Should Metformin Be Used in Every Patient With Type 2 Diabetes?

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

Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)1, 2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.

However, metformin is underused. A 2012 study showed that only 50 percent to 70 percent of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.3 This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.4

Evidence metformin is effective

The United Kingdom Prospective Diabetes Study (UKPDS)5 found that metformin significantly reduced the incidence of the following:

• Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87).
• Myocardial infarction (HR 0.61, 95% CI 0.41–0.89).
• Diabetes-related death (HR 0.58, 95% CI 0.37–0.91).
• All-cause mortality (HR 0.64; 95% CI 0.45–0.91).

The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,6 a multicenter trial conducted in the Netherlands, evaluated the effect of adding metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.

The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,7 a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about three years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause and death from any cause.

These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.

What about metformin use with contrast agents?

Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.8

Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.

The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.9, 10

The ACR divides patients taking metformin into 2 categories:

• No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m2.
• Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m2 or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.11

For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.

For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.

Metformin and insulin

The ADA recommends1 continuing metformin after initiating insulin. However, in clinical practice, it is often not done.

Clinical trials have shown that combining metformin with insulin significantly improves glycemic control, prevents weight gain, and decreases insulin requirements.12, 13 One trial13 also looked at cardiovascular end points during a 4-year follow-up period; combining metformin with insulin decreased the macrovascular disease-related event rate compared with insulin alone.

In the HOME trial,6 which added metformin to the existing insulin regimen, both groups gained weight, but the metformin group had gained about 3 kg less than the placebo group at the end of the 4.3-year trial. Metformin did not increase the risk of hypoglycemia, but it also did not reduce the risk of microvascular disease.

Concomitant metformin reduces costs

These days, practitioners can choose from a large selection of diabetes drugs. These include insulins with better pharmacokinetic profiles, as well as newer classes of noninsulin agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues.

Metformin is less expensive than these newer drugs, and using it concomitantly with other diabetes drugs can decrease their dosage requirements, which in turn decreases their monthly costs.

Take-home points

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.

References

1. American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care. 2018;41(suppl 1):S73-S85. doi:10.2337/dc18-S008
2. 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. doi:10.4158/CS7-201-0153
3. Hampp C, Borders-Hemphill V, Moeny DG, Wysowski DK. Use of antidiabetic drugs in the US, 2003-2012. Diabetes Care. 2014;37(5):1367-1374. doi:10.2337/dc13-2289
4. Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364-1379. doi:10.2337/dc12-0413
5. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854-865. pmid:9742977
6. Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009;169(6):616-625. doi:10.1001/archinternmed.2009.20
7. Hong J, Zhang Y, Lai S, et al; SPREAD-DIMCAD Investigators. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care. 2013;36(5):1304-1311. doi:10.2337/dc12-0719
8. Glucophage (metformin hydrochloride) and Glucophage XR (extended-release) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf. Accessed December 5, 2018.
9. Eppenga WL, Lalmohamed A, Geerts AF, et al. Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study. Diabetes Care. 2014;37(8):2218-2224. doi:10.2337/dc13-3023
10. 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. doi:10.2337/dc14-0464
11. American College of Radiology (ACR). Manual on Contrast Media. Version 10.3. https://www.acr.org/Clinical-Resources/Contrast-Manual. Accessed December 5, 2018.
12. 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. doi:10.1002/14651858.CD002967
13. Eppenga WL, Lalmohamed A, Geerts AF, et al. Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study. Diabetes Care. 2014;37(8):2218-2224. doi:10.2337/dc13-3023

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