New drug development: Simultaneous inhibition of SGLT-1 and SGLT-2 in type 1 diabetes

Sotagliflozin is a new inhibitor of the sodium–glucose cotransporters. Unlike jardiance, invokana and farxiga, which are primarily SGLT-2 reducers, sotagliflozin is a concomitant inhibitor of both intestinal SGLT-1 and renal SGLT-2 enzymes. 

InTandem3, a phase 3 clinical trial, evaluated sotagliflozin 400 mg/day vs. placebo in patients with type 1 diabetes. About 1,400 participants were followed for 24 weeks. By the end of the study, adults receiving sotagliflozin performed overall better than their placebo counterparts: A1c dropped by ~0.5%, weight by ~6 lbs, systolic blood pressure by ~ 4 mmHg and insulin dose by ~ 3 units/day.

Interesting to note that participants who achieved A1c < 7.0% with sotagliflozin did not experience higher rates of severe hypoglycemia or diabetic ketoacidosis, yet sotagliflozin participants with A1c > 7.0% underwent significantly more of such adverse events. I suspect that type 1 diabetic patients with very high hour-to-hour glucose variability ("highly brittle") were the ones who experienced simultaneously higher A1c, hypoglycemia and DKA.

Although A1c reduction is not too impressive, sotagliflozin could get FDA approval in the context of its other metabolic benefits; weight loss and systolic BP lowering. Patients need to be selected carefully prior to initiation of the SGLT-1 & -2 inhibitor. I anticipate that those with lower baseline glucose variability and higher BMI would benefit most.

GT

 


N  E  J  M

inTandem3, Phase 3

September 2017

Background: In most patients with type 1 diabetes, adequate glycemic control is not achieved with insulin therapy alone. We evaluated the safety and efficacy of sotagliflozin, an oral inhibitor of sodium–glucose cotransporters 1 and 2, in combination with insulin treatment in patients with type 1 diabetes.

Methods: In this phase 3, double-blind trial, which was conducted at 133 centers worldwide, we randomly assigned 1,402 patients with type 1 diabetes who were receiving treatment with any insulin therapy (pump or injections) to receive sotagliflozin (400 mg per day) or placebo for 24 weeks.

The primary end point was a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization.

Secondary end points included the change from baseline in glycated hemoglobin level, weight, systolic blood pressure, and mean daily bolus dose of insulin.

Results:

A significantly larger proportion of patients in the sotagliflozin group than in the placebo group achieved the primary end point (200 of 699 patients [28.6%] vs. 107 of 703 [15.2%], P<0.001).

The least-squares mean change from baseline was significantly greater (P≤0.002 for all comparisons) in the sotagliflozin group than in the placebo group for:

A1c (difference, −0.46 %),

Weight (−2.98 kg),

Systolic BP (−3.5 mmHg),

Mean daily bolus dose of insulin (−2.8 units/day)

The rate of severe hypoglycemia was similar in the sotagliflozin group and the placebo group (3.0% [21 patients] and 2.4% [17], respectively).

The rate of documented hypoglycemia with a blood glucose level of <55 md/dL was significantly lower in the sotagliflozin group than in the placebo group.

The rate of diabetic ketoacidosis was higher in the sotagliflozin group than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively).

Conclusions:

Among patients with type 1 diabetes who were receiving insulin, the proportion of patients who achieved a A1c lower than 7.0% with no severe hypoglycemia or diabetic ketoacidosis was larger in the group that received sotagliflozin than in the placebo group.

However, the rate of diabetic ketoacidosis was higher in the sotagliflozin group.

 


More from the publication:

The incidence of type 1 diabetes, which currently affects 29 million adults worldwide, is rising. In the United States, the number of patients with type 1 diabetes who are younger than 20 years of age may triple within 30 years.

Less than one third of adults with type 1 diabetes achieve a glycated hemoglobin level lower than 7.0%, and most are overweight or obese.

Patients with type 1 diabetes also face risks of complications or death from severe hypoglycemia and diabetic ketoacidosis. The ideal treatment for type 1 diabetes should enable patients to maintain a glycated hemoglobin level lower than 7.0% without weight gain or an increased risk of hypoglycemia and diabetic ketoacidosis.

Sotagliflozin (LX4211) is a new oral inhibitor of sodium–glucose cotransporters 1 and 2 (SGLT1 and SGLT2).

SGLT1 inhibition reduces glucose absorption in the proximal intestine, which significantly blunts and delays postprandial hyperglycemia.

SGLT2 inhibition decreases proximal renal glucose reabsorption.

In phase 2 studies, the administration of sotagliflozin improved glycemic control and lowered body weight among patients with type 1 or 2 diabetes; it also reduced glycemia, despite a decreased bolus dose of insulin, among patients with type 1 diabetes.

No oral medication has been approved for use in combination with insulin to lower the glucose level in patients with type 1 diabetes.

We report the results of the inTandem3 trial, a phase 3 clinical trial that assessed the effects of sotagliflozin as compared with placebo with respect to glycemic control and the occurrence of severe hypoglycemia and diabetic ketoacidosis among adults with type 1 diabetes who were receiving their usual insulin therapy.

