Metformin for Adults 65 and Older: School, Cognitive Activity, and Physical Exercise Considerations

Does metformin get in the way of exercise after 65?

The boxed warning names what raises the risk of metformin-associated lactic acidosis: renal impairment, certain drugs such as the carbonic anhydrase inhibitor topiramate, age 65 or older, radiologic studies with contrast, surgery and other procedures, hypoxic states such as acute congestive heart failure, excessive alcohol intake, hepatic impairment, and mitochondrial disease [1]. Exertion and classroom work are not on that list.

The label states that metformin decreases liver uptake of lactate, raising blood lactate levels, which may increase the risk of lactic acidosis, especially in patients already at risk [1].

The label separately addresses restricted food and fluid intake during procedures and serious conditions involving low oxygen. It says metformin should be temporarily discontinued while a patient has restricted food and fluid intake, as during surgery or other procedures, and discontinued when a hypoxic event such as acute heart failure, cardiovascular collapse, myocardial infarction or sepsis occurs [1]. It also warns against excessive alcohol intake because alcohol potentiates metformin's effect on lactate metabolism [1].

What did the exercise trials in older adults actually measure?

Two small randomized trials in older men looked at muscle function and physical capacity rather than at glucose control.

In one trial, 70 men received placebo and 62 received metformin for 16 weeks; their average ages were about 73 and 70, respectively. Handgrip strength, gait speed and short physical performance battery scores improved with metformin, and plasma markers of neuromuscular junction breakdown fell [2]. That trial reported a dose of 1,700 mg twice daily [2], which exceeds the immediate-release label's adult maximum of 2,550 mg per day [1].

The second trial enrolled 101 men with sarcopenia (47 on metformin, 54 on placebo) plus 52 men without sarcopenia, and used 1.7 g twice daily for four months. Handgrip strength and sarcopenia-related quality-of-life scores improved; body composition and gait speed did not change [3].

Both trials were small, short, and limited to men, so they do not establish what metformin does to exercise capacity in a 70-year-old woman with type 2 diabetes.

The Diabetes Prevention Program compared metformin with a lifestyle program that included weight-loss and physical-activity goals, as well as with placebo. It randomized 3,234 non-diabetic adults with elevated fasting and post-load glucose to placebo, metformin 850 mg twice daily, or a lifestyle program aiming for at least 7% weight loss and at least 150 minutes of physical activity per week. Over an average 2.8 years, diabetes incidence fell 58% with lifestyle and 31% with metformin versus placebo, and lifestyle was significantly more effective [5]. At 15 years the reductions were 27% with lifestyle and 18% with metformin [6]. Participants' mean age was 51, so this is not a study of people over 65 [5].

What does the label say about being 65 or older?

Age 65 or older sits in the boxed warning; the label says the risk increases with age because elderly patients are more likely to have hepatic, renal or cardiac impairment, and directs that renal function be assessed more frequently in elderly patients [1]. An eGFR should be obtained at least annually in everyone taking metformin, and more often in patients at risk of renal impairment, such as the elderly [1].

The renal rules are specific: metformin is contraindicated at an eGFR below 30 mL/min/1.73 m2; starting is not recommended at 30 to 45; if eGFR later falls below 45, the benefit and risk of continuing should be assessed; and it should be discontinued if eGFR falls below 30 [1].

The label describes the onset of lactic acidosis as subtle, with malaise, myalgias, respiratory distress, somnolence and abdominal pain, and laboratory findings of blood lactate above 5 mmol/L, anion gap acidosis without ketonuria, and metformin levels generally above 5 mcg/mL [1]. If lactic acidosis is suspected, the label says to stop metformin and begin supportive measures in hospital, with prompt hemodialysis recommended [1].

For iodinated contrast, the label says to stop metformin at the time of or before the procedure in patients with eGFR between 30 and 60, a history of hepatic impairment, alcoholism or heart failure, or when intra-arterial contrast is used; eGFR is rechecked 48 hours later and metformin restarted only if renal function is stable [1].

Does metformin affect memory, classes or cognitive work?

The label's vitamin B12 warning is the closest link to nerve function. It reports that in 29-week trials, about 7% of patients had a fall to subnormal vitamin B12 levels, that the fall may be associated with anemia but appears rapidly reversible with discontinuation or B12 supplementation, and it directs that hematologic parameters be measured annually and vitamin B12 every 2 to 3 years [1].

In the Diabetes Prevention Program follow-up, low B12 (203 pg/mL or less) occurred in 4.3% of metformin users versus 2.3% of placebo users at 5 years, and 7.4% versus 5.4% at 13 years (not statistically significant). Combined low and borderline-low B12 (298 pg/mL or less) was more common with metformin at 5 years (19.1% versus 9.5%) and at 13 years (20.3% versus 15.6%), and the odds of deficiency rose 13% per year of metformin use [8]. Anemia was more common with metformin but did not track B12 status; neuropathy was more common in metformin users with low B12, and the authors suggested routine B12 testing be considered [8].

On cognition itself, a 2019 review notes some evidence that metformin may reduce dementia risk in rodents, and that improving metabolic health may be one route to brain health with age [9]. That is not a trial result in people. A 2016 review described plans to test metformin against age-related disease in the TAME trial; it did not report results [4].

Dosing around a busy week: meals, GI effects and limits

Immediate-release metformin starts at 500 mg twice daily or 850 mg once daily with meals, increasing by 500 mg weekly or 850 mg every 2 weeks to a maximum of 2,550 mg per day in divided doses; doses above 2,000 mg may be better tolerated three times daily with meals [1]. Extended-release starts at 500 mg once daily with the evening meal, increases by 500 mg weekly to a maximum of 2,000 mg once daily, and the tablets are swallowed whole and not crushed, cut or chewed [7].

Gastrointestinal effects are the practical scheduling problem. In the label's U.S. trial of immediate-release metformin up to 2,550 mg per day (141 patients versus 145 on placebo), diarrhea occurred in 53% versus 12%, nausea or vomiting in 26% versus 8%, and diarrhea led to discontinuation in 6% [1]. In placebo-controlled extended-release trials (781 patients versus 195), diarrhea occurred in 10% versus 3% and led to discontinuation in 0.6% [7]. The label cautions that rates from different trials cannot be directly compared [7]. A retrospective chart review of 471 patient charts (310 eligible patients on extended-release, 158 on immediate-release) found the overall frequency of GI adverse events similar between the two formulations [10].

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Low blood sugar and combination therapy

The label's hypoglycemia warning is specific to combinations: with insulin or an insulin secretagogue such as a sulfonylurea, hypoglycemia risk rises and lower doses of those agents may be needed [1].