FDA has issued a warning about a possible link between use of SGLT2 inhibitors and ketoacidosis.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel medication class indicated for use in patients with type 2 diabetes mellitus. They function by inhibiting the reuptake of glucose from the urine in the kidneys, thus reducing plasma glucose concentrations.1
SGLT2 inhibitors have been shown effective in lowering fasting and postprandial blood glucose alone and in conjunction with other therapies.2 In addition, A1c reductions up to 1% have been seen in clinical trials.3
With a low incidence of hypoglycemia and weight loss, use of SGLT2 inhibitors has been increasing. Safety and efficacy has not been established in type 1 diabetic patients, but they are currently being studied for this indication and some off-label use has been seen in this population.4
In May 2015, FDA issued a warning about a possible link between use of SGLT2 inhibitors and ketoacidosis.5 A search of the FDA Adverse Events Reporting System on July 7 yielded 54 cases of acidosis, including ketoacidosis and metabolic acidosis in patients using an SGLT2 inhibitor.6 Hospitalization occurred in 35 of these cases and four involved off-label use, most likely in type 1 diabetics. Published case reports are currently limited, but show interesting correlations between patients.7,8,9
Three cases occurred 2-13 days after a patient started or restarted SGLT2 inhibitors. These patients had reduced insulin production.7,9 Two cases involved patients with a significantly reduced carbohydrate intake, ranging from no carbohydrates per day (the result of acute food intolerance) to 66 grams of carbohydrates/day.7,9 No patients had a blood glucose level greater than 250 mg/dl; the highest blood glucose was 191 mg/dl.7,8,9
Diabetic ketoacidosis usually affects type 1 diabetics, and presents once blood glucose is greater than 250mg/dl. These four cases and most of those reported to the FDA involved type 2 diabetics, a patient population that is at lower risk of developing diabetic ketoacidosis. It is important to note that administration of insulin resolved each of these published cases of ketoacidosis or metabolic acidosis.7,8,9
The June 2015 FDA warning states that reduced food and fluid intake, reduced insulin dose, and major illness may contribute to ketoacidosis in patients taking SGLT2 inhibitors.5 Currently, in regard to treatment guidelines, there are no strong recommendations for the amount of carbohydrate a diabetic should consume at each meal. However, it is common practice to limit carbohydrates in meals to improve glycemic control.
Some diabetics may completely cut out carbs; this type of diet, even in a nondiabetic person, places individuals at risk of developing ketoacidosis. In fact, there have been cases reported of ketoacidosis in nondiabetics who followed the Atkins diet.10
Another potential mechanism of acidosis in patients taking SGLT2 inhibitors is the reduction of insulin from injections.
When initiating a SGLT2 inhibitor, many clinicians decrease the insulin dose to reduce the side effect of hypoglycemia. With less insulin on board, there is potential to increase the breakdown of fatty acids in adipose tissue, ultimately resulting in ketogenesis in the liver. This is likely to be exacerbated in a type 2 diabetic experiencing decreased endogenous insulin production due to beta cell dysfunction. In addition, SGLT2 inhibitors may increase the reabsorption of ketones from the urine, further predisposing a patient to developing ketoacidosis.
It is also known that some SGLT2 inhibitors increase the levels of glucagon. This increase, especially in connection with reduced insulin, causes fatty acid breakdown and the formation of ketones.11
Lastly, known side effects of SGLT2 inhibitors include urinary tract infections. It is unknown whether this side effect plays a role in the development of ketoacidosis, but it may be an influencing insult to homeostasis for a person already on the brink of developing ketoacidosis.3
In light of current available information, some key patient-specific criteria may be identified to aid in prevention of acidosis - if indeed there is a link.
Ketogenesis occurs when low levels of insulin are present. It might be appropriate to make sure that a patient is still producing endogenous insulin before an SGLT2 inhibitor is initiated and especially before insulin injections are stopped or insulin doses drastically reduced.
Patients should be advised not to substantially reduce or stop insulin therapy after starting an SGLT2 inhibitor without consulting their healthcare provider. Patients should consume some carbohydrates while taking an SGLT2 inhibitor. Ketoacidosis may be masked in patients who take SGLT2 inhibitors, as the result of euglycemia and reduced ketones in the urine.
Most important, upon recognition of signs of ketoacidosis such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, unusual fatigue or sleepiness, the SGLT2 inhibitor should be discontinued following confirmation of ketosis.5
1. Chao, EC. SGLT-2 Inhibitors: A new mechanism for glycemic control. doi:10.2337/diaclin.32.1.4. Clin Diabetes. January 2014 vol. 32 no. 1 4-11.
2. Stenlöf KL, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Published online before print Jan 24, 2013, doi: 10.1111/dom.12054. Diabetes Obes Metab. 2013 Apr;15(4):372–82.
3. Canagliflozin [package insert]. FDA.
4. Sands AT, Zambrowicz BP, Rosenstock J, et al. Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in type 1 diabetes. Diabetes Care. July 2015, vol. 38 no. 7, 1181–1188.
5. FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. (2015, May 5). Retrieved July 28, 2015.
6. MedWatch Drug Adverse Events (AERS). Search criteria: dapagliflozin, empagliflozin, canagliflozin, and acidosis on July 7, 2015.
7. Hayami T, Kato Y, Kamiya H, et al. Case of ketoacidosis by a sodium-glucose cotransporter 2 inhibitor in a diabetic patient with a low-carbohydrate diet. Published online before print February 25, 2015, doi: 10.1111/jdi.12330. J Diabetes Investig.
8. Burr K, Nguyen A-T, Rasouli N. A case report of ketoacidosis associated with canagliflozin (Invokana). Endocrine Society (March 7, 2015). Retrieved June 26, 2015.
9. Hine J, Paterson H, Abrol E, et al. SGLT inhibition and euglycaemic diabetic ketoacidosis. Published online May 27, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00204-1. The Lancet, vol 3, July 2015.
10. Shah P, Isley W. Ketoacidosis during a Low-Carbohydrate Diet. NEJM. January 2006; 354:97-98.
11. Taylor SI, Blau JE, Rother KI. Perspective: SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015; 100(8):2849.
Lindsay Sheehanis an ambulatory care clinic leader, Carolinas Medical Center–Northeast, Concord, N.C. Duke Calfasis a 2016 PharmD candidate at Wingate University School of Pharmacy, Wingate, N.C.