Type 1 diabetes (T1D) is characterized by the complete loss of insulin production, and thus insulin replacement serves as the backbone of our therapeutic approach to this disease. Unfortunately, despite increasing utilization of several novel insulin delivery systems and continuous glucose monitoring (CGM) over the past few years, only 17% of youth and 21% of adults are able to achieve their hemoglobin A1c (HbA1c) goals, which, in turn, leads to an increased risk of diabetes-associated micro- and macrovascular complications.1 Yet intensification of insulin therapy is often limited by the associated risks of severe hypoglycemia and weight gain. At least 12% of US adults with T1D experience severe hypoglycemia over the course of one year.2 An additional concern is weight gain linked to increased insulin doses, with the prevalence of overweight and obesity in those with T1D increasing from 48% in young adults to 68% in those over the age of 50.1 The consequences of increased body mass index (BMI) in this population are concerning, since T1D already confers a high baseline risk of cardiovascular disease.3 In fact, data from one epidemiologic study showed that life expectancy is reduced by 11-13 years in patients with T1D, largely attributable to deaths from ischemic heart disease.4

Given the limitations and suboptimal outcomes of current approaches to treating T1D, adjunctive therapies with non-insulin agents used in type 2 diabetes (T2D) have been studied for years, the goal being to improve glycemic control and lower insulin requirements. One example is the sodium-glucose cotransporter inhibitors (SGLTi), which have been suggested as potentially useful when paired with insulin in T1D patients. Firstly, their mechanism of action is independent of insulin action and so should be effective in all types of diabetes and at all stages of disease. Specifically, SGLT2 is responsible for 90% of glucose reabsorption in the proximal tubule of the kidneys, with SGLT1 having a lesser role in the kidney and facilitating glucose absorption in the small intestine.5,6 Blockade of SGLT2, therefore, increases glucosuria and results in glucose-lowering and weight loss with minimal hypoglycemia while inhibition of SGLT1 reduces intestinal glucose transit, with both blunting postprandial hyperglycemia.5,6 Perhaps more importantly, several members of the SGLTi class have been shown to reduce heart failure hospitalizations, decrease the rates of major adverse cardiovascular events (including cardiovascular mortality), and slow the progression of chronic kidney disease (CKD) in patients with T2D.7 Moreover, these clinically significant cardiovascular and renal benefits appear to be independent of baseline HbA1c and body weight and have also been demonstrated in patients without diabetes, such as in heart failure and CKD populations.8, 9, 10, 11 As a result, SGLT2i are now part of the guideline-directed therapeutic approaches to improving outcomes in heart failure and CKD, irrespective of the presence or absence of diabetes.12, 13, 14 Although T1D patients were either specifically excluded (due to concerns regarding the risk of ketoacidosis) or minimally represented in the trials that identified these cardiovascular and renal benefits, it is tempting to extrapolate their findings to this population.

Given the potential for SGLTi to address several unmet needs in the treatment of T1D, several double-blind, placebo-controlled, randomized controlled trials have been conducted to investigate the benefits and risks of using these agents as an adjunct to insulin therapy in this population.