SGLT2 Inhibitors: Mechanism of Action, Pros, and Cons

Sodium glucose cotransporter 2 (SGLT2) inhibitors are among the newest classes of oral agents to treat type 2 diabetes mellitus (T2DM). In early 2013, the FDA approved canagliflozin (Invokana),¹ followed in January 2014 by approval of dapagliflozin (Forxiga).² A third SGLT2 inhibitor, empagliflozin, is currently under review.

SGLT inhibitors block the SGLT2 protein involved in 90% of glucose reabsorption in the proximal renal tubule, resulting in increased renal glucose excretion and lower blood glucose levels. These agents probably also increase insulin sensitivity, decrease gluconeogenesis, and improve insulin release from pancreatic beta cells.³

The results of several recent studies seem to parallel those of pre-marketing studies. Advantages of SGLT2 inhibitors include:

   o Insulin-independent action: allows SGLT2 inhibitors to be used at various stages during the progression of T2DM⁴

   o Improved glycemia, A1C reductions: ranging from 0.6% to nearly 1% in some studies^4,7

   o Mild reduction in blood pressure, possibly related to sodium loss

   o Low risk of hypoglycemia^4,5

   o Modest weight loss^5,6

Recent studies have also confirmed the main adverse effects of SGLT2 inhibitors:

   o Mycotic genital infections and urinary tract infections secondary to glucosuria^4,5,7-9

   o Polyuria: possible increased risk of renal impairment secondary to dehydration^4,8

   o Volume depletion: hypotension, dizziness, fainting^7,8

   o Cardiovascular: possible increased risk of ischemic stroke within the first 30 days of treatment, according to interim results from the Canagliflozin Cardiovascular Assessment Study (CANVAS)¹⁰

   o Contraindicated in T1DM, patients prone to urinary ketones or hematuria, or those with severe renal impairment¹

Surprising Findings

Unexpected results related to the homeostatic effects of SGLT2 inhibitors have been reported in 2 recent studies. Both report that SGLT2 inhibitors seem to paradoxically increase glucagon levels and production of endogenous glucose.

In the first study, Ferrannini and colleagues¹¹ in Italy and Germany evaluated 66 patients with T2DM who received a 5-hour meal tolerance test followed by a 3-hour fasting period. Participants were evaluated after receiving a single dose and following 4-week treatment with empagliflozin. Key results included¹¹:

   o Increased insulin sensitivity

   o Significantly increased glucagon response

   o An increase in endogenous glucose production of approximately 25% after 3 hours of fasting

   o After 4 weeks of treatment, HbA1C and fasting glucose levels declined significantly, the increase in endogenous glucose production slowed, and the rise in glucagon, although still increased, was also blunted

The authors emphasized that the rise in endogenous glucose production balanced the amount of glucose lost through renal excretion. Without the rise in endogenous glucose production, they estimated, postprandial glucose levels would have decreased by about 50% instead of 12%, as observed in the study.

In a similar study, Merovci and colleagues¹² at the University of Texas Health Science Center assessed 18 diabetic men randomized to either dapagliflozin or placebo for 2 weeks. Key results indicated that dapagliflozin¹²:

   o Markedly lowered fasting plasma glucose level, improved muscle insulin sensitivity, and increased insulin-mediated tissue glucose disposal by about 18%

   o Increased endogenous glucose production: by day 3 the amount produced was approximately half the glucose excreted renally secondary to SGLPT2 inhibition

   o Increased glucagon level by 23% 

The authors estimated that had the increase in endogenous glucose production not occurred, dapagliflozin would have had double the effect on lowering fasting plasma glucose levels. 

“A decrease in fasting plasma glucose concentration potentially could lead to an increase in hepatic glucose production, due to removal of the inhibitory effect of hyperglycemia on hepatic glucose production,” the authors wrote. “This raises the interesting possibility of the existence of a novel reflex arc-either directly or neurally mediated between the kidney and the liver/pancreas.”

One possible strategy to counteract this effect, the authors suggested, would be to combine SGLT2 inhibitors with the glucagon-inhibiting properties of incretin mimetics.  

SGLT2 Inhibitors as Add-on Therapy

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%.⁷

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.⁸

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.⁶

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.⁴Take-Home Points

SGLT2 inhibitors:

   o Induce glycosuria, improve glycemia, reduce A1C levels, have low risk of hypoglycemia, and modestly reduce weight and blood pressure.

   o Increase the risk of genital mycotic infections, polyuria, and volume depletion, and may increase the risk of ischemic stroke, especially early in treatment.

   o Could increase glucagon levels and endogenous glucose production, although the mechanism remains unclear.

   o As add-on therapy, could improve glycemic control and help stabilize insulin dosage.

References:

• 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/.