Can Addition of Pioglitazone to SGLT2 Inhibitor in Type 1 Diabetic Patients Amplify the Decrease in HbA1c and Prevent the Increase in Plasma Ketone Concentration?

Insulin deficiency, due to autoimmune destruction of beta cells, is the primary factor responsible for the development of T1DM, and insulin replacement therapy is the mainstay for the management of hyperglycemia. However, insulin therapy often is associated with adverse events, including weight gain which promotes insulin resistance leading to an increase in insulin demand. This results in a self-perpetuating vicious cycle whereby the increase in insulin dose causes weight gain that worsens insulin sensitivity, and further enhances insulin requirement. Hyperinsulinemia per se also induces insulin resistance.

To break this cycle, adjunctive therapies have been added to insulin in T1DM patients to lower the plasma glucose concentration. However, the addition of metformin, pioglitazone, and GLP-1 agonists to insulin in T1DM patients have not provided convincing evidence for a clinically meaningful reduction in the HbA1c or significant reduction in daily insulin dose.

SGLT2 inhibitors (SGLT2i) are a novel class of antidiabetic agents which reduce the plasma glucose concentration by inhibiting renal glucose reuptake and producing glucosuria. Because of this unique mechanism of action, which is independent of insulin secretion and insulin action, SGLT2i have proven to be very effective in lowering the plasma glucose concentration in T1DM. Initial proof of concept studies have demonstrated that, compared to placebo, all members of this class (dapagliflozin, empagliflozin, canagliflozin and sotagliflozin) effectively lower the plasma glucose concentration, HbA1c and daily insulin dose in T1DM without increased risk of hypoglycemia. Further, SGLT2i improved cardiovascular risk factors in T1DM by promoting weight loss and decreasing blood pressure.

Despite the promising potential for SGLT2i as adjunctive therapy to insulin in T1DM, recent large clinical trials have demonstrated two important limitations to this therapeutic strategy: First, although the decrease in HbA1c caused by SGLT2i in T1DM patients was statistically significant, the absolute decrease was relatively modest (0.30-0.45%). The investigators, previously have shown that SGLT2i stimulate an increase in the basal rate of hepatic glucose production (HGP) in T2DM patients. This SGLT2i-induced increase in HGP offsets by approximately one half the amount of glucose lost in the urine. Therefore, the investigators have hypothesize that, similar to what they have observed in T2DM patients, the addition of SGLT2i to insulin in T1DM patients stimulates HGP thereby attenuating the decrease in HbA1c. Further, the decrease in daily insulin dose after initiating therapy with SGLT2i in T1DM patients would be expected to enhance the increase in HGP and diminish the decrease in HbA1c. Thus, preventing the increase in HGP caused by SGLT2i in T1DM can be expected to markedly amplify the clinical efficacy of SGLT2i and enhance the reduction in HbA1c.

A second limitation of the use of SGLT2i an adjunct therapy to insulin in T1DM patients is the increase in diabetic ketoacidosis (DKA) risk. In three large clinical trials , the addition of SGLT2i to insulin in T1DM patients was associated with a 3-6% increase in DKA risk (see Table 1 below). Because of the significant morbidity and mortality associated with DKA, the increased DKA risk in T1DM has raised concerns about the use of SGLT2i as an adjunct therapy to insulin in T1DM patients despite their multiple metabolic benefits.