SGLT2 Inhibitors: Are We Throwing the Baby Out With the Bathwater?

Crosby Tindal, Pharm.D., SUPERVALU

Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are the most controversial novel antidiabetic medications. Their benefits appear to far exceed those expected from their modest antihyperglycemic effects alone. Randomized controlled trials (RCT) continue to suggest several protective cardiovascular and renal effects. However, these same trials and ongoing post-marketing surveillance have identified several risks associated with SGLT2i. Careful consideration must be taken when weighing potential benefits and risks for patients with type 2 diabetes.  

Evidence: As recently published in Lancet, Zelniker and colleagues conducted a systematic review and meta-analysis of cardiovascular and renal outcomes trials using SGLT2i. This analysis included the EMPA-REG OUTCOME, CANVAS (CANVAS and CANVAS-R), and DECLARE-TIMI trials (n=34,322). The investigators stratified patients according to baseline presence of atherosclerotic cardiovascular disease (ASCVD) vs. cardiac risk factors, heart failure, and glomerular filtration rate (eGFR). Zeliker et al. concluded that use of SGLT2i reduced major adverse cardiovascular events (MACE) by 11% (HR 0.89 [95% CI 0.83-0.96]) but only in those with established ASCVD (HR 0.86 [95% CI 0.80-0.93]). SGLT2i reduced the risk of cardiovascular death or hospitalization for heart failure by 23% (HR 0.77 [95% CI 0.71-0.84]) in all patients regardless of baseline ASCVD or history of heart failure.

Higher baseline renal function was associated with a larger response to SGLT2i for prevention of hospitalization for heart failure.1 This risk was reduced by 40% in patients with a baseline eGFR less than 60 mL/min (HR 0.5 [95% CI 0.47-0.77], 31% in patients between 60-90 mL/min (HR 0.69 [95% CI 0.57-0.83], and non-significantly in patients above 90 mL/min. SGLT2i use reduced risk for worsening renal function, end-stage renal disease, or renal death (HR 0.55 [95% CI 0.48-0.64]) with a magnitude of reduction directly proportional to baseline renal function. Patients with eGFR of less than 60 mL/min at baseline experienced a 33% risk reduction (HR 0.67 [95% CI 0.51-0.89]), those 60-90 ml/min a 44% risk reduction (HR 0.56, [95% CI 0.46-0.70]), and those 90 ml/min or greater a 56% risk reduction (HR 0.44, [95% CI 0.32-0.59]). This was independent of ASCVD at baseline. Evidence of renoprotective effects is corroborated by other emerging data. In July of 2018, Janssen Pharmaceuticals announced the early termination of the CREDENCE trial based on achievement of pre-specified efficacy endpoints.CREDENCE was a Phase 3 trial evaluating the composite endpoint of time to dialysis or kidney transplant, doubling in serum creatinine, and renal or cardiovascular death in patients taking canagliflozin or placebo with baseline chronic kidney disease (CKD).

In May of 2015 the FDA warned of SGLT2i use and risk for diabetic ketoacidosis (DKA). Between March 2013 and May 2015, 73 cases of DKA were reported to the FDA Adverse Drug Event Reporting System (FAERS) database. Notably, at least 15 of these were in patients with type 1, for which SGLT2i use is off-label and without the recommendation of the American Diabetes Association (ADA).  Zelnicker et al. found an increased relative risk of 2.2 [95 % CI 1.25-3.87] but a low absolute incidence; less than 1 per 1000 patient years. In a review of SGLT2i-associated DKA events, Goldenberg et al. identified several risk factors including insulin non-adherence, discontinuation, or dose reduction; severe acute illness with dehydration, low-carbohydrate diets, intense exercise, surgery, or alcohol binges.

SGLT2i use may increase risk for Fournier’s gangrene. In August 2018 FDA issued a drug safety communication warning of this association based on 12 cases between March 2013 and May 2018. Fournier’s gangrene is extremely rare, but more common in males than females. However, 5 of the 12 cases identified by FDA occurred in women. FDA simultaneously reviewed FAERS for other antihyperglycemic agents over a period of more than 30 years and identified only 6 cases, all male.Urinary tract (UTI) and genital mycotic infections are a well-recognized adverse effect of SGLT2i. CANVAS reported an incidence of male genital infection, mycotic female genital infection, and UTI of 34.9, 68.8, and 40.0, respectively, per 1000 patient years in the canagliflozin group. It is notable that these were adjudicated and reported separately. Interestingly, there was no significant difference in incidence of UTI in DECLARE-TIMI 58, though this trial did report a 0.9% risk of genital infection vs. 0.1% with placebo. Similarly, in EMPA-REG OUTCOME, empagliflozin did not appear to increase risk for UTI or complicated UTI but did increase risk for genital infection (6.4% vs. 1.8%) with a similar effect in males and females (although females had a higher absolute risk).

CANVAS raised alarm over risk for lower limb amputation (6.3 vs. 3.4 per 1000 patient years).EMPA-REG OUTCOME did not directly adjudicate this event, but there was no significant difference in amputation rates for patients in DECLARE-TIMI 58.  Buse and colleagues analyzed data from four large U.S. claims databases, including 142,000 patients taking canagliflozin, 110,000 taking empagliflozin dapagliflozin, and 460,000 using other antidiabetic medications. This analysis of more than 700,000 patients using SGLT2i for a median duration of 6 months found no increased risk for below knee amputation.

