Metformin Plus Insulin vs Sulfonylureas and Relation to CV Events and Death

CL Roumie, RA Greevy, CG Grijalva, AM Hung, X Liu, HJ Murff, TA Elasy, MR Griffin


Preferred second-line medication for diabetes treatment after metformin failure remains uncertain.

To compare time to acute myocardial infarction (AMI), stroke, or death in a cohort of metformin initiators who added insulin or a sulfonylurea.

Retrospective cohort constructed with national Veterans Health Administration, Medicare, and National Death Index databases. The study population comprised veterans initially treated with metformin from 2001 through 2008 who subsequently added either insulin or sulfonylurea. Propensity score matching on characteristics was performed, matching each participant who added insulin to 5 who added a sulfonylurea. Patients were followed through September 2011 for primary analyses or September 2009 for cause-of-death analyses.

Risk of a composite outcome of AMI, stroke hospitalization, or all-cause death was compared between therapies with marginal structural Cox proportional hazard models adjusting for baseline and time-varying demographics, medications, cholesterol level, hemoglobin A1c level, creatinine level, blood pressure, body mass index, and comorbidities.

Among 178 341 metformin monotherapy patients, 2948 added insulin and 39 990 added a sulfonylurea. Propensity score matching yielded 2436 metformin + insulin and 12 180 metformin + sulfonylurea patients. At intensification, patients had received metformin for a median of 14 months (IQR, 5-30), and hemoglobin A1c level was 8.1% (IQR, 7.2%-9.9%). Median follow-up after intensification was 14 months (IQR, 6-29 months). There were 172 vs 634 events for the primary outcome among patients who added insulin vs sulfonylureas, respectively (42.7 vs 32.8 events per 1000 person-years; adjusted hazard ratio [aHR], 1.30; 95% CI, 1.07-1.58; P = .009). Acute myocardial infarction and stroke rates were statistically similar, 41 vs 229 events (10.2 and 11.9 events per 1000 person-years; aHR, 0.88; 95% CI, 0.59-1.30; P  = .52), whereas all-cause death rates were 137 vs 444 events, respectively (33.7 and 22.7 events per 1000 person-years; aHR, 1.44; 95% CI, 1.15-1.79; P = .001). There were 54 vs 258 secondary outcomes: AMI, stroke hospitalizations, or cardiovascular deaths (22.8 vs 22.5 events per 1000 person-years; aHR, 0.98; 95% CI, 0.71-1.34; P = .87).

Among patients with diabetes who were receiving metformin, the addition of insulin vs a sulfonylurea was associated with an increased risk of a composite of nonfatal cardiovascular outcomes and all-cause mortality. These findings require further investigation to understand risks associated with insulin use in these patients.

CL Roumie, RA Greevy, CG Grijalva, AM Hung, X Liu, HJ Murff, TA Elasy, MR Griffin
Association Between Intensification of Metformin Treatment With Insulin vs Sulfonylureas and Cardiovascular Events and All-Cause Mortality Among Patients With Diabetes
JAMA 2014 Jun 11;311(22)2288-2296

Expert Comment
David Rakel MD, FAAFP

Numbers or Outcomes?
The dichotomy between managing numbers and the outcomes achieved in diabetes treatment is described in two articles published in JAMA. Willia et al1 provided a nice review of insulin therapy and show that insulin is the most efficient way to lower HgbA1c. Roumie et al2 showed that adding insulin to metformin, when compared with insulin plus sulfonylurea, was associated with a 1.3-fold risk for cardiovascular events or all-cause mortality and a 1.85-fold risk for death from cancer.
This study brings back memories of the ACCORD study, which showed that intensive therapy that included more insulin (77% of patients in intensive group vs 55% in standard group) was associated with a 22% increased risk for death from any cause.3
We cannot live without insulin, but too much (insulin resistance) can cause harm. Insulin increases inflammation, weight gain, and risk for hypoglycemic events. Insulin resistance is also associated with hypertension, atherosclerosis, malignancy, and a hypercoagulable state.
This is a reminder to intensify therapy that can preserve islet beta-cell function so we do not have to add as many medicines to treat organ failure (Figure). The more we can shift focus to “A” interventions, hopefully the less medicine (“B” interventions) is needed.

Insulin-Resistence (2)

 “A” Interventions:

Remember the results of the Diabetes Preventions Trial. Lifestyle habits (average of 8 lbs of weight loss, exercise, and improved nutrition) reduced the progression to diabetes by 58% compared with metformin at 28%.4 The PREDIMED study showed that a Mediterranean diet was associated with a 52% decreased incidence of diabetes in those at high risk.5
The most important therapies to preserve pancreatic function should be familiar:

  • Weight loss if overweight
  • Exercise and movement to push sugar into the cells
  • A Mediterranean diet that is rich in multi-colored fresh whole foods
  • Soluble fiber (eg, 1 tsp psyllium in water before meals or 1–2 tbsp daily)
  • Metformin

“B” Interventions:
We do not want to increase insulin when there is resistance with high levels (see A in the figure). Once the ongoing disease causes beta-cell failure, the time has come to add more medicine (see B in the figure).

  • Glitazones: Pioglitazone vs placebo in 602 patients with pre-diabetes significantly reduced the risk for diabetes but was associated with weight gain and edema.6
  • Consider sulfonylureas before insulin.2
  • Glucagon-like peptide-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, and dulaglutide)
  • Dipeptidyl pepdidase-4 inhibitor (sitagliptin, vildagliptin, linagliptin, and others)

“A” interventions are most powerful in improving outcomes and reversing the disease process, while “B” interventions are needed to support organ failure. These studies show that, although insulin improves HgbA1c numbers, it does not always correlate with improved outcomes.


  1. Wallia A, Molitch ME. Insulin therapy for type 2 diabetes mellitus. JAMA. 2014;311(22):2315-2325.
  2. Roumie CL, Greevy RA, Grijalva CG, et al. Association between intensification of metformin treatment with insulin vs sulfonylureas and cardiovascular events and all-cause mortality among patients with diabetes. JAMA. 2014;311(22):2288-2296.
  3. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559.
  4. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343-1350.
  5. Salas-Salvado J, Bullo M, Babio N, et al. Reduction in the incidence of type 2 diabetes with the Mediterranean diet: results of the PREDIMED-Reus nutrition intervention randomized trial. Diabetes Care. 2011;34(1):14-19.
  6. DeFronzo RA, Tripathy D, Schwenke DC, et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011;364(12):1104-1115.