Choosing an SGLT-2 Inhibitor for a Patient With Type 2 Diabetes: Which Agent (if Any) Is Best?

AUTHORS:
Eric A. Dietrich, PharmD, BCPS, and Kyle Davis, PharmD, BCPS

CITATION:
Dietrich EA, Davis K. Choosing an SGLT-2 inhibitor for a patient with type 2 diabetes: Which agent (if any) is best? Consultant. 2016;56(11):1008-1009.

The armamentarium of medications for the treatment of type 2 diabetes mellitus (T2DM) has increased substantially over the past 5 to 10 years, most recently with oral medications such as sodium-glucose cotransporter 2 (SGLT-2) inhibitors.

Improving on previous drug classes such as the sulfonylureas, SGLT-2 inhibitors have a low risk for hypoglycemia, lead to modest weight loss, and can also help lower blood pressure; once-daily dosing is an additional advantage. Potential adverse events include dehydration, hyperkalemia, increases in genital mycotic infections, and rarely euglycemic ketoacidosis.

Three SGLT-2 inhibitors are available in the United States: canagliflozin, dapagliflozin, and empagliflozin. All 3 are brand-name, are administered orally once daily, and lead to similar hemoglobin A_1c (HbA_1c) reductions of 1% to 1.5% on average. Are these agents considered equivalent, or is one agent likely the preferred SGLT-2 inhibitor?

Patient Case

JM is a 61-year-old man with a history of hypertension, T2DM, hyperlipidemia, and obesity. He is currently taking lisinopril 20 mg daily, atorvastatin 10 mg daily, metformin 1000 mg twice daily, and a multivitamin. He continues to struggle with diet and exercise, and his body mass index is 30.5 kg/m².

All of his laboratory test results are normal, with the exception of a glycated hemoglobin (HbA_1c) level of 8.1%. His most recent blood pressure reading is 145/92 mm Hg, and his creatinine clearance is greater than 60 mL/min. Given that his HbA_1c is above goal and that his diet and lifestyle interventions are optimized, JM is ready to add an additional agent. He would like to avoid anything injectable, and given his weight and blood pressure, he would like to avoid any agents that would worsen either (or both) of these parameters. Given the favorable effects of SGLT-2 inhibitors on weight, blood pressure, and HbA_1c, he agrees to try an agent from this class.

Is there a specific advantage afforded by any one of the options?

The Evidence

Data about the safety of canagliflozin and dapagliflozin are limited, but studies are under way to evaluate such outcomes. The CANVAS study¹ is being conducted to investigate the long-term cardiovascular (CV) safety of canagliflozin and is set to conclude in early 2017. Dapagliflozin has been shown to at least have a neutral effect on CV events in a meta-analysis from its premarketing studies.² DECLARE-TIMI58,³ a long-term CV safety study of dapagliflozin, is ongoing and is set to conclude in April 2019. The neutral study results are encouraging in that canagliflozin and dapagliflozin do not appear to worsen CV risk.

The EMPA-REG OUTCOME study⁴ was a prospective, randomized, double-blind, placebo-controlled study evaluating the CV safety of empagliflozin dosed at 10 mg or 25 mg once daily. A total of 7020 patients were randomly assigned to one agent or the other and were included in the study analysis. Patients’ cases were followed for a median of 2.6 years, and patients’ baseline characteristics were similar between groups. The primary outcome (composite of nonfatal myocardial infarction, nonfatal stroke, or CV death) occurred less frequently in the empagliflozin group compared with the placebo group (hazard ratio, 0.86; 95% confidence interval, 0.74-0.99; P < .001 for noninferiority and P = .04 for superiority). This translates into 6.5 fewer events per 1000 patient-years for the composite outcome. Individually, the CV mortality rate, the all-cause mortality rate, and the hospitalization rate for heart failure were also improved with empagliflozin compared with placebo. Empagliflozin led to improvements in glucose levels and modest improvements in lipid levels, waist circumference, and body weight. Importantly, there was no significant difference in the rate of serious adverse events between the 2 groups, with the exception of sepsis secondary to urinary tract infection occurring in 0.4% in the empagliflozin group and 0.1% in the placebo group; genital infections occurred at a higher rate in the empagliflozin group, as well.⁴

Clinical Application

While HbA_1c lowering is strongly correlated with a reduction in microvascular events, to date no clear consistent benefits in terms of reducing macrovascular events have been shown. This makes the results of the EMPA-REG OUTCOME study potentially more relevant in that empagliflozin is the only SGLT-2 inhibitor to date to show a clear reduction in the rate of CV events, and it may be one of the few T2DM treatments that directly confers a reduction in CV events. The ongoing CANVAS and DECLARE-TIMI58 studies will add further information on the other SLGT-2 inhibitors; given this class’s unique advantage of improving weight, lipid levels, glucose levels, and blood pressure, the improvements in CV benefits may be a class effect (and potentially be unrelated to the HbA_1c lowering afforded by these agents).

All agents are administered once daily and are available only as brand-name drugs; as a result, there does not appear to be a significant dosing advantage or financial advantage to one agent. Adverse effects are generally similar among the agents, as well; although there had been some initial concern that dapagliflozin may increase the risk for certain cancers (breast and bladder), the event rates were extremely low, and dapagliflozin is not considered to be the definitive cause. However, some authors have recommend avoiding administering dapagliflozin with pioglitazone given the uncertainty of these agents and the risk of bladder cancer.⁵ Currently, only empagliflozin has been shown to reduce CV events, so this should represent the treatment of choice if an SGLT-2 inhibitor is selected, given the lack of other substantial mitigating factors with regards to agent selection. While the CANVAS and DELCARE-TIMI58 studies may also show a reduction in CV events, the potential for these studies to show benefit cannot be considered equivalent to the documented benefit from empagliflozin in the EMPA-REG OUTCOME study.

Outcome of the Case

Viable treatment options for JM include a sulfonylurea, an SGLT-2 inhibitor, or a dipeptidyl peptidase 4 (DPP-4) inhibitor such as sitagliptin, given his desire to take an oral medication. The sulfonylurea will lead to weight gain, while the DPP-4 inhibitor will be unlikely to get his HbA_1c level to goal. Furthermore, given the advantages of the SGLT-2 inhibitor with respect to weight and blood pressure, which are comorbidities that JM struggles with, this class likely represents the most appropriate option. Given the CV benefits of empagliflozin, this agent would be selected over the other SGLT-2 inhibitors.

Empagliflozin should be started at a dose of 10 mg daily. JM should be counseled to increase his fluid intake and to monitor for signs of dehydration. He should also be counseled on the risk of mycotic infections. Lastly, JM should continue monitoring his blood pressure and glucose level and should strive for optimal diet and exercise regimens.

Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of an anticoagulation clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.

Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville and completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Ochsner Medical Center in Jefferson, Louisiana.

References:

1. CANagliflozin cardioVascular Assessment Study (CANVAS). NCT01032629. ClinicalTrials.gov, a service of the US National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT01032629. Accessed October 16, 2016.
2. Sonesson C, Johansson PA, Johnsson E, Gause-Nilsson I. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis. Cardiovasc Diabetol. 2016;15:37. doi:10.1186/s12933-016-0356-y.
3. Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58). NCT01730534. ClinicalTrials.gov, a service of the US National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT01730534. Accessed October 16, 2016.
4. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.
5. Liakos A, Karagiannis T, Bekiari E, Boura P, Tsapas A. Update on long-term efficacy and safety of dapagliflozin in patients with type 2 diabetes mellitus. Ther Adv Endocrinol Metab. 2015;6(2):61-67.