In the inTandem3 trial involving patients with type 1 diabetes who were receiving any approved insulin, the percentage of patients who achieved the primary end point of a glycated hemoglobin level lower than 7.0% at week 24 and no episode of severe hypoglycemia or diabetic ketoacidosis was higher in the group that received sotagliflozin than in the placebo group (28.6% vs. 15.2%). However, the rates of diabetic ketoacidosis and hypoglycemia were higher in the sotagliflozin group than in the placebo group. The use of sotagliflozin was also associated with significant decreases in A1c level, fasting plasma glucose level, insulin dose, weight, and systolic blood pressure.

Roughly two thirds of adult patients with type 1 diabetes have a glycated hemoglobin level of 7.0% or higher, and up to two thirds are overweight or obese. The baseline characteristics of the patients in our trial are consistent with these data; 71% of the patients had a baseline BMI of 25 or higher, and by design, all patients who underwent randomization had a glycated hemoglobin level of 7.0% or higher at screening.

Reductions in the glycated hemoglobin level are usually associated with an increased incidence of hypoglycemia and weight gain.

However, the target glycated hemoglobin level (<7.0%) was achieved in approximately twice as many patients in the sotagliflozin group as in the placebo group, and the target level was achieved without weight gain in three times as many patients in the sotagliflozin group as in the placebo group.

In phase 2 trials, sotagliflozin, empagliflozin, and canagliflozin were associated with significant decreases in the glycated hemoglobin level among patients with type 1 diabetes. The design of our phase 3 trial allowed us to evaluate the effects of sotagliflozin in combination with insulin therapy in a setting that resembles day-to-day clinical practice. By week 24, the difference between the sotagliflozin group and the placebo group in the reduction of the glycated hemoglobin level from baseline was 0.46 percentage points.

Slightly more patients in the sotagliflozin group than in the placebo group had severe hypoglycemia (21 and 17 patients, respectively), but the event rate (the rate per person-year) of documented hypoglycemia, with a threshold for blood glucose level of either ≤70 or ≤55 mg/dL was lower in the sotagliflozin group than in the placebo group.

Modest but significant weight loss occurred in the sotagliflozin group, possibly because of increased glycosuria, reduced insulin doses, or other unknown factors. Sotagliflozin treatment also led to significant reductions in blood pressure.

Other randomized, controlled trials that have evaluated the adjunctive use of liraglutide, sitagliptin, and metformin in patients with type 1 diabetes have not shown consistent or sustained reductions in the glycated hemoglobin level or have shown increases in episodes of severe hypoglycemia or diabetic ketoacidosis. The use of off-label adjunctive therapy is uncommon, and the only therapy other than insulin that is approved for the treatment of type 1 diabetes is injectable pramlintide, which modestly reduces the glycated hemoglobin level and weight but is associated with an increased risk of severe hypoglycemia and is thus used infrequently. Reductions in the glycated hemoglobin level, systolic blood pressure, and weight must be maintained for a long-term period to reduce the risk of complications associated with diabetes, but mean changes in these outcomes may be less robust in short-term studies.

Therefore, the decision to use adjunctive therapy can currently be based only on clinical assessment of metabolic needs in patients in whom insulin alone is unlikely to be sufficiently effective.

In our trial, the addition of sotagliflozin to existing insulin regimens improved glycemic control and led to reductions in the total, bolus, and basal doses of insulin. A decrease in insulin dose may be a risk factor for diabetic ketoacidosis.

Regulatory authorities have required that warnings about diabetic ketoacidosis be added to prescribing labels for the SGLT2 inhibitor class, because these agents have been associated with diabetic ketoacidosis in patients with type 1 or type 2 diabetes. When SGLT inhibitors are administered, monitoring for ketosis, particularly during metabolically stressful situations, is required. SGLT inhibitors should be discontinued before scheduled surgical procedures, and patients and clinicians should remain in close consultation regarding other forms of behavioral and physiological stress.

Diabetic ketoacidosis may occur more frequently among those who use an insulin pump, because of kinked catheters, infusion-set problems, and other operational failures, and therefore, those who use an insulin pump may require closer monitoring.

Our trial has some limitations. First, the long-term effects of sotagliflozin cannot be determined from this 24-week trial. Second, data on glycated hemoglobin levels were masked to investigators after screening to make the trial design consistent with other trials of sotagliflozin, and if investigators had had access to the data, they may have adjusted insulin therapy more aggressively to meet target glycated hemoglobin levels. Third, this trial employed measures to mitigate the risk of diabetic ketoacidosis that may have been more intensive than those used in typical clinical practice. Fourth, reductions in the glycated hemoglobin level, fasting plasma glucose level, and episodes of documented hypoglycemia suggest decreased glucose variability, but data from continuous glucose monitoring were not analyzed in this trial. Blinded data from continuous glucose monitoring will be analyzed in the recently completed inTandem1 and inTandem2 trials. Fifth, no artificial pancreas system had been approved at the time of trial initiation. Since sotagliflozin treatment was associated with a decrease in insulin dose, its use in patients who use a currently approved artificial pancreas system may require further evaluation.

In summary, among adult patients with type 1 diabetes who were receiving insulin therapy, the proportion of patients who achieved a glycated hemoglobin < 7.0% and had no severe hypoglycemia or diabetic ketoacidosis was larger in the group that received sotagliflozin than in the placebo group.

However, the rates of diabetic ketoacidosis and severe hypoglycemia were HIGHER among patients who received sotagliflozin, but did not achieve the target glycated hemoglobin level than among those who received placebo.