Sodium-glucose cotransporter 2 inhibitors for type 1 diabetes: Ready for prime time?
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have rapidly become an established treatment for type 2 diabetes. SGLT2 inhibitors don’t cause hypoglycemia, help with weight loss, and now have favorable cardiovascular outcomes data from two major trials (EMPA-REG , CANVAS ) that are also supported by observational studies (CVD-REAL ). Furthermore, data from mechanistic studies and secondary analysis from the cardiovascular outcome trials suggest they may also have reno-protective effects [4, 5].
SGLT2 inhibitors act directly on the kidney to produce glycosuria, so the glucose-lowering effect is independent of insulin secretion. Consequently, SGLT2 inhibitors are expected to be effective glucose-lowering agents, not only in type 2 diabetes, but also as an adjunct to insulin in people with type 1 diabetes, and perhaps help mitigate against the weight gain that is a frequent consequence of intensive insulin treatment. Recent trials have supported this concept, so are we ready to embrace SGLT2 inhibitors as a treatment for people with type 1 diabetes?
UPDATE | John Wilding provides his updated thoughts following presentation of the latest data at the ADA 2018 conference. Is he swayed by the findings? (3:43)
Trials of SGLT2 inhibitors in type 1 diabetes: Glucose lowering and weight reduction
Short-term open-label clinical trials of SGLT2 inhibitors in type 1 diabetes showed promise, with improvements in glycated hemoglobin (HbA1c), body weight, and, in a study using continuous glucose monitoring, a reduction in glycemic variability [6, 7]. This has recently been confirmed in larger phase III studies with both the SGLT2 inhibitor dapagliflozin  and the combined SGLT1/SGLT2 inhibitor sotagliflozin . The most important clinical effects seen with dapagliflozin were a 0.45% reduction in HbA1c from a baseline of 8.53%, 3.1 kg weight loss, and a decrease of 5 units per day of insulin required. There was an excess of genital tract infections and a numerical increase in patients developing ketoacidosis during the trial (three cases on placebo, four with 5 mg, and five with 10 mg dapagliflozin) . One trial which randomized 1402 patients (40% on insulin pumps) 1:1 to sotagliflozin or placebo showed a 0.45% lower HbA1c and about 3 kg of weight loss with sotagliflozin compared with placebo, with less hypoglycemia, and a 3 unit per day reduction in bolus insulin dose. However, 3% of patients on sotagliflozin experienced an episode of ketoacidosis compared with 0.6% of controls .
Adverse effects: Focus on ketoacidosis
Ketoacidosis emerged as a potential adverse effect in patients treated with SGLT2 inhibitors largely as a result of off-label use in patients with type 1 diabetes, or in patients misdiagnosed with type 2 diabetes who actually had late-onset autoimmune diabetes . The downside is that most of the trials of SGLT2 inhibitors in type 1 diabetes have also suggested a small increased risk of ketoacidosis. Although most cases of ketoacidosis were recognized quickly and treated appropriately, this represents a risk for patients, especially as patient selection may be less careful and the degree of monitoring and supervision may be less intense in the real world than in clinical trials.
Are we ready for prime time?
Although the evidence for glucose lowering, sparing of insulin requirements, and some weight loss seems robust, these effects are modest at best, and the real or perceived risk of ketoacidosis cannot be ignored. It has been suggested that these risks can be managed by ensuring patients and physicians are well educated , but the real world is less forgiving and the reality is that up to 5% patients with type 1 diabetes will experience an episode of ketoacidosis each year , a proportion of which are fatal. A small increase in the risk of ketoacidosis might be considered acceptable if there was robust evidence that use of SGLT2 inhibitors reduced the risk of severe adverse outcomes, such as renal failure and cardiovascular disease, in type 1 diabetes but until such evidence is available, we should be very cautious about adopting SGLT2 inhibitors as adjunctive therapy to insulin in people with type 1 diabetes.
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- Neal B, Perkovic V, Mahaffey KW et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644–657.
- Kosiborod M, Cavender MA, Fu AZ et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation 2017; 136: 249–259.
- Cherney DZ, Perkins BA, Soleymanlou N et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014; 129: 587–597.
- Wanner C, Inzucchi SE, Lachin JM et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323–334.
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- 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 2015; 38: 1181–1188.
- Dandona P, Mathieu C, Phillip M et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol 2017; 5: 864–876.
- 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: 2337–2348.
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- Ferrannini E, Solini A. SGLT inhibition in T1DM-Definite benefit with manageable risk. Nat Rev Endocrinol 2017; 13: 698–699.
- Farsani SF, Brodovicz K, Soleymanlou N, Marquard J, Wissinger E, Maiese BA. Incidence and prevalence of diabetic ketoacidosis (DKA) among adults with type 1 diabetes mellitus (T1D): A systematic literature review. BMJ Open 2017; 7: e016587.