Possible Side Effects of Metformin Use in Patients with Type 2 Diabetes

By Vinni Makin, MBBS, MD, FACE, and M. Cecilia Lansang, MD, MPH

Metformin improves glycemic control without tending to cause weight gain or hypoglycemia. It may also have cardiovascular benefits. Metformin is an inexpensive agent that should be continued, if tolerated, in those who need additional agents for glycemic control. It should be considered in all adult patients with type 2 diabetes, with possible exceptions noted below.

What about the renal effects?

Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.

Revised labeling

Metformin’s labeling,1 revised in 2016, states the following:

• If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m2, metformin is contraindicated
• If the eGFR is between 30 and 45 mL/min/1.73 m2, metformin is not recommended
• If the eGFR is below 45 mL/min/1.73 m2 in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.1

These labeling revisions were based on a systematic review by Inzucchi, et al.2 that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus, et al. 3 showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m2. Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.4

Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR5, instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race and weight.

Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.

Gastrointestinal Effects

Metformin’s gastrointestinal adverse effects such as diarrhea, flatulence, nausea, and vomiting are a barrier to its use. The actual incidence rate of diarrhea varies widely in randomized trials and observational studies, and gastrointestinal effects are worse in metformin-naive patients, as well as those who have chronic gastritis or Helicobacter pylori infection.7

We have found that starting metformin at a low dose and up-titrating it over several weeks increases tolerability. We often start patients at 500 mg/day and increase the dosage by one 500-mg tablet every one to two weeks. Also, we have noticed that intolerance is more likely in patients who eat a high-carbohydrate diet, but there is no high-level evidence to back this up because patients in clinical trials all undergo nutrition counseling and are therefore more likely to adhere to the low-carbohydrate diet.

Also, the extended-release formulation is more tolerable than the immediate-release formulation and has similar glycemic efficacy. It may be an option as first-line therapy or for patients who have significant adverse effects from immediate-release metformin.8 For patients on the immediate-release formulation, taking it with meals helps lessen some gastrointestinal effects, and this should be emphasized at every visit.

Finally, we limit the metformin dose to 2,000 mg/day, rather than the 2,550 mg/day allowed on labeling. Garber et al9 found that the lower dosage still provides the maximum clinical efficacy.

Other Cautions

Metformin should be avoided in patients with acute or unstable heart failure because of the increased risk of lactic acidosis.

It also should be avoided in patients with hepatic impairment, according to the labeling. But this remains controversial in practice. Zhang et al10 showed that continuing metformin in patients with diabetes and cirrhosis decreases the mortality risk by 57% compared with those taken off metformin.

Diet and lifestyle measures need to be emphasized at each visit. Wing et al11 showed that calorie restriction regardless of weight loss is beneficial for glycemic control and insulin sensitivity in obese patients with diabetes.

References

1. Glucophage (metformin hydrochloride) and Glucophage XR (extended-release) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf. Accessed December 5, 2018.
2. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312(24):2668-2675.
3. Lazarus B, Wu A, Shin JI, et al. Association of metformin use with risk of lactic acidosis across the range of kidney function: a community-based cohort study. JAMA Intern Med. 2018;178(7):903-910.
4. Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2003;(2):CD002967.
5. American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care. 2018; 41(suppl 1):S73-S85.
6. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2018 executive summary. Endocr Pract. 2018;24(1):91-120.
7. Richy FF, Sabidó-Espin M, Guedes S, Corvino FA, Gottwald-Hostalek U. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study. Diabetes Care. 2014;37(8):2291-2295.
8. American College of Radiology (ACR). Manual on Contrast Media. Version 10.3. www.acr.org/Clinical-Resources/Contrast-Manual. Accessed December 5, 2018.
9. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med. 1997;103(6):491-497.
10. Zhang X, Harmsen WS, Mettler TA, et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology. 2014;60(6):2008-2016.
11. Wing RR, Blair EH, Bononi P, Marcus MD, Watanabe R, Bergman RN. Caloric restriction per se is a significant factor in improvements in glycemic control and insulin sensitivity during weight loss in obese NIDDM patients. Diabetes Care. 1994;17(1):30-36.

Note: This is an abridged version of an article originally published in the Cleveland Clinic Journal of Medicine.