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Daily Pill Optimizes Insulin Use and Reduces A1c For Type 1 Diabetes

Dec 15, 2020
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: A'Kira Shavers,  PharmD Candidate, South College School of Pharmacy

An oral medication like TTP399 that does not increase risk of low blood sugar could provide an alternative to insulin. 

New studies have investigated a once-daily pill to optimize insulin therapy and reduce HbA1c among adults diagnosed with type 1 diabetes.  Recent research from a phase 2 Simplici-T1 trial showed a new pill known as a novel liver-selective glucokinase activator, also known as TTP399, showed a placebo-subtracted HbA1c reduction of 0.32% at 12 weeks when compared with a placebo.  Carmen Valcarce, Ph.D., chief scientific officer of vTv Therapeutics, told Healio that this might be the first adjunctive therapy that showed improved glycemic control without the increased risk of hypoglycemia.  She also suggested that the fear of hypoglycemia is what keeps many patients from achieving their target goals.  TTP399 works by selectively activating glucokinase, a key regulator of glucose metabolism in the liver.  When this activation happens, an increase in glucose utilization is present, which lowers blood glucose.  Simplici-T1 is the first study to test the actual activation of glucokinase in people with type 1 diabetes, while evaluating the once-daily oral TTP399’s effects compared to insulin therapy.   


The Simplici-T1 is a randomized, double-blind, adaptive study assessing the safety and efficacy of the TTP399 compared to insulin therapy in adults diagnosed with type 1 diabetes.  Valcarce also shared at the virtual European Association for the Study of Diabetes annual meeting that in a study of 190 participants with type 2 diabetes, TTP399 showed a reduction of HbA1c by a mean of 0.9 percent when compared to a placebo. The researchers used a dual statistical approach to evaluate the effect of 800 milligrams of TTP399 in 85 adults. The primary statistical analysis assessed the impact of the once-daily pill on HbA1c regardless of the treatment adherence and noted insulin therapy changes. The study achieved the primary objective by showing an improvement in HbA1c for TTP399 compared with placebo at week 12 (P= 0.03).   

Researchers performed a second estimated analysis to eliminate the possibility that the reduction in HbA1c was driven by excess insulin administration, which was noted at greater than three units per day. Based on this assessment, all participants treated with TTP399 achieved a placebo-subtracted decrease in HbA1c of 0.32 percent (P= 0.001).  The participants who were assigned TTP399 experienced a 0.21 percent reduction in HbA1c; those given a placebo showed a 0.11 percent increase in their HbA1c.  The average HbA1c was 7.6 percent after optimized insulin periods. The researchers stated that they did not notice any between-group differences in treatment-emergent adverse effects overall or when they stratified by organ class. Neither group experienced any DKA or severe hypoglycemia; however, there was one incident in the placebo group.  TTP399 showed a reduction in extreme and symptomatic hypoglycemic events by 40 percent in comparison to placebo.  Twenty percent assigned to placebo and 12 percent given TTP399 experienced at least one severe or symptomatic hypoglycemic event during the trial. The daily time spent in the recommended glucose range showed an improvement by approximately 2 hours among participants who received TTP399 in comparison to placebo (P= 0.03).  The group assigned to TTP399 also showed a total daily mealtime bolus insulin decrease by an average of 11 percent compared to the baseline (P= 0.02).   

This phase 2 study was directed in two parts but under the same protocol to evaluate the safety and efficacy of TTP399 for all adults with type 1 diabetes during a 12-week phase of daily dosing for a multi-week insulin optimization placebo run-in period.  Part 1 had 19 participants using insulin pump therapy and continuous glucose monitoring.  Part 2 enrolled 85 participants who used pump therapy or multiple daily injections.  Valcarce summarized in her interview with Healio that the addition of TTP399 added a new tool into the toolbox for patients diagnosed with type 1 diabetes. At this time, the only treatment is insulin, and it is not as easy to use. The new simple treatment gave a sense of comfort when worried about hypoglycemia and helped people achieve their target glucose.   

Practice Pearls:  

  • Once a day pill for type 1 diabetes helps patients increase their adherence.  
  • Once a day pill for type 1 diabetes helps decrease the fear of experiencing hypoglycemia or hypoglycemic events. 
  • It is still very beneficial for patients to continually monitor their blood sugar and A1C.   


C. Valcarce, et al. The Simplici-T1 trial: activation of glucokinase by TTP399 improvesglycaemic control in patients with type 1 diabetes. EASD oral presentation, 22. September 2020 

Schaffer, Regina. “Investigational Once-Daily Pill Reduces HbA1c in Type 1 Diabetes, without Hypoglycemia.” Healio, October 15, 2020  


A’Kira Shavers, PharmD candidate 2021, South College School of Pharmacy