PERSPECTIVE: Diabetes management with SGLT2 inhibitors changing directions- Dr Anoop Misra, Dr Amrita Ghosh

There have been remarkable changes in the treatment of type 2 diabetes during the last decade. Focus has shifted from older class of drug (except metformin) to newer agents like Dipeptidyl Peptidase-4 inhibitors, Sodium -glucose Cotransporter-2 inhibitors, and Glucagon-like-peptide-1 receptor agonist. A key reason behind this major change in treatment approach has been trials following the US Food and Drug Administration 's requirement for Cardiovascular Safety Outcomes Trials (CVOT) for all newly introduced anti-hyperglycemic agents (AHAs).

Since then, there is an increasing realization that besides efficacy in lowering glycaemia, clinicians should consider the efficacy of the AHAs on blood pressure, weight, cardiovascular disease (CVD), and renal dysfunction. During the last 5 years, we have seen multiple placebo-controlled CVOT looking at all these outcomes.

One of the major trials of the decade is Empagliflozin Cardiovascular Outcome Study (EMPA-REG Outcome). The results were so remarkable as to change the paradigm of diabetes management. Empagliflozin showed positive results including a reduction in 3-point Major Adverse Cardiac Events (MACE), reduction in cardiovascular death, fall in hospitalization due to heart failure as well as reduction in all-cause mortality.

The second and equally important trial was Canagliflozin Cardiovascular Assessment study (CANVAS programme). This trial also showed almost similar results; reduction of 3-point MACE, hospitalization due to heart failure. A minor setback was increased incidence of toe amputation seen in this trial.

The largest and the longest trial was Dapagliflozin and Cardiovascular Outcome (DECLARE-TIMI 58). The study included 10,186 subjects without any prior CVD. Use of Dapagliflozin resulted in a reduction in cardiovascular death and hospitalization due to heart failure but it did not result in a significant decrease in MACE.

All these major trials have reaffirmed that the use of SGLT2 inhibitors results in major cardiovascular benefits with a remarkably consistent effect on the decrease in hospitalization due to heart failure.

A recently concluded trial, the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation study (CREDENCE) aimed to evaluate the efficacy and safety of canagliflozin 100mg/day versus placebo to standard care (angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers). The study was halted recently, nearly a year sooner than planned, based independent data monitoring committee's interim analysis which showed that it met pre-specified criteria for efficacy. Based on these significant findings, the pharmaceutical company has submitted a supplemental new drug application to the U.S. FDA for canagliflozin for the treatment of chronic kidney disease in patients with type 2 diabetes.

Given these findings and experience in India (including experience in about 20, 000 patients on our database), we have become wiser in using SGLT2 inhibitors. Clearly, these drugs stand out as drug of choice in patients of diabetes with heart failure and/or CVD. In other patients of diabetes (without cardiovascular disease and heart failure), use of SGLT2 must be individualized based on patient profile and possible adverse effects.

However SGLT2 inhibitors have to be used with caution. The most frequent adverse effect includes genital mycotic and urinary tract infections. In our published report comprising of 1297 patient with 12 months follow up, we have reported that these drugs lead to genital mycotic infections in 9.4% cases¹.^.We have also reported serious, but an infrequent side effect of diabetic ketoacidosis in one patient along with ketonuria in 10 patients.² Further, equally serious adverse reaction of emphysematous pyelonephritis has been recently reported by us in one patient.³Moreover, we have seen one case of amputation (not reported) but no case of fracture. Rare but very serious adverse effects of Fournier's gangrene (12 cases) and acute pancreatitis (few cases reported by U.S.FDA, 20 cases from Canada) have also been reported recently. Personally, these side effects have not been by us.

In recent times, US FDA issued drug safety communications regarding SGLT 2 inhibitors pointing out to certain side effects with the drug including diabetic ketoacidosis, severe urinary tract infections, bone fracture, and recently, Fournier's gangrene.^4,5 Further, just last week, the Central Drugs Control Standards Organization (CDSCO), India, has directed that the manufacturers of SGLT2 inhibitors should include safety warning in the package for Fournier's gangrene.⁶

To summarize, major trials, post-marketing data, and clinicians experience have reaffirmed our confidence in SGLT2 inhibitors as AHAs with multiple beneficial effects. Recent reports of newer adverse events should not dampen our enthusiasm in using these drugs. If patients are chosen wisely and educated well about the drug, adverse effects are minimized.

Dr Anoop Misra is a renowned endocrinologist and chairman of Fortis Centre for Diabetes, Obesity, and Cholesterol (C-DOC) and heads, National Diabetes Obesity and Cholesterol Foundation (NDOC). He is a former honorary physician to the Prime Minister of India. Dr Amrita Ghosh is a noted diabetologist practicing at Fortis C Doc with a special interest in Type 1 diabetes and insulin pump therapy.

References

1.Ghosh A, Gupta R, Singh P, et al. Sodium-glucose cotransporter-2inhibitors in patients with type 2 diabetes in North India: A 12-month prospective study in real-world setting. Int J ClinPract2018;72:e13237.

2.Ghosh A, Gupta R, Misra A. Ketonuria/ketonemia associated with the use of sodium–glucose cotransporter 2 (SGLT-2)inhibitors in type 2 diabetes: a report of three cases from New Delhi, India. JDiabetes. 2016;8:738‐739

3.Gupta R, GhoshA,Misra A.Case of acute unilateral emphysematous pyelonephritis and bacteraemia on treatment with canagliflozin Postgrad Med J2018;94:714–715

4.FDA. FDA warns about rare occurrences of a serious infection of the genital area withSGLT2 inhibitors for diabetes. 2018. Available: https://www. fda. gov/ Drugs/ DrugSafety/ucm617360. htm [Accessed Mar 2019].

5.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.2018. Available: https://www. fda. gov/ Drugs/ DrugSafety/ ucm475463. htm [Accessed Mar 2019]