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By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a fourth sodium-glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus. These drugs block the transporter that mainly is involved in the reabsorption of glucose from kidneys back into the systemic circulation, which results in increased glucose excretion in the urine. Ertugliflozin joins the previously approved SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin. Ertugliflozin is marketed as Steglatro. It also is approved as a fixed combination with sitagliptin (Steglujan) and metformin (Stegluromet).
Ertugliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.1 The fixed combinations are indicated when both ertugliflozin and sitagliptin or ertugliflozin and metformin are appropriate.1
The recommended starting dose is 5 mg once daily in the morning with or without food.1 Clinicians may increase the dose up to a maximum dose of 15 mg once daily if adequate glycemic control has not been achieved and the dose is tolerated.1 Renal function should be assessed before starting ertugliflozin and periodically thereafter. Ertugliflozin should not be started or continued in patients with an estimated glomerular filtration rate between 30 and < 60 mL/min/1.73m2. Ertugliflozin is available as 5 mg and 15 mg tablets. It also is available in combinations with sitagliptin (5 mg/100 mg and 15 mg/100 mg), and with metformin (2.5 mg/500 mg, 2.5 mg/1,000 mg, 7.5 mg/500 mg, 7.5 mg/1,000 mg).
Ertugliflozin provides another competitor in the SGLT2 inhibitor market.
The most frequent adverse event is female genital mycotic infections (9-12% vs. 3% for placebo).1 Other adverse events associated with SGLT2 inhibitors are increase in low-density lipoprotein cholesterol, dehydration/hypotension, urosepsis and pyelonephritis, renal impairment, and diabetic ketoacidosis.1,3 Increased risk of lower limb amputation has been reported for another SGLT2 inhibitor (canagliflozin). In Phase III studies, the frequency of similar events was 0.2% in the 5 mg group and 0.5% in the 15 mg group compared to 0.1% in the comparator group.1 Long-term safety has not been established with ertugliflozin, including effects on cardiovascular risk or outcomes.
The efficacy and safety for FDA approval was based on seven randomized, double-blind, placebo- or active comparator-controlled clinical studies involving 4,863 subjects with type 2 diabetes. In the placebo-controlled study, ertugliflozin 5 mg and 15 mg were compared to placebo in a 26-week study. Subjects were treatment-naïve or on no antihyperglycemic treatment ≥ 8 weeks before the run-in period. Mean baseline HbA1c levels were 8.2%, 8.4%, and 8.1%, and mean baseline fasting plasma glucose were 181 mg/dL, 179 mg/dL, and 180 mg/dL, respectively. At week 26, mean differences from placebo were -0.6% and -31 mg/dL for 5 mg patients and -0.7% and -36 mg/dL for 15 mg patients, respectively. In addition, there was a mean 2 kg loss in body weight between ertugliflozin and placebo. When ertugliflozin was added to metformin monotherapy (≥ 1,500 mg/day), similar magnitudes of change in HbA1c and fasting plasma glucose were observed. In an active-controlled, 52-week study, ertugliflozin was noninferior to glimepiride as an add-on to metformin.
In other studies, ertugliflozin plus sitagliptin added to metformin produced greater HbA1c reduction than either alone plus metformin. Additionally, ertugliflozin added to sitagliptin and metformin was more effective than placebo plus sitagliptin and metformin. Similar to other SGLT2 inhibitors, the glucose-lowering effect declines with declining renal function. Currently, there are no published direct comparisons among the SGLT2 inhibitors. However, the results of placebo-controlled studies indicate the lowering effect on HbA1c is similar to that reported in two large placebo-controlled studies with canagliflozin and empagliflozin.2,5
SGLT2 inhibitors are the newest class of antihyperglycemic drugs. In 2008, the FDA issued a guidance directing new therapies for diabetes to undergo assessments for cardiovascular outcomes.4 So far, two glucagon-like peptide agonists (liraglutide and semaglutide) and two SGLT2 inhibitors (canagliflozin and empagliflozin) have been reported to reduce the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.3 Both liraglutide and empagliflozin are FDA approved to reduce the risk of cardiovascular events in patients with established cardiovascular disease. In the same study, canagliflozin was associated with lower limb (primarily toe or metatarsal) amputations, resulting in a boxed warning.2,6 The cardiovascular safety and outcome trial for dapagliflozin and ertugliflozin is expected to be completed in 2019. The American Association of Clinical Endocrinologists/American College of Endocrinology guideline lists SGLT2 drugs as potential alternatives to metformin as monotherapy, in combination with metformin as dual therapy and triple therapy.7 Because of limited clinical experience, the role of ertugliflozin remains to be determined, as current clinical evidence seems to favor empagliflozin. The daily cost is $8.94 for ertugliflozin, $17,45 for ertugliflozin/sitagliptin, and $8.94 for ertugliflozin/metformin. Availability is expected in February 2018.
Financial Disclosure: Internal Medicine Alert’s Physician Editor Stephen Brunton, MD, is a retained consultant for Abbott Diabetes, Becton Dickinson, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi; he serves on the speakers bureau of AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, and Novo Nordisk. Contributing Editor Louis Kuritzky, MD, is a retained consultant for and on the speakers bureau of Allergan, Daiichi Sankyo, Lilly, and Lundbeck. Peer Reviewer Gerald Roberts, MD; Editor Jonathan Springston; Executive Editor Leslie Coplin; and Editorial Group Manager Terrey L. Hatcher report no financial relationships relevant to this field of study.