Sodium–glucose cotransporter-2 inhibition and acidosis in patients with type 2 diabetes: a review of US FDA data and possible conclusions

Abstract

Objective: To evaluate whether adverse event reports to the US Food and Drug Administration on incidents of ketoacidosis from use of sodium glucose cotransport inhibitors (SGLT2 inhibitors) provide insight into ways this new class of drugs is being prescribed with other antihyperglycemic agents; to examine possible mechanisms to explain ketoacidosis. Design and methods: Reports of adverse events concerned to SGLT2 inhibitors, namely, empagliflozin, dapagliflozin, and canagliflozin were obtained under the Freedom of Information Act for 5 years ending in August 31, 2015. The data were evaluated for incidents of ketoacidosis by looking for keywords such as diabetic ketoacidosis, ketoacidosis, lactic acidosis, acidosis, and metabolic acidosis. Results were tabulated individually for empagliflozin (n=260 adverse event reports), dapagliflozin (n=520), and canagliflozin (n=2159). Adverse events were categorized according to age, gender, and insulin use. Results: There were 46, 144, and 450 reports of ketoacidosis concerned with the use of empagliflozin, dapagliflozin, and canagliflozin, respectively. The use of SGLT2 inhibitors was not strictly limited to patients with type 2 diabetes but was cut across categories of insulin use, including a total of 172 cases of SGLT2-related ketoacidosis in individuals above the age of 40 who were not on insulin. Conclusion:Further studies should focus to detect pleiotropic effects of SGLT2 inhibitors, particularly with other oral antihyperglycemic drugs or insulin. A review of the literature suggests that patients with type 2 diabetes with low C-peptide level may be at increased risk of ketoacidosis, particularly if they are on statins and diuretics due to hypokalemia and impaired release of insulin. More studies are warranted to further clarify these mechanisms.

Pioglitazone prevents the increase in plasma ketone concentration associated with dapagliflozin in insulin‐treated T2DM patients: Results from the Qatar Study

“…Collectively, the present results suggest that pioglitazone inhibits the increase in ketone production caused by SGLT2i, and we hypothesize that combination therapy with pioglitazone plus SGLT2i will reduce the risk of ketoacidosis in T2DM patients . Consistent with this hypothesis, only four of 64 (6.25%) patients who were receiving pioglitazone as part of their background therapy were reported to have developed ketoacidosis following SGLT2i administration compared to 36% of insulin‐treated T2DM patients . A larger study is warranted to examine whether the addition of pioglitazone to dapagliflozin therapy prevents the SGLT2i‐induced increase in plasma ketone concentration and the development of euglycaemic ketoacidosis reported with SGLT2i therapy .…”

“…In one case series, 59% of T2DM patients who developed diabetic ketoacidosis (n = 34) were receiving two or more daily insulin injections . Moreover, 36% of T2DM patients (n = 640) reported to the adverse event centre of the US Food and Drug Administration as having diabetic ketoacidosis as the result of SGLT2i use were receiving insulin as part of their background therapy, suggesting that the presence of insulin in background antidiabetic therapy does not reduce the risk of diabetic ketoacidosis associated with SGLT2i use. Collectively, the present results suggest that pioglitazone inhibits the increase in ketone production caused by SGLT2i, and we hypothesize that combination therapy with pioglitazone plus SGLT2i will reduce the risk of ketoacidosis in T2DM patients .…”

“…7 Consistent with this hypothesis, only four of 64 (6.25%) patients who were receiving pioglitazone as part of their background therapy were reported to have developed ketoacidosis following SGLT2i administration 7,[9][10][11] compared to 36% of insulin-treated T2DM patients. 14 reported with SGLT2i therapy. 7,[9][10][11] We did not measure plasma-free FIGURE 1 Plasma ketone concentration at baseline and after treatment with pioglitazone plus dapagliflozin A, or dapagliflozin alone, B in T2DM patients fatty acid concentration in the present study.…”

Diabetic Ketoacidosis in a Patient with Type 1 Diabetes on Sodium-glucose Co-transporter-2 Inhibitors—a Case Report

“…16 There have been several reports of diabetic ketoacidosis with the use of SGLT2 inhibitors in both T1D and T2D. 17 In phase II and III studies of SGLT2 inhibitors in patients with T1D the incidence of diabetic ketoacidosis has been as high as 3-9%.…”

Sodium-glucose Co-transporter-2 Inhibitors in Type 1 Diabetes—a Dangerous Ally

“…In a recent review of FDA adverse event reporting data, the authors found 46, 144, and 450 reports of ketoacidosis associated with empagliflozin, dapagliflozin, and canagliflozin. 34 There have been some case reports from southeast Asian countries 35,36 and reports of ketonemia and ketonuria in patients from India.…”