Sotagliflozin in Conjunction with Insulin for Type 1 Diabetes Reduces Average Blood Glucose Levels

One-year results of North American inTandem1 study show decreased HbA1c levels and lower risk of severe hypoglycemia

News provided by

Jun 24, 2018, 04:00 ET

ORLANDO, Fla., June 24, 2018 /PRNewswire-USNewswire/ -- People with type 1 diabetes (T1D) who take 200 mg or 400 mg of sotagliflozin in addition to optimized insulin therapy have statistically lower HbA1c levels and weight, as well as low incidence of severe hypoglycemia after a year of treatment, compared to those who take a placebo with optimized insulin, according to the study, "Fifty-Two-Week Efficacy and Safety of Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Adults with Type 1 Diabetes (inTandem1)," presented today at the American Diabetes Association's^® (ADA's) 78th Scientific Sessions^® at the Orange County Convention Center. The study results are outlined in detail in an article published online today in Diabetes Care, the ADA's peer-reviewed research journal dedicated to diabetes treatment and prevention.

Sotagliflozin is an investigational dual inhibitor of sodium glucose transport proteins 1 and 2 (SGLT1 and SGLT2)—two proteins responsible for glucose regulation. Inhibition of SGLT1 delays and reduces glucose absorption in the proximal intestine, improving postprandial (post meal) glycemic control. SGLT2 inhibition results in loss of glucose into the urine. Sotagliflozin is the first dual SGLT1/SGLT2 inhibitor to be extensively studied in humans.

The inTandem1 study, a double-blind, phase 3 trial conducted at 75 sites in the U.S. and Canada, compared the safety and efficacy of two different doses of oral sotagliflozin—each used in addition to optimized insulin—to optimized insulin alone. The study enrolled a total of 793 adults with T1D who used an insulin pump or were on multiple-injection therapy (meaning they used one or two injections of long-acting insulin along with injections of rapid or short-acting insulin before each meal throughout a 24-hour period). The participants had HbA1c levels between 7.0 and 11 percent prior to the study. After six weeks of insulin optimization, participants were randomly assigned to one of three groups: 268 received a placebo; 263 received 200 mg of sotagliflozin; and 262 received 400 mg of sotagliflozin, each taken once daily before the first meal of the day.

In 2017, a comparison of the treatment groups after 24 weeks was reported, and the results for the primary endpoints of inTandem 1, 2 and 3 were disclosed. After 24 weeks, HbA1c levels, body weight and systolic blood pressure were significantly reduced with sotagliflozin added to optimized insulin compared to optimized insulin alone.

This latest study investigated the effects of the treatment for a total of 52 weeks and evaluated change in average blood glucose (HbA1c levels) and body weight, as well as safety. After 52 weeks, patients who received sotagliflozin in addition to optimized insulin had sustained reduction in HbA1c levels and body weight, and lower total daily insulin dose compared to optimized insulin alone.

Sotagliflozin use was also associated with fewer low blood glucose events requiring assistance (severe hypoglycemia), despite lower average blood glucose. A total of 17 participants, each from the 200 mg sotagliflozin and 400 mg groups (6.5 percent from each group), reported episodes of severe hypoglycemia compared to 26 participants (9.7 percent) from the placebo group, who reported severe hypoglycemia events.

Researchers noted that there is an increased risk of diabetic ketoacidosis (DKA) through SGLT2 inhibition, and the study results showed that DKA was seen in a greater proportion of patients treated with sotagliflozin added to optimized insulin than those patients treated with optimized insulin alone. Of the participants, nine patients (3.4 percent) from the 200 mg group and 11 patients (4.2 percent) in the 400 mg group experienced DKA compared to one patient (0.4 percent) from the placebo group. According to the study authors, this increased risk of DKA could potentially be managed with patient education and increased monitoring.

Overall, the data indicated that more of the patients taking sotagliflozin added to optimized insulin therapy achieved the combined goal (the net clinical benefit) of an average blood glucose below the ADA-recommended target without severe hypoglycemia and without DKA. For net clinical benefit, 69 patients (26.2 percent) from the 200 mg group and 85 (32.4 percent) from the 400 mg group achieved this endpoint compared to 51 (19 percent) from the placebo group at 52 weeks.

