Empagliflozin (Jardiance) new indication - reduces mortality in type 2 diabetes mellitus

A middle-aged patient with diabetes mellitus type 2, CAD, HTN, and obesity is in clinic for a followup appointment 1 year after his diagnosis with diabetes.  His medications include lisinopril, atorvastatin, aspirin, and metformin (started 1 year ago and titrated to maximum tolerated dose).  Today in clinic, his BP = 148/88 mm Hg, HR = 78 bpm, and HbA1c = 7.6%.  In addition to metformin, are there any other antihyperglycemic medications that we can use to reduce his risk of cardiovascular events?

For many years, metformin was the only antihyperglycemic medication proven to reduce mortality in patients with diabetes mellitus type 2 (as per the UKPDS trial).  Other classes of medications such as the sulfonylureas, thiazolidinediones, and DPP-4 inhibitors have only been shown to reduce HbA1c and/or microvascular events.  This month, the FDA approved
empagliflozin (Jardiance) to reduce the risk of cardiovascular death in adults with diabetes mellitus type 2 and cardiovascular disease.

A look at the evidence

This label change was the result of the 2015 EMPA-REG OUTCOME study which looked at empagliflozin compared to placebo in >7000 patients with diabetes mellitus type 2 who had established cardiovascular disease.  Patients received empagliflozin 10 mg daily, 25 mg daily, or placebo for a median of ~3 years.  Background glycemic control was allowed with other medications and standard treatments to reduce other cardiovascular risks were encouraged.  The primary endpoint was a composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke.  Results were that the composite outcome was significantly less in the empagliflozin group compared to placebo [10.5% vs. 12.1%; HR=0.86 (CI 0.74-0.99); p=0.04 for superiority].  There were significantly fewer events in the empagliflozin group for death from CV causes, death from any cause, and hospitalization for heart failure (this is important because some other antihyperglycemic agents have been associated with more heart failure).

Other findings of the EMPA-REG OUTCOME study

• There were no differences in rates of fatal or nonfatal MI or strokes
• Most patients did not acheive HbA1c goals (7.81% empagliflozin vs. 8.16% placebo at the end of the study) and there wasn't much of a difference between the groups - this brings into question the mechanism behind CV risk reduction
• The empagliflozin group had small decreases in weight, waist circumference, uric acid level, and blood pressure but small increases in LDL and HDL
• Rates of hypoglycemia were comparable among study groups

About empagliflozin

Empagliflozin is a sodium-dependent glucose cotransporter-2 (SGLT2) inhibitor which works by blocking the reabsorption of glucose by the kidney, allowing it to pass out of the body through the urine (usually the kidney reabsorbs all of the filtered glucose).  Common adverse effects include urinary and genital infections and there have been two FDA warnings about the risks of ketoacidosis since its approval.  In cases of ketoacidosis, the blood glucose levels may only be slightly increased from normal so be mindful for symptoms in the setting of near normoglycemia (ie. dyspnea, nausea, vomiting, abdominal pain, confusion, fatigue).

Back to the patient case

Our patient looks like he is a candidate for empagliflozin, starting at 10 mg orally once daily.  SGLT2 inhibitors are one of the recommended "add-on" therapies to metformin in the current ADA diabetes mellitus type 2 guidelines (alongside sulfonylureas, TZDs, DPP-4 inhibitors, GLP-1 agonists, or insulin) and the guidelines make no preference for any particular class, leaving it to patient-specific factors.  Empagliflozin also has the benefits of reducing this obese patient's weight, BP, and HbA1c without the risks of hypoglycemia (this is a pro compared to secretagogues, TZDs, and insulin which tend to increase weight) but he should be counseled about the signs of ketoacidosis.  To learn more about metformin and its place in therapy and updated prescribing information, click here.

Take home points:

• Empagliflozin has a large study that shows a small but significant reduction in death and heart failure hospitalizations (NNT for primary outcome = 63 patients for ~3 years) compared to placebo in patients with diabetes and CV disease
• Empagliflozin can cause urinary and genital infections and ketoacidosis with near normal glucose
• Because of its mechanism (spilling glucose through the urine), it may develop a role in diabetes mellitus type 1

Refrences:
American Diabetes Association: Standards of medical care in diabetes - 2016. Diabetes Care 2016;39(1).
Triplitt CL, Repas T, Alvarez C.  Chapter 57. Diabetes mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e.  New York, NY: McGraw-Hill;2014.
Zinman B, Wanner C, Lachin JM, et al.  Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.  N Engl J Med  2015;373:2117-28.

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