin with sulphonylurea therapy.
This study has implications for our patients with diabetes who are still on metformin. This potential benefit beyond that of glucose lowering may suggest that they should be continued on their metformin unless there are gastrointestinal side effects or their eGFR levels mandate that the metformin be ceased. Further, those patients who are at risk of dementia including those have the apoE4 gene variant or have a family history of dementia may benefit from ongoing metformin treatment.
References:
1. UK Prospective Diabetes Study (UKPDS) Group . Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854-865.
2. Landin K, Tengborn L, Smith U. Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors. J Intern Med. 1991;229(2):181-187
3. Dean A, Nilsen M, Loughlin L, Salt IP, MacLean MR. Metformin reverses development of pulmonary hypertension via aromatase inhibition. Hypertension. 2016;68(2):446-454.
4. Campbell JM, Stephenson MD, de Courten B, Chapman I, Bellman SM, Aromataris E. Metformin use associated with reduced risk of dementia in patients with diabetes: a systematic review and meta-analysis. J Alzheimers Dis. 2018;65(4):1225-1236
5. Scherrer JF, Salas J, Floyd JS, Farr SA, Morley JE, Dublin S. Metformin and sulfonylurea use and risk of incident dementia. Mayo Clin Proc. 2019;94(8):1444-1456
6. Zimmerman SC, Ferguson EL, Choudhary V, Ranatunga DK, Oni-Orisan A, Hayes-Larson E, Duarte Folle A, Mayeda ER, Whitmer RA, Gilsanz P, Power MC, Schaefer C, Glymour MM, Ackley SF. Metformin Cessation and Dementia Incidence. JAMA Netw Open. 2023 Oct 2;6(10):e2339723.
7.Cheng C, Lin CH, Tsai YW, Tsai CJ, Chou PH, Lan TH. Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J Gerontol A Biol Sci Med Sci. 2014;69(10):1299-1305.