"More than 1.25 million adults in the U.S. live with T1D, and more than 75 percent of these people who use insulin alone have blood glucose levels above target," said lead study investigator John Buse, MD, PhD, director of the Diabetes Center, director of the NC Translational and Clinical Sciences Institute, and executive associate dean for clinical research at the University of North Carolina School of Medicine in Chapel Hill. "Despite recent advances, the challenges of T1D management, specifically hypoglycemia or fear of hypoglycemia, weight gain, glucose variability and patient burden, prevent many patients from reaching their treatment goals. The profile of sotagliflozin to improve glucose control beyond what can be achieved with intensified insulin alone while addressing these challenges has the potential to improve the lives of people with T1D."

To speak with Dr. Buse, please contact the ADA Press Office on-site at the Orange County Convention Center on June 22 - 26, by phone at 407-685-4010 or by email at [email protected].

The American Diabetes Association's 78th Scientific Sessions, to be held June 22-26, 2018, at the Orange County Convention Center in Orlando, is the world's largest scientific meeting focused on diabetes research, prevention and care. During the five-day meeting, more than 16,000 health care professionals from around the world will have exclusive access to more than 3,000 original diabetes research presentations, participate in provocative and engaging exchanges with leading diabetes experts, and can earn Continuing Medical Education (CME) or Continuing Education (CE) credits for educational sessions. The program is grouped into eight theme areas: Acute and Chronic Complications; Behavioral Medicine, Clinical Nutrition, Education and Exercise; Clinical Diabetes/Therapeutics; Epidemiology/Genetics; Immunology/Transplantation; Insulin Action/Molecular Metabolism; Integrated Physiology/Obesity; and Islet Biology/Insulin Secretion. Felicia Hill-Briggs, PhD, ABPP, President of Health Care and Education, will deliver her address, "The American Diabetes Association in the Era of Health Care Transformation," on Saturday, June 23, and Jane E.B. Reusch, MD, President of Medicine and Science, will present her address, "24/7/365 – Lifetime with Diabetes," on Sunday, June 24. In total, the 2018 Scientific Sessions includes 375 oral presentations; 2,117 poster presentations, including 47 moderated poster discussions; and 297 published-only abstracts. Join the Scientific Sessions conversation on social media using #2018ADA.

About the American Diabetes Association
Nearly half of American adults have diabetes or prediabetes; more than 30 million adults and children have diabetes; and every 21 seconds, another individual is diagnosed with diabetes in the U.S. Founded in 1940, the American Diabetes Association (ADA) is the nation's leading voluntary health organization whose mission is to prevent and cure diabetes, and to improve the lives of all people affected by diabetes. The ADA drives discovery by funding research to treat, manage and prevent all types of diabetes, as well as to search for cures; raises voice to the urgency of the diabetes epidemic; and works to safeguard policies and programs that protect people with diabetes. In addition, the ADA supports people living with diabetes, those at risk of developing diabetes, and the health care professionals who serve them through information and programs that can improve health outcomes and quality of life. For more information, please call the ADA at 1-800-DIABETES (1-800-342-2383) or visit diabetes.org. Information from both of these sources is available in English and Spanish. Find us on Facebook (American Diabetes Association), Twitter (@AmDiabetesAssn) and Instagram (@AmDiabetesAssn).

212-OR

Fifty-Two-Week Efficacy and Safety of Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as
Adjunct Therapy to Insulin in Adults with Type 1 Diabetes (inTandem1)

78th Scientific Sessions
News Briefing: Adjunctive Therapies in Type 1 and Type 2 Diabetes, Sunday, June 24, 7:15 a.m., ET

Session Type: Oral Presentations
Session Title: Clinical Trials in Type 1 Diabetes
Location: W308
Session Time: Sunday, June 24, 2018, 2:15 pm - 4:15 pm

