Should older T2D continue their metformin?

13th April 2024, A/Prof Chee L Khoo


We are all used to metformin being the first line glucose lowering agent when type 2 diabetes (T2D) is diagnosed. (Well, I know some you also use metformin before diabetes is diagnosed but that’s a different story). Glucose lowering efficacy of metformin is not that terrific as we now have much stronger glucose lowering agents available. It is tempting to put metformin aside and go for the bigger guns. Further, as we now aim for diabetes remission in many of our patients with T2D, it is also tempting to cease metformin when the HbA1c drop below 6.5% or lower. Should we bother with metformin anymore?

Obviously, we have patients that we have to dose reduce or cease altogether because of renal impairment reasons or because gastrointestinal side effects. Metformin treatment reduces incidence of diabetes complications and diabetes-related and all-cause mortality (1). Metformin may also 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).

There are randomised controlled trials (RCT) which demonstrate that metformin improves cognition and reduces dementia risk in patients with T2D although this might be related to the benefit of glucose lowering (4). Data relating to cognitive benefit from glucose lowering is not always consistent. In the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) RCT there was no cognitive benefit for an intensive glucose-control strategy. Perhaps, the cognitive benefit of metformin therapy is not related to glucose lowering (5-6).

Observational studies have found that initiating metformin treatment was associated with a benefit in dementia risk compared with other glucose lowering agents (4,7). However, confounding by diabetes severity and duration may bias associations (4).

In a recent study published in JAMA, Zimmerman S et al investigated the association between termination of metformin treatment for reasons unrelated to kidney dysfunction and dementia incidence (8). They used de-identified health records from Kaiser Permanente Northern California (KPNC) health care system which is an integrated health care delivery system with 4.6 million members. They looked at men 45-69 years old who had used metformin and were free of dementia. Participants were followed up from the first availability of electronic health records (starting in 1996) until administrative censoring, age 90 years, death, the start of a 90-day membership gap, or dementia diagnosis.

A routine user was any individual who remained on metformin at the age when the matched early terminator ceased using metformin. Early terminators were defined as individuals who stopped using metformin without prior history of abnormal kidney function. Each early terminator were matched with 4 routine users (that are still using metformin). They excluded individuals who stopped using metformin but had no anti-diabetes medication prescriptions within 1 month, given that prescription nonadherence may be a sign of incipient dementia or particularly good control of blood glucose with nonpharmacologic interventions. They adjusted for demographic characteristics (gender, age at metformin initiation, race and ethnicity, educational attainment, nativity, parental nativity, and survey language) and low-density lipoprotein and HbA1c levels at the time of metformin termination.


They found that terminating metformin treatment was associated with increased dementia incidence in a diverse cohort of older adults. Most of this association was not accounted for by increases in HbA1c levels or insulin use 1 or 5 years after cessation of treatment with metformin. In minimally adjusted models, early terminators had 1.21 times the hazard of dementia diagnosis compared with routine users (HR, 1.21; 95% CI, 1.15-1.28). In a fully adjusted model, early terminators had 1.21 times the hazard of dementia diagnosis compared with routine users.

Another way of looking the benefits of continued metformin use is to look at the acceleration of dementia between the groups. Total estimated acceleration of dementia diagnosis ranged from 0.91 years (95% CI, −0.57 to 2.42 years) for HbA1c level at 1 year to 1.75 years (95% CI, 0.15 to 3.44 years) for HbA1c level at 5 years. The mediated acceleration contributed by changes in HbA1c level or insulin use ranged from no contribution (0.00 years (95% CI, −0.02 to 0.02 years) for insulin use at 5 years to 0.07 years (95% CI, 0.02 to 0.13 years) for HbA1c level at 1 year, suggesting that a small fraction of the acceleration of dementia diagnosis could be attributed to measured changes in HbA1c level or insulin use.

In summary, while metformin is not the efficacious glucose lowering agent for patients with T2D, it is still worthwhile keep our patients on metformin unless, renal function prevent us from using metformin. It is also important to remember that most outcome trials of SGLT2 inhibitors and GLP1-RAs have patients on metformin as well as the active comparator. Further, with fixed dose combinations, addition of metformin to an SGLT2 inhibitor or DPP4 inhibitor doesn’t add to pill burden.


  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. doi:10.1016/S0140-6736(98)07037-8
  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. doi:10.1111/j.1365-2796.1991.tb00328.x
  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. doi:10.1161/HYPERTENSIONAHA.116.07353
  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. Gerstein  HC, Miller  ME, Byington  RP,  et al; Action to Control Cardiovascular Risk in Diabetes Study Group.  Effects of intensive glucose lowering in type 2 diabetes.   N Engl J Med. 2008;358(24):2545-2559. doi:10.1056/NEJMoa0802743
  6. Launer  LJ, Miller  ME, Williamson  JD,  et al; ACCORD MIND investigators.  Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy.   Lancet Neurol. 2011;10(11):969-977. doi:10.1016/S1474-4422(11)70188-0
  7. 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. doi:10.1016/j.mayocp.2019.01.004
  8. Zimmerman SC, Ferguson EL, Choudhary V, et al. Metformin Cessation and Dementia Incidence. JAMA Netw Open. 2023;6(10):e2339723. doi:10.1001/jamanetworkopen.2023.39723