Sodium-Glucose Cotransporter-2 Inhibitors for Treating Type 2 Diabetes

Diabetes is a complex disease affecting 29.1 million individuals in the United States. It contributes to a multitude of complications, such as heart disease, eye damage, kidney failure, and lower-limb amputations.^1,2 The use of diet, exercise, and medications is imperative for improving glycemic control. Although many medications can be used to treat type 2 diabetes (T2D), sodium-glucose cotransporter-2 (SGLT2) inhibitors is a newer medication class that lowers plasma glucose and improves glycemic control. The 3 FDA-approved SGLT2 inhibitors are canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga, AstraZeneca), and empagliflozin (Jardiance, Boehringer Ingelheim). Canagliflozin was the first approved SGLT2 inhibitor in March 2013.^1,2

Pharmacology^3-6

SGLT2 is a transporter in the proximal renal tubules that reabsorbs glucose from the tubular lumen. By inhibiting the reabsorption of glucose, more glucose is excreted in the urine and the plasma glucose is lowered.

Therapeutic Use, Dosing, and Administration^3-6

SGLT2 inhibitors are FDA-approved to improve glycemic control in adults with T2D in addition to diet and exercise. These medications are orally administered once daily. The starting dose of canagliflozin, dapagliflozin, and empagliflozin is 100 mg, 5 mg, and 10 mg daily, respectively. The dose may be increased to 300 mg, 10 mg, and 25 mg daily if the goal glycated hemoglobin (A1C) is not achieved. Canagliflozin should be administered before the first meal of the day; dapagliflozin and empagliflozin should be administered in the morning, but without regard to food. Dose reductions or discontinuation may be required in patients with renal or hepatic impairment.

Comparative Efficacy⁷

To date, there have been no direct comparisons among SGLT2 inhibitors, but a recent meta-analysis compared efficacy and safety among them. The analysis of 38 trials lasting at least 24 weeks each compared approved doses of canagliflozin, dapagliflozin, or empagliflozin to placebo or other glucose-lowering drugs in adults with T2D. Some trials involved SGLT2 inhibitor monotherapy, whereas others involved other concomitant diabetes medications. Primary outcomes included A1C, weight reduction, and genitourinary infections, among other measures.

A1C data were available from all trials, and each SGLT2 inhibitor demonstrated a significant reduction in A1C compared with placebo. The mean A1C reduction compared with placebo is summarized in the Table.

Canagliflozin 300 mg demonstrated superior A1C-lowering compared with all doses of dapagliflozin and empagliflozin (P <.05). SGLT2 inhibitors were also associated with statistically significant weight loss (P <.05), with mean weight loss ranging from 1.58 kg (dapagliflozin 5 mg) to 2.47 kg (canagliflozin 300 mg). Safety data indicate that all SGLT2 inhibitors increased the risk of genitourinary infection, with no significant differences between each medication. Odds ratios ranged from 4.2 (95% CI, 2.7-6.3) for empagliflozin 10 mg to 5.9 (95% CI, 4.0-8.3) for canagliflozin 300 mg. Overall, SGLT2 inhibitors can lower A1C, but canagliflozin may be superior to other SGLT2 inhibitors in terms of lowering A1C. Additionally, all SGLT2s inhibitors increase the risk of genital infection compared with placebo.

Warnings/Adverse Reactions^3-6,8

Warnings include hypotension, ketoacidosis, renal impairment, urosepsis and pyelonephritis, hypoglycemia with insulin or insulin secretagogues, genital mycotic infections, and increased low-density lipoprotein cholesterol (2.9%-8.0%). SGLT2 inhibitors may also cause genitourinary infections and increased urination due to increased excretion of glucose. Package inserts warn of bone fractures, but a meta-analysis including 38 randomized controlled trials (follow-up: at least 24 weeks) and 30,384 patients did not find statistically significant evidence that SGLT2 inhibitors increase bone fracture risk (OR, 1.02; 95% CI, 0.84-1.23). Dapagliflozin may be associated with bladder cancer, although data are insufficient to conclude if this is a causal relationship. The FDA recently issued a warning about ketoacidosis risk and urinary tract infections (UTIs).

Interactions^3-6

SGLT2 inhibitors may interfere with urine glucose tests and 1,5-anhydroglucitol assays; other methods should be used to monitor glycemic control. Uridine’5 diphospho-glucuronosyltransferase (UGT) enzyme inducers (eg, rifampin) decrease exposure and thus may decrease efficacy. Consider increasing to maximum dosage if UGT inducers are coadministered. Canagliflozin may increase exposure of digoxin; patients taking both canagliflozin and digoxin should be monitored closely.

Place in Therapy^9-13

The American Diabetes Association recommends metformin as initial oral therapy for T2D, but SGLT2 inhibitors can be considered as add-on therapy if a patient’s A1C goal is not achieved after 3 months. Patient preference must be considered when deciding among SGLT2 inhibitors, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, or insulin. Benefits of SGLT2 inhibitors include low risk of hypoglycemia and modest weight loss, but these medications are also associated with UTI and high cost.

The average wholesale price of all doses of canagliflozin, dapagliflozin, and empagliflozin is $470 per bottle of 30 tablets. SGLT2 inhibitors are associated with significant benefits and costs that should be carefully weighed with each patient. The FDA required several postmarketing studies in order to evaluate aspects such as cardiovascular outcomes, bladder cancer, pancreatitis, liver abnormalities, bone safety, and use in pediatric patients; these studies may impact the utility of SGLT2 inhibitors in the future.

Jennifer L. Cruz, PharmD, BCPS, is an assistant professor of clinical education at UNC Eshelman School of Pharmacy. Katherine Summers is a PharmD candidate at UNC Eshelman School of Pharmacy.

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References

• 2014 National Diabetes Statistics Report. CDC website. cdc.gov/diabetes/data/statistics/2014StatisticsReport.html. Updated May 15, 2015. Accessed July 18, 2016.
• Facts & Comparisons eAnswers website. St. Louis, MO: Wolters Kluwer Health, Inc. online.factsandcomparisons.com. Updated June 2016. Accessed July 18, 2016.
• Invokana [package insert]. Titusville, NJ: Janssen Pharmaceuticals. Updated June 2, 2016.
• Farxiga [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals. Updated June 14, 2016.
• Jardiance [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals. Updated March 30, 2016.
• Lexicomp [online database]. Wolters Kluwer Health website. online.lexi.com/action/home. Accessed July 18, 2016.
• Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab. 2016;18(8):783-794. doi: 10.1111/dom.12670.
• Tang HL, Li DD, Zhang JJ, et al. Lack of evidence for a harmful effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2016. doi: 10.1111/dom.12742.
• American Diabetes Association. Standards of Medical Care in Diabetes — 2016. J Clin Appl Res Educ: Diabetes Care. 2016;39(suppl 1). care.diabetesjournals.org/content/suppl/2015/12/21/39.Supplement_1.DC2/2016-Standards-of-Care.pdf. Accessed July 18, 2016.
• Red Book Online. Truven Health Analytics website. www.micromedexsolutions.com. Accessed July 19, 2016.
• FDA approves Invokana to treat type 2 diabetes [news release]. FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm. Published March 29, 2013. Accessed July 26, 2016.
• FDA approves Farxiga to treat type 2 diabetes [news release]. FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm380829.htm. Published January 8, 2014. Accessed July 26, 2016.
• FDA approves Jardiance to treat type 2 diabetes [news release]. FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm407637.htm. Published August 1, 2014. Accessed July 26, 2016.