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What Happens When You Have Two SGLT Inhibitors: SGLT-1 + SGLT-2 = ?

New dual drug could be a diabetes breakthrough.

If we look at the science behind the SGLT-2 inhibitors, theoretically it should cause an excretion of 160g of glucose daily, but clinically we are only seeing 50% of the predicted glucose being excreted.  We assume that it is because of other compensatory reabsorption by the SGLT-1 site.  So what will happen if we have a combination product of SGLT-1 and a SGLT-2 inhibitor?

Enter sotagliflozin, Lexicon Pharmaceuticals’ dual SGLT-inhibitor in Phase 3 studies. But, first let’s review what we already know about the single entity, the SGLT-2 inhibitor, that is already a blockbuster drug.

New type 2 diabetes challengers have emerged over the past three years. These new challengers — Johnson & Johnson’s Invokana, AstraZeneca’s Farxiga, and Eli Lilly and Boehringer Ingelheim’s Jardiance — are part of a new class of drugs known as SGLT-2 inhibitors. Instead of working through the pancreas and liver, as prior diabetes medications have, SGLT-2 inhibitors block the absorption of glucose in the kidneys, allowing patients to excrete excess glucose through their urine.

What’s different about SGLT-2s is that they also demonstrated the intriguing side effects of weight loss and reduced systolic blood pressure. Again, with weight and hypertension being common issues among type 2 diabetes patients, this could give these drugs preference among physicians over the likes of Januvia.  Plus, AACE has already given their approval to use it as the first drug of choice for newly diagnosed type 2 patients and we are seeing studies looking at its use for type 1 diabetes.

Further setting the stage for the SGLT-2 drugs was the data release from Eli Lilly and Boehringer Ingelheim detailing superior long-term cardiovascular outcome results for Jardiance, which led to a 32% relative reduction in all-cause risk of death.

If an SGLT-2 inhibitor can do all this, what can the addition of an SGLT-1 inhibitor do?

The drug, known as sotagliflozin, is a brand-new duo SGLT-inhibitor. But instead of solely targeting SGLT-2 within the kidneys, it also targets SGLT-1 inhibitors located in the intestinal tract. Both inhibitors work to block glucose absorption, which should presumably lead to improved glycemic balance. Sotagliflozin inhibits both sodium-glucose cotransporter type 2, or SGLT2, a transporter responsible for most of the glucose reabsorption performed by the kidney, and sodium-glucose cotransporter type 1, or SGLT1, a transporter responsible for glucose and galactose absorption in the gastrointestinal tract, and to a lesser extent than SGLT2, glucose reabsorption in the kidney. Our scientists identified mice lacking SGLT1, SGLT2 or both as having potent anti-diabetic phenotypes across multiple measures of glucose control and metabolism, and found that compounds inhibiting both targets had a favorable preclinical profile relative to compounds selective for SGLT2.

Lexicon Pharmaceuticals, Inc. announced that its pivotal inTandem2 Phase 3 clinical trial of sotagliflozin met its primary endpoint, showing a statistically significant reduction in A1C at 24 weeks in patients with type 1 diabetes on optimized insulin therapy.

The double-blind, placebo controlled, Phase 3 study known as inTandem2 randomized 782 adult patients with type 1 diabetes on insulin pump or multiple daily injection therapy who had an A1C level entering the study between 7.0% and 11.0%.  The three-arm study evaluated two doses of sotagliflozin, 200mg and 400mg, each taken once daily before the first meal of the day, against placebo.  Prior to randomization, insulin was optimized for all patients over a six-week period, with the objective of improving glycemic control using insulin alone.  After completion of this optimization period, patients were maintained on optimized insulin and randomized to one of two doses of sotagliflozin or placebo, and their baseline, post-optimization A1C was measured.  The mean baseline A1C levels after the six-week optimization period were 7.80%, 7.74% and 7.71% for patients randomized to the placebo, 200mg and 400mg arms, respectively.  

The primary endpoint of the study was change in A1C from baseline after a 24-week period of treatment. The trial has a double-blind long-term extension of 28 weeks, with a total treatment duration of 52 weeks. There were 257 patients in the placebo arm, 261 patients in the 200 mg dose arm and 263 patients in the 400 mg dose arm. The overall mean placebo-adjusted A1C reduction at week 24 was 0.36% in the 200 mg dose arm (p<0.001) and 0.35% in the 400 mg dose arm (p<0.001).

Top-line results from Lexicon’s type 1 diabetes study showed an average A1C reduction of 0.43% from the baseline with a once-daily 200 mg dose and a 0.49% A1C reduction with a once-daily 400 mg dose. The statistically significant improvement met the study’s primary endpoint and likely sets sotagliflozin up for an approval to treat type 1 diabetes.

If your patient has diabetes (type 1 or type 2), the success of sotagliflozin in its phase 3 trial for type 1 diabetes is encouraging. Sotagliflozin could provide differentiation from the SGLT-2 inhibitors, giving consumers a new option to fight diabetes. With an FDA approval in type 1 diabetes looking likely based on its phase 3 top-line data, all eyes can now turn to its late-stage type 2 diabetes trials.

Practice Pearls:

  • Sotagliflozin could provide differentiation from the SGLT-2 inhibitors, giving consumers a new option to fight diabetes.
  • Sotagliflozin significantly improved glycemic control, without increasing the rate of hypoglycemia measurements.
  • This sotagliflozin-mediated improvement in glycemic control was comparable to that achieved by raising the insulin dose alone, but was not accompanied by the increased rate of hypoglycemia measurements observed with the higher insulin dose.

 

Diabetes Metab Syndr Obes. 2015; 8: 121–127.