Metformin, a dimethylbiguanide, has been the preferred first-line oral antidiabetic therapy since its first reported use in the treatment of type 2 diabetes mellitus in 1957. Metformin originates from a plant called Galega officinalis, which was found to have a glucose-lowering effect due to the guanidine derivatives it contains1. The drug functions by inhibiting hepatic gluconeogenesis, reducing intestinal glucose absorption,
and enhancing glucose uptake and utilization2. Although in the 1970s there were concerns about metformin
and its association with lactic acidosis due to a high incidence of concomitant administration with phenformin (which was later withdrawn from the market), clinical experience in countries outside the United States showed that the two drugs had different pharmacokinetics3. Interest in the use of metformin was renewed following the findings of the UK Prospective Diabetes Study (UKPDS) in 1998. The study found a reduction in microvascular complications in patients with intensive glucose control; moreover, a subgroup analysis in obese patients on metformin showed a risk reduction of 32% (95% CI 13-47, p=0.002) for any diabetes-related endpoint, 42% for diabetes-related death (9-63, p=0.017) and 36% for all-cause mortality (9-55, p=0.011)4.

     Use of metformin has been associated with reduced risk of heart failure. One example, a population-based retrospective study done in Taiwan that utilized a nationwide administrative database, found that the hospitalization for heart failure was reduced in patients taking metformin. The reduction was 42.5% in those with 29.5–61.6 months use, and 67.3% in those with more than 61.6 months of metformin therapy. Subgroup analysis found that in the elderly, where incidence of heart failure is increased, the beneficial effect of metformin was still seen5. As this study included data collected from 2006 up until 2011, sodium-glucose cotransporter-2 (SGLT-2) inhibitors were not utilized during this time. Patients on incretin-based therapy were excluded from analysis.
This study showed that with early and continuous use of metformin there was a protective effect against heart failure, findings that may drive future prospective studies to further explore the association.

     Post hoc analysis from the Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus trial (SAVOR-TIMI 53) reported a lower risk of all-cause mortality in patients who used metformin, although there was no reduction in composite endpoint of cardiovascular death, myocardial infarction, or ischemic stroke. Subgroup analysis of those with chronic kidney disease, as well as those with prior heart failure, did not show a similar benefit. Meta-analysis of 25 other studies including the SAVOR-TIMI 53 showed that metformin use was associated with reduction in all-cause mortality (HR 0.74; 95% CI 0.68-0.81)6.

     As reported in the Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes (VERIFY) trial, newly diagnosed type 2 diabetes mellitus patients who were given metformin in combination with the dipeptidyl peptidase-4 (DPP-4) inhibitor had a two-year therapeutic window. A total of 2001 patients participated in the study and were randomized to receive either metformin with placebo or metformin with vildagliptin during the first phase of treatment. The primary efficacy endpoint of the study was the time of randomization to initial treatment failure, which was defined as a glycated hemoglobin of at least 7% at two consecutive scheduled visits. The median observed time to treatment failure in the monotherapy group was 36.1 months, while those in the early combination therapy group was estimated to be 61.9 months; beyond the median 59.8 months of the study follow-up. The incidence of treatment failure occurred in 43.6% of the combination group as compared to 62.1% in the metformin-only group7. A retrospective cohort study on the combination of sitagliptin (another DPP-4 inhibitor) and metformin also supported the findings of the VERIFY study. The combination resulted in a reduction in the need to initiate insulin with an unadjusted odds ratio of 0.75 (95% CI 0.63–0.89; P<0.01)8.

     These results are just some of the findings reported this year in relation to metformin. Most guideline recommendations continue to identify metformin as a first-line drug for the treatment of type 2 diabetes mellitus along with lifestyle interventions9,10. As our current armamentarium includes newer agents that show cardiovascular benefits, it is also vital to review the role of metformin, the most widely prescribed medication in the treatment of diabetes.

References:

  1. Bailey CJ. Metformin: historical overview. Diabetologia. 2017; 60(9):1566–1576.
  2. Gong L, Goswami S, Giacomini KM, et al. Metformin pathways: pharmacokinetics and pharmaco-
    dynamics.     Pharmacogenet Genomics. 2012;22(11):820–827.
  3. Misbin RI. The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care. 2004 Jul 1;27(7):1791-3.
  4. King P, Peacock I, Donnelly R. The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol. 1999;48(5):643–648.
  5. Tseng CH. Metformin use is associated with a lower risk of hospitalization for heart failure in patients with Type 2 Diabetes Mellitus: a Retrospective Cohort Analysis. J Am Heart Assoc. 2019;8(21):e011640.
  6. Bergmark BA, Bhatt DL, McGuire DK, et al. Metformin use and clinical outcomes among patients with diabetes with or without heart failure or kidney dysfunction: Observations from the SAVOR-TIMI 53 Trial. Circulation. 2019;140(2):1004-1014.
  7. Matthews DR, Paldánius PM, Proot P, et al. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial.
    Lancet. 2019     ;394(10208):1519-1529.
  8. Campbell SA, Light PE, Simpson SH. Costarting sitagliptin with metformin is associated with a lower likelihood of disease progression in newly treated people with type 2 diabetes: a cohort study.
    Diabet Medicine. 2019 Oct 16. doi: 10.1111/dme.14154. [Epub ahead of print].
  9. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2019. Diabetes Care. 2019 Jan 1;42(Supplement 1):S90-102.
  10. Lipsombe L, Booth G, Butalia S, et al. Pharmacologic Glycemic Management of Type 2 Diabetes in Adults. Can J Diabetes. 2018;42(Suppl 1):S88-S103.

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