Surprise findings for treatment class and appropriate patient selection
An ideal patient for these agents would be one who needs additional glycemic control, has excessive weight, and has elevated blood pressure.
The SGLT2 inhibitors have been shown to reduce glycosylated hemoglobin (A1C) by about 0.7%–1%, lower blood pressure, and result in weight loss. These agents cause intravascular volume contraction, resulting in modest reductions in blood pressure. In terms of weight loss, there was about a 5- to 10-lb weight loss in patients taking these agents.
These medications are effective only in those with sufficient renal function; canagliflozin and empagliflozin are not recommended for patients with an estimated glomerular filtration (eGFR) rate of less than 45 mL/min/1.73 m, and dapagliflozin is not recommended for those with an eGFR less than 60 mL/min/1.73 m.
Concurrent medications also need to be assessed as the use of loop diuretics may further increase the risk for dehydration and hypotension. The increased risk of genital mycotic infections with the SGLT2 inhibitors also must be considered, especially in patients who have a history of these types of infections.
Patients should be informed that the medications should be taken in the morning with or without food, but that canagliflozin’s label specifically states it should be taken before the first meal of the day.
To help prevent dehydration, patients should be encouraged to drink one to two extra glasses of water per day above what they usually drink. “Patients should also have a thorough understanding of the risks of genital mycotic infections and potential signs and symptoms indicative of these types of infections.”
Hyperkalemia is a concern with canagliflozin, and bladder cancer is a warning on the dapagliflozin label.
Patients with moderate renal impairment and those taking medications that may also cause hyperkalemia—such as ACE inhibitors or angiotensin receptor blockers—are at greater risk for elevated potassium levels with canagliflozin.
Bladder cancer is a warning specific to dapagliflozin. According to the labeling, data from 22 clinical studies showed that newly diagnosed bladder cancer was reported in 0.17% of patients treated with dapagliflozin (n = 10/6045) compared with 0.03% of patients treated with placebo or a comparator (n = 1/3512).
Studies looking at add-on treatment with SGLT2 inhibitors have found their effects on glycemic control to be roughly additive. Recent examples include:
Canagliflozin with metformin and pioglitazone: A randomized, double-blind, phase 3 study of 342 patients already receiving metformin and pioglitazone who received canagliflozin or placebo over a 26-week period. Results showed that canagliflozin at doses of 100 or 300 mg significantly lowered HbA1c by about −0.89%.
Canagliflozin with metformin, compared with glimepiride: In a 52-week, randomized, double-blind, phase 3 trial of patients inadequately controlled on metformin in 19 countries, canagliflozin 100 mg was similar to glimepiride in lowering HbA1c, and canagliflozin 300 mg provided greater HbA1c reductions than glimepiride.
Dapagliflozin with metformin: A systematic literature review of RCTs with diabetes patients inadequately controlled with metformin found that dapagliflozin had a similar effect on HbA1c after 1 year, compared with DPP-4 inhibitors, thiazolidinediones, sulphonylureas, and GLP-1 inihibitors.
Dapagliflozin with insulin: A 24-week, randomized, placebo-controlled, double-blind trial with 808 patients found that mean HbA1c decreased by −0.6% to −0.8% with dapagliflozin therapy after 104 weeks. Insulin dose increased in the placebo group, but remained stable in the dapagliflozin group.
The American Diabetes Association Standards of Medical Care in Diabetes are fairly consistent with previous recommendations in terms of selecting pharmacotherapy for patients. Metformin remains the preferred option for those with type 2 diabetes, used in combination with behavioral modifications, for patients who do not have contraindications to this agent. For patients who do not attain A1C targets after 3 months of metformin monotherapy, a two-drug regimen is recommended, which can include the addition of an SGLT2 inhibitor.
Within the standards, the SGLT2 inhibitors are characterized as having intermediate efficacy, a low risk for hypoglycemia, weight loss, genitourinary and dehydration adverse effects, and an associated high cost. These agents are also listed as an option for patients who require select three-drug regimens and as initial monotherapy for patients with contraindications to metformin.
- Induce glycosuria, improve glycemia, reduce A1C levels, have low risk of hypoglycemia, and modestly reduce weight and blood pressure.
- Increase the risk of genital mycotic infections, polyuria, and volume depletion, and may increase the risk of ischemic stroke, especially early in treatment.
- Could increase glucagon levels and endogenous glucose production, although the mechanism remains unclear.
- As add-on therapy, could improve glycemic control and help stabilize insulin dosage.
FDA News Release. FDA approves Invokana to treat type 2 diabetes. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm. Accessed March 28, 2014.
FDA News Release. FDA approves Farxiga to treat type 2 diabetes. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm380829.htm. Accessed March 28, 2014.
Nair S, Joseph F, Ewins D, et al. From history to reality: sodium glucose co-transporter 2 inhibitors—a novel therapy for type 2 diabetes mellitus. Pract Diabetes Int. 2010;27:311–316. http://dx.doi.org/10.1002/pdi.1509
Wilding JP, Woo V, Rohwedder K, et al; Dapagliflozin 006 Study Group. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab. 2013 Aug 1 [Epub ahead of print]. doi:10.1111/dom.12187. http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1111%2Fdom.12187
Rosenstock J, Seman L J, Jelaska A, et al. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab. 2014;15:1154–1160. doi:10.1111/dom.12185 http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1111%2Fdom.12185
Goring S, Hawkins N, Wygant G, et al. Dapagliflozin compared with other oral anti-diabetes treatments when added to metformin monotherapy: a systematic review and network meta-analysis. Diabetes Obes Metab. 2013 Nov 14 [Epub ahead of print]. doi:10.1111/dom.12239. http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1111%2Fdom.12239
Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab. 2014 Feb 15 [Epub ahead of print]. doi:10.1111/dom.12273. http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1111%2Fdom.12273
Cefalu WT, Leiter A, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2103;382:941-950. http://www.ncbi.nlm.nih.gov/pubmed/?term=The+Lancet%2C++2103%2C+382+941+%E2%80%93+950.
Johnsson KM, Ptaszynska A, Schmitz B, et al. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013;27:479-484. doi:10.1016/j.jdiacomp.2013.04.012. http://www.ncbi.nlm.nih.gov/pubmed/?term=Journal+of+Diabetes+and+Its+Complications.+2013%3B+27+(5)%3A+479-484.
Center for Drug Evaluation and Research. Summary Review for Canagliflzin. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000SumR.pdf. Accessed March 28, 2014.
Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499-508. http://www.jci.org/articles/view/72227.
Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124:509-514. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904617/.