Clinical Question

Which additional drug is most effective at reducing microvascular and macrovascular cardiovascular events in patients with type 2 diabetes mellitus who take metformin?

Bottom Line

Although absolute event numbers are small and not always statistically significant, liraglutide (Victoza) is consistently the best second drug to prevent cardiovascular events in patients with type 2 diabetes who take metformin. A study that reported glycemic control favored sitagliptin (Januvia), but liraglutide was significantly better at preventing cardiovascular events. A limitation was that there were no sodium-glucose cotransporter-2 (SGLT-2) inhibitors in the study because they were not approved by the U.S. Food and Drug Administration for use with metformin in 2013 when the study began. A follow-up study comparing SGLT-2 inhibitors with glucagon-like peptide-1 (GLP-1) agonists as a second drug is needed. (Level of Evidence = 1b)

Synopsis

The authors recruited 5,047 participants who had type 2 diabetes for less than 10 years and were diagnosed after the patient was 30 years of age. All participants were taking metformin. The authors included an active run-in period to try to titrate metformin to a target dosage of 2,000 mg per day. At the end of the run-in period, eligible participants had to have an A1C level between 6.8% and 8.5%. Those participants were randomly assigned to one of four therapies: (1) insulin glargine at an initial dosage of 20 units daily and adjusted upward, as needed; (2) the sulfonylurea glimepiride beginning at 1 to 2 mg per day to a maximum of 8 mg per day in divided doses; (3) liraglutide, a GLP-1 agonist, starting at 0.6 mg per day and titrating to 1.8 mg per day, as tolerated; or (4) the dipeptidyl-peptidase-4 inhibitor sitagliptin, 100 mg per day, with the dosage adjusted on the basis of renal function. At baseline, the participants' mean age was 57 years, 20% were Black, and most were being treated for comorbid hypertension and hyperlipidemia. After a mean of five years of follow-up, there was no significant difference among groups in microvascular outcomes such as albuminuria, peripheral neuropathy, and renal impairment (defined as a glomerular filtration rate of less than 60 mL per minute per 1.73 m²). The primary cardiovascular outcome was the likelihood of any cardiovascular event, including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina warranting hospitalization, hospitalization for heart failure, or any need for revascularization. These occurred significantly less often in the liraglutide group (6.6% vs. 9.0% to 9.6% for the other groups; hazard ratio is significantly lower for liraglutide vs. sitagliptin comparison 0.68; 95% CI, 0.51 to 0.90). Liraglutide had the lowest rate of major adverse cardiovascular events (3.8% vs. 4.7% to 5.5%), hospitalizations for heart failure (1.1% vs. 2.1% to 2.4%), cardiovascular death (0.7% vs. 1.3% to 1.7%), and all-cause mortality (2.1% vs. 3.2% to 3.4%).