Why and when to use this therapy to treat patients who have type 2 diabetes.
The FDA has approved four sodium-glucose co-transporter 2 (SGLT2) inhibitors in the last 2 years: canagliflozin (Invokana, Jansssen), dapagliflozin (Farxiga, AstraZeneca), and empagliflozin (Jardiance, Boehringer Ingelheim), and Ertugliflozin (Steglatro, Merck/Pfizer). There is a lot of interest from clinicians to learn more about these agents and how they fit into the armamentarium of medications used to manage type 2 diabetes, key differences within the class, and appropriate patient selection.
SGLT2, which is expressed in the proximal renal tubule, is responsible for the reabsorption of filtered glucose from the tubular lumen. Inhibition of SGLT2 results in reduced reabsorption of filtered glucose and increased urinary glucose excretion. 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.
In the beginning there was hesitancy to use these agents as with most new treatment therapies, especially for the potential for dehydration and genital infections. But with any drug, once you have the experience of positive results and few side effects, you lose the apprehension to prescribe them.
The results of several recent studies seem to parallel those of pre-marketing studies. Advantages of SGLT2 inhibitors include:
- Insulin-independent action: allows SGLT2 inhibitors to be used at various stages during the progression of T2DM
- Improved glycemia, A1C reductions: ranging from 0.6% to nearly 1% in some studies
- Mild reduction in blood pressure, possibly related to sodium loss
- Low risk of hypoglycemia
- Modest weight loss
Recent studies have also confirmed the main adverse effects of SGLT2 inhibitors:
- Mycotic genital infections and urinary tract infections secondary to glucosuria
- Polyuria: possible increased risk of renal impairment secondary to dehydration
- Volume depletion: hypotension, dizziness, fainting
- 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)
- Contraindicated in T1DM, prone to urinary ketones or hematuria, or those with severe renal impairment
Unexpected results related to the homeostatic effects of SGLT2 inhibitors have been reported in two recent studies. Both report that SGLT2 inhibitors seem to paradoxically increase glucagon levels and production of endogenous glucose.
In the first study, E. Ferrannini and colleagues 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 included:
- Increased insulin sensitivity
- Significantly increased glucagon response
- An increase in endogenous glucose production of approximately 25% after 3 hours of fasting
- 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, A. Merovci and colleagues at the University of Texas Health Science Center assessed 18 men with diabetes randomized to either dapagliflozin or placebo for two weeks. Key results indicated that dapagliflozin:
- Markedly lowered fasting plasma glucose level, improved muscle insulin sensitivity, and increased insulin-mediated tissue glucose disposal by about 18%
- Increased endogenous glucose production: by day 3 the amount produced was approximately half the glucose excreted renally secondary to SGLT2 inhibition
- 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.
Go to Part 2: appropriate patient selection; counseling pearls; select differences; SGLT2 Inhibitors as additional therapy; practice guidelines; Practice Pearls
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