Sodium glucose cotransporter (SGLT) inhibitors, including empagliflozin, dapagliflozin, canagliflozin and ertugliflozin, have become widely used glucose-lowering drugs in patients with type 2 diabetes (T2D).1 SGLT inhibitors block the reabsorption of glucose in the kidney and increase glucose excretion, thereby lowering blood glucose levels. 2 They are taken orally and do not require dose titration. In addition to reducing levels of plasma glucose, glycated haemoglobin (HbA1c), weight and blood pressure, these drugs have demonstrated cardiac and renal protective effects in selected patient cohorts. 3,4 These benefits have led to considerable enthusiasm for the drugs and investigation of their use as an adjunct to insulin in patients with type 1 diabetes (T1D). 5 Data from a number of large randomised controlled studies has been released in recent years and show that SGLT inhibitors led to improvements in glycaemic control, with clinically meaningful reductions of around 0.3–0.4% in HbA1c and weight loss in patients with T1D without increasing the risk of hypoglycaemia. 6¬–12 As a result, several SGLT inhibitors are currently under review by the US Food and Drug Administration (FDA) and European regulatory agencies as an adjunct to insulin therapy in people with T1D, and these agents are increasingly being used off-label in the management of people with T1D.
Unfortunately, an important safety concern has dampened enthusiasm for SGLT inhibition in T1D. Clinical trials have shown an increased the risk of diabetic ketoacidosis (DKA), sometimes in patients with almost normal blood glucose levels, with an average incidence of around 3% in all studies. 6–12 This risk might be greater in routine clinical use where patients are not monitored as closely as in clinical trials. The risk was first reported in 2015 and the authors recommended that patients with T1D and T2D who experience nausea, vomiting, or malaise or develop metabolic acidosis while taking SGLT-2 inhibitor therapy should be evaluated for the presence of urine and/or serum ketones. They also advised that SGLT inhibitors should only be used with great caution, extensive counselling, and close monitoring in the setting of T1D. 13
A consensus report by an international panel of 26 clinicians and researchers was published in Diabetes Care, based on a comprehensive review of clinical trials, and provides management strategies for reducing the risk for DKA. 14 At the International Conference of Advanced Technologies & Treatments for Diabetes Congress, which was held on 20–23 Februarry 2019 in Berlin, Thomas Danne (Professor of Paediatrics at the Children’s Hospital ‘Auf der Bult’, Hannover) presented a summary of these recommendations. 15 The most important criterion for selecting the appropriate patients for SGLT inhibitor therapy is normal ketone levels, defined as blood concentration below 0.6 mmol/L and negative urinary ketones. Individual patient factors, such as ability to follow regular diets, adhere to prescribed treatment protocols and ketone monitoring regimens, and not consume excessive amounts of alcohol, may also be considered. Insulin doses should be adjusted cautiously and monitored on an individual patient level to prevent DKA. SGLT inhibitors should not be prescribed to pregnant women with T1D or patients who are following low-carbohydrate or ketogenic diets. In addition, patients using an insulin pump are at increased risk of DKA due to the possibility of malfunction. The authors noted that treatment with SGLT inhibitors in patients using insulin pumps with automated features including low glucose insulin suspend and hybrid closed loop has not been well studied. 14,15
SGLT inhibitor therapy should be initiated at the lowest dose possible when blood ketone levels are <0.6 mmol/L. Ideally, patients should self-monitor capillary blood levels of beta-hydroxybutyrate, with retesting of glucose and ketone levels every 1–3 hours if elevated ketones are detected, but monitoring urine ketones is acceptable. SGLT inhibitor therapy should be discontinued if the patient experiences nausea, vomiting, unusual abdominal discomfort, has a scheduled medical procedure, or has elevated ketones. When patients are switching their type of insulin therapy, for example from injections to a pump, the use of SGLT inhibitors should be discontinued until insulin doses are adjusted and ketone levels are normal. Appropriate education is essential for both the patient and the clinician to be aware of the factors affecting ketone levels and what to do if ketone levels rise. In addition, emergency departments should be aware that DKA can present without overtly elevated glucose levels in patients treated with SGLT-inhibitors. 14,15
The committee recommended that future studies evaluate the efficacy and safety of SGLT inhibitors in real-world settings. Research is also needed to determine whether patients with extremely high HbA1c are at an elevated risk for DKA and therefore should not take SGLT inhibitors. There is a need for clinical guidelines for the reduction of insulin that establish timeframes for monitoring ketones. 14,15
SGLT inhibitors have shown potential benefit as an adjunct treatment in people with T1D not achieving adequate glycaemic control with insulin alone, but the increased risk of DKA is an important safety concern that must be managed. These recommendations have provided a much-needed starting point for the safe use of SGLT-inhibitor therapy in this population. 15
- Shyangdan DS, Uthman OA, Waugh N. SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus: a systematic review and network meta-analysis. BMJ Open. 2016;6:e009417.
- Mosley JF, 2nd, Smith L, Everton E, et al. Sodium-glucose linked transporter 2 (SGLT2) inhibitors in the management of type-2 diabetes: a drug class overview. P T. 2015;40:451–62.
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.
- Cherney DZ, Perkins BA. Sodium-glucose cotransporter 2 inhibition in type 1 diabetes: simultaneous glucose lowering and renal protection? Can J Diabetes. 2014;38:356–63.
- Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: the DEPICT-1 52-week study. Diabetes Care. 2018;41:2552–9.
- Mathieu C, Dandona P, Gillard P, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 Study): 24-week results from a randomized controlled trial. Diabetes Care. 2018;41:1938¬–46.
- Rosenstock J, Marquard J, Laffel LM, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care. 2018;41:2560–9.
- Buse JB, Garg SK, Rosenstock J, et al. Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: the North American inTandem1 Study. Diabetes Care. 2018;41:1970–80.
- Garg SK, Henry RR, Banks P, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med. 2017;377:2337–48.
- Danne T, Cariou B, Banks P, et al. HbA1c and hypoglycemia reductions at 24 and 52 weeks with sotagliflozin in combination with insulin in adults with type 1 diabetes: the European inTandem2 Study. Diabetes Care. 2018;41:1981–90.
- Henry RR, Thakkar P, Tong C, et al. Efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes. Diabetes Care. 2015;38:2258–65.
- Peters AL, Buschur EO, Buse JB, et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38:1687–93.
- Danne T, Garg S, Peters AL, et al. International consensus on risk management of diabetic ketoacidosis in patients with type 1 diabetes treated with sodium-glucose cotransporter (SGLT) inhibitors. Diabetes Care, 2019; doi: 10.2337/dc18-2316. [Epub ahead of print].
- Danne T. Report on the consensus on SGLT in T1D. Presented at the International Conference of Advanced Technologies & Treatments for Diabetes Congress, 20–23 Februarry 2019, Berlin, Germany.
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