Treatment of T2DM after metformin: what’s next?

Pharmacologic options for the treatment of type 2 diabetes mellitus have expanded over the past ten years.  Metformin has remained the first-line agent due to a well-established safety and efficacy, low cost, and data demonstrating a reduction in cardiovascular events.1  It is pretty clear from a number of studies that metformin therapy should be maximized, which in some patients may require doses above 2000 mg/day. 2  Second-line treatments include a variety of agents, including basal insulin, dipeptidyl-peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, and thiazolidinediones.  Metformin is synergistic with many of the other agents, and should not be discontinued as beneficial effects can be seen even in patients taking insulin as the second line agent. 3 The 2016 treatment recommendations detail the above mentioned medications as all viable options for second-line therapy with no preference to one drug class over the other. 1 While this seems like this might open up treatment options for clinicians, it often in fact, leaves clinicians wondering about the BEST next option for their patients.  All of the options will always have a cost/benefit ratio, and so trying to choose the best agent that minimizes patient out of pocket costs is important.  In that regard, SGLT2s from all the current manufacturers have co-pay cards to minimize the cost (for patients not on Medicare).

The likely reason for no definitive recommendation for a second-line agent is that controversy exists regarding which agents should be used for the treatment of T2DM in those who cannot achieve glycemic control with metformin alone.  The newer agents, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors are effective, exhibit positive/neutral effects on body weight, and pose minimal risk of hypoglycemia in comparison to other available agents to treat hyperglycemia. Trials have been completed, or are ongoing, regarding the cardiovascular effects of these agents.3-9   and in the case of empagloflozin, the results of a recent trial have resulted in the manufacturer seeking a cardiovascular risk reduction, and leading to a debate on whether FDA should grant this request ( 5  Thus far, CV outcomes have either been positive or neutral with these agents leading clinicians to head towards those agents even though the cost may be higher.

Recently, the FDA has issued concerns regarding the newest agents, the SGLT2 inhibitors regarding the risk for acute kidney injury and ketoacidosis leaving us scratching our heads again, especially after some data exists that there many actually be reno-protection from this drug class (  Time and studies will tell which may be the best second line agents, but it is always important to consider patient out-of-pocket costs especially since diabetes patients take many different medications for diabetes, hypertension, and dyslipidemia…and more.



  1. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2016;39(Suppl 1)
  2. Hirst JA, Farmer AJ, Ali R, et al. Quantifying the effect of metformin treatment and dose on glycemic control. Diabetes Care. 2012;35:446-454.
  3. Holden SE, Jenkins-Jones S, Currie CJ. (2016) Association between insulin monotherapy versus insuln plus metformin and the risk of all-cause mortality and other serious outcomes: a retrospective cohort study. PLoS ONE 11(5):e0153594. Doi:10.137/journal.pone.0153594.
  4. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015 Dec 3;373(23):2247-57.
  5. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128.
  6. Scirica BM, Bhatt DL, Braunwald E, et al; for the SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326.
  7. White WB, Cannon CP, Heller SR, et al; for the EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-1335.
  8. Zannad F, Cannon CP, Cushman WC, et al; for the EXAMINE Investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE:  a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067-2076.
  9. Van der Werf F, Armstrong P. Trial evaluating cardiovascular outcomes with sitagliptin in patients with type 2 diabetes: TECOS. Presented at ESC Congress 2015. London, England, UK. Abstract 3147.