A recently published meta-analysis puts metformin to the test to see how well it lines up against other T2DM medications that comprise the “All-Star Team” members.
In an increasingly complex T2DM treatment landscape, selecting the most appropriate medication can be challenging. Take insulin, for example: based on the duration of action, there are six different types. Within each type, there are multiple injectable products (n): rapid (n=5), short (n=3), intermediate (n=2), long (n=4), ultra-long (n=1) and mixed (n=5) — in total 20 available insulin products.1,2 At least one thing has remained relatively simple when treating T2DM, with a few exceptions: start with metformin, and continue as long as tolerated.1,3 In their network meta-analysis Tsapas et al. questioned if metformin, which this year celebrates its 63rd anniversary for its use in T2DM, continues to earn its spot as a key member on the T2DM Medication All-Star Team.
Tsapas et al. indirectly compared the benefits and harms of 21 T2DM interventions from 9 different drug classes. Databases including MEDLINE, EMBASE, and Cochrane were searched for randomized controlled studies conducted in patients with T2DM that included one or more primary (hemoglobin A1c, all-cause mortality) or secondary (vascular events, severe hypoglycemia, hospitalization from heart failure) outcomes of interest. A total of 453 studies were selected. Drug classes included: metformin, sulphonylureas (S.U.), pioglitazone, dipeptidyl peptidase-4 (DDP-4) inhibitors, glucagon-like peptide-1 agonist (GLP-1 RAs), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, insulin, alpha-glucosidase inhibitors, and meglitinides. Traditionally, one major limitation of comparing diabetes medications is the lack of direct head-to-head studies.4 To overcome this, Tsapas et al. used a network meta-analysis approach. Data were divided into two main networks: monotherapy in drug naïve patients and add-on to metformin-based background therapy. Networks were further subdivided into high or low cardiovascular (CV) risk. No studies of drug-naïve patients at high CV risk were included in the analysis.4
In drug-naïve patients on monotherapy, all interventions reduced hemoglobin A1c compared to placebo. When compared to metformin monotherapy, all treatments except DDP-4 inhibitors showed similar reductions in hemoglobin A1c. In drug-naïve patients, severe hypoglycemia did not differ in any treatment group compared to metformin or placebo. A neutral effect on death and vascular outcomes was observed in drug naïve patients at low CV risk for all interventions. In patients on metformin-based background therapy, the most significant placebo adjusted reduction in hemoglobin A1c was seen with GLP-1 RAs and insulin. The incidence of severe hypoglycemia was highest with S.U.s and insulin. In patients with low CV risk on metformin-based background therapy, GLP-1 RAs as a class were associated with the lowest risk of death due to any cause compared to placebo. However, when analyzed individually, all GLP-1 RAs were comparable to placebo, and no intervention differed significantly from placebo on CV death. Compared to the placebo in the low CV risk group, the incidence of heart attack was lower with GLP-1 RAs and SGLT-2, and no difference between treatments was observed on hospitalizations due to heart failure. In high CV risk patients on metformin-based background therapy, death due to any cause was lower with oral semaglutide, liraglutide, extended-release exenatide, empagliflozin, and dapagliflozin. Empagliflozin, oral semaglutide, and liraglutide were also associated with a decreased risk of CV death. Compared to placebo in this high CV risk group, there was no observed between-treatment difference for heart attacks, and hospitalization due to heart failure was reduced with the SGLT-2 inhibitors: empagliflozin, canagliflozin, and dapagliflozin, and increased with pioglitazone.4
The use of metformin, in low CV risk treatment naïve patients, was at least as effective at reducing hemoglobin A1c and preventing death and vascular events as alternative monotherapies. In patients already taking metformin, adding a GLP-1 RA or insulin resulted in the most considerable reductions in hemoglobin A1C, and in patients at high CV risk, select SGLT-2 inhibitors and GLP-1 RAs resulted in lower rates of death. In either high or low CV risk patients, benefits on vascular outcomes, if observed, were more frequent with select GLP-1 RAs and SGLT-2 inhibitors. Despite the limitations of indirect comparisons, these findings are informative. They support that more than 60 years later, metformin, either alone or in combination, is still a key player on the T2DM Medication All-Star Team.
- In patients with newly diagnosed T2DM without contraindications, start with metformin and continue if tolerated.
- When considering which medication to add to metformin, first determine the patient’s risk of cardiovascular disease.
- In patients on metformin at high risk of cardiovascular disease, consider adding a select SGLT-2 inhibitor or GLP-1 RA, with proven mortality and vascular benefits.
References for “T2DM Medications: All-Star Team Lineup”:
- American Diabetes Association. “Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2020.“ Diabetes Care vol. 43 (Supplement 1) (2020): S98-S110; doi:10.2337/dc20-S009
- Clinical Resource, ”Comparison of Insulins.” Pharmacist’s Letter. Therapeutic Research Center, LLC. Stockton, CA. Available at https://pharmacist.therapeuticresearch.com. Assessed July 7, 2020
- Garber, Alan J, et al. “Consensus Statement by the American Association of Clinical Endocrinologists and the American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm-2020 Executive Summary.“ Endocr Pract vol. 26,1 (2020):107-139. doi:10.4158/CS-2019-0472
- Tsapas, Apostolos, et al. “Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes.“ Ann Intern Med. (2020). doi:10.7326/M20-0864
Louise Brown, PharmD Candidate, University of Colorado Skaggs School of Pharmacy and Pharmaceutical SciencesPage Break
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