Finally, SGLT2i have been associated with increased risk of bone fracture. CANVAS reported an incidence of 15.4 fractures per 1000 patient years with canagliflozin vs. 11.9 for placebo (P=0.02). However, both EMPAREG-OUTCOME and DECLARE-TIMI 58 found no significant difference in fractures with SGLT2i compared to placebo. In September 2015, FDA revised label requirements of canagliflozin to include warnings of increased risk of fractures. FDA pooled data from 9 clinical trials and determined that over a mean exposure of 85 weeks, incidence of bone fracture for placebo, 100 mg daily, and 300 mg daily canagliflozin was 1.1, 1.4, and 1.5 per 100 patient years respectively. Interestingly, this review determined these fractures were more likely to be associated with ‘low-trauma’ falls while CANVAS reported a non-significant difference in ‘low-trauma’ fractures. This may be due to small SGLT2i-induced increases in serum phosphate (between 2.9 and 5.2% with canagliflozin) which may trigger an increase in parathyroid hormone activity and subsequent calcium release from bone stores.   

Discussion: SGLT2i appear to confer a modest benefit to risk for adverse cardiovascular effects, but only in patients with established ASCVD. They offer a far greater benefit with respect to reduction in cardiovascular death or hospitalization for heart failure and progression of renal disease that is independent of baseline ASCVD or heart failure. Initiation of an SGLT2i earlier (that is, in patients with more preserved eGFR) results in a greater renoprotective effect. Concern for adverse effects may discourage use of SGLT2i. The most well-established of these is risk for genital mycotic infections (especially in females), and to a far lesser extent UTI/urosepsis. SGLT2i have a similar magnitude of increased risk for genital infections in men and women, but women have a higher absolute risk. Fournier’s gangrene, while extremely rare, is increased in both sexes but by a greater magnitude in women. SGLT2i are associated with an approximate doubling in risk for DKA, but mostly in conjunction with other precipitating factors. Absolute risk for DKA in any patient with type 2 remains very low regardless of SGLT2i use. Further, this can be mitigated by avoidance of precipitating circumstances, holding the drug during severe acute illness, and maintaining proper hydration. The paradoxical risk for amputation observed in CANVAS is not corroborated by other data. Finally, SGLT2i may affect bone mineral density, but this is not universally substantiated and the magnitude of this effect appears small.

Clinical Impact: There is no ‘ideal’ candidate for an SGLT2i. However, this does not preclude their use in patients who are adequately monitored, on safe concomitant medication regimens, and with established comorbidities such as ASCVD, CHF, or CKD. SGLT2i undeniably increase risk for genital infections, but data for other adverse effects is far less robust and conclusive. Conversely, SGLT2i confer profound and irrefutable benefits such as preservation of renal function, avoidance of hospitalization in heart failure, and secondary prevention of ASCVD. The adverse events associated with SGLT2i are much rarer and far more easily-managed than occurrence of MACE, hospitalization for heart failure, or progression of renal disease. These outcomes are far more likely to occur in patients with type 2 diabetes and can result in irreparable damage with lasting repercussions in terms of quality of life and total cost of care. 

References:

  1. Zelniker TA, Wiviott SD, Kyungah Im IR, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcomes trials. Lancet. 2019;393(10166):31-39.

  2. Schaffer, R. Helio - Endocrine Today. CREDENCE trial stopped early for favorable CKD findings with canagliflozin. July 19, 2018. https://www.healio.com/endocrinology/diabetes/news/online/%7Ba1b88b95-5637-4f7c-a12b-ac913a976ed8%7D/credence-trial-stopped-early-for-favorable-ckd-findings-with-canagliflozin. Accessed February 15, 2019.

  3. Food and Drug Administration: FDA Drug Safety Communication: FDA Revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. Date last modified 1-19-2018. https://www.fda.gov/Drugs/DrugSafety/ucm475463.htm Accessed February 15, 2019.

  4. American Diabetes Association. Standards of Medical Care in Diabetes: Chapter 9 - Pharmacologic Approaches to Glycemic Treatment. Diabetes Care. 2019;42(suppl 1):S90-102.

  5. Goldenberg RM, Berard LD, Cheng AYY, et al. SGLT2 Inhibitor-associated diabetic ketoacidosis: clinical review and recommendations for prevention and diagnosis. Clin Ther. 2016;38(12):2654-2664.

  6. Food and Drug Administration: FDA Drug Safety Communication: FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. Date last modified 9-7-2018. https://www.fda.gov/Drugs/DrugSafety/ucm617360.htm Accessed February 15, 2019.

  7. Perkovic NV, Mahaffey KW, de Zeeuw D, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Eng J Med. 2017;317(7):644-657.

  8. Wiviott SD, Raz MP, Bonaca O, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Eng J Med. 2019;380(4):347-357.

  9. Zinman B, Wanner C, Lachin J, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Eng J Med. 2015;373(22):2217-28.

  10. Buse JB, Ryan P, Schuemie M, et al. Canagliflozin (CANA) vs. other antihyperglycemic agents on the risk of below-knee amputation (BKA) for patients with T2DM—a real-world analysis of >700,000 U.S. patients. Poster presentation at: ADA 2018 78th Scientific Sessions; June 22-26, 2018; Orlando, FL. Poster 4-LB.

  11. Food and Drug Administration: FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. Date last modified 1-15-2016. https://www.fda.gov/Drugs/DrugSafety/ucm461449.htmAccessed February 15, 2019.

  12. Filippatos TD, Tsimihodimos V, Liamis G, and Elisaf MS. SGLT2 Inhibitors-induced electrolyte abnormalities: an analysis of the associated mechanisms. Diabetes Metab Syndr. 2018;12(1):59-63.