JOHN B. BUSE, SATISH K. GARG, JULIO ROSENSTOCK, TIMOTHY S. BAILEY, PHILLIP L. BANKS, BRUCE W. BODE, THOMAS DANNE, JAKE A. KUSHNER, WENDY LANE, PABLO LAPUERTA, DARREN K. MCGUIRE, ANNE L. PETERS, JOHN H. REED, SANGEETA SAWHNEY, PAUL STRUMPH, Chapel Hill, NC, Aurora, CO, Dallas, TX, Escondido, CA, The Woodlands, TX, Atlanta, GA, Hannover, Germany, Houston, TX, Asheville, NC, Basking Ridge, NJ, Los Angeles, CA, Roswell, GA

Sotagliflozin (SOTA) is a dual SGLT1 and SGLT2 inhibitor in development as adjunct therapy to insulin in T1D. In this double-blind, 52-week North American trial, 793 adults with T1D treated with multiple daily insulin injections (40%) or pump (60%) were randomized 1:1:1 to placebo (n=268), SOTA 200 mg (n=263) or SOTA 400 mg (n=262) once daily after 6 weeks of insulin optimization. Primary endpoint was change from baseline in A1C at Week 24. Other endpoints included A1C, weight, bolus insulin and FPG changes at Week 52, patient (pt) reported outcomes and net clinical benefit (NCB), assessing the proportion of pts with A1C <7.0% without severe hypoglycemia (SH) or diabetic ketoacidosis (DKA).

Baseline characteristics were similar between groups. Compared with placebo, SOTA 200 and 400 mg improved A1C and pt satisfaction at Week 24 and reduced A1C, weight, bolus insulin, FPG and pt distress at Week 52. More pts achieved NCB with SOTA vs. placebo (each P<0.05; Table). The highest incidence of SH was in the placebo arm; more genital mycotic infections, diarrhea and DKA events (more with pump than MDI) were in the SOTA arms (Table).

In conclusion, SOTA 200 and 400 mg were associated with statistically significant A1C reductions that were sustained (P<0.05) at Week 52, with an increased (but low) rate of DKA, and a lower incidence of SH, when compared with placebo.

Efficacy (mITT population) and Safety (safety population) Results
	Placebo n=268	SOTA 200 mg n=263	SOTA 400 mg n=262
Mean A1C at Baseline, after 6-week insulin optimization, %	7.54	7.61	7.56
Outcomes at Week 24
A1C LSM difference from placebo, % ± SE (P- value)	-	-0.36±0.05(<0.001)	-0.41±0.05 (<0.001)
Outcomes at Week 52
A1C LSM difference from placebo, % ± SE (P-value)	-	-0.25±0.06 (P<0.001)	-0.31±0.06 (P<0.001)
FPG LSM difference from placebo, mmol/L ± SE	-	-0.68±0.31 (P=0.028)	-1.08±0.31 (P<0.001)
Body weight LSM difference from placebo, kg ± SE (P-value)	-	-3.14±0.34 (P<0.001)	-4.32±0.35 (P<0.001)
Mean daily bolus insulin dose at Baseline, IU	31.7	30.3	30.8
Bolus insulin dose mean change from Baseline, % ± SE	7.01±3.40	-1.48±3.40	-8.63±3.42
Bolus insulin dose LSM difference from placebo, % ± SE (P-value)	-	-5.53±4.59 (P=0.23)	-15.63±4.60 (P<0.001)
Net clinical benefit at Week 52
A1C <7.0% without SH and without DKA, n (%)	51 (19.0)	69 (26.2)	85 (32.4)
Safety outcomes over 52 weeks
Any TEAE, n (%)	216 (80.6)	215 (81.7)	209 (79.8)
TEAEs leading to study discontinuation, n (%)	11 (4.1)	13 (4.9)	17 (6.5)
Treatment-emergent serious adverse events, n (%)	20 (7.5)	27 (10.3)	29 (11.1)
Death, n (%)	1 (0.4)	0	0
DKA, n (%)¹	1 (0.4)	9 (3.4)	11 (4.2)
Severe hypoglycemia, n (%)¹	26 (9.7)	17 (6.5)	17 (6.5)
Diarrhea², n (%)	18 (6.7)	22 (8.4)	27 (10.3)
Genital mycotic infection, n (%)	9 (3.4)	24 (9.1)	34 (13.0)
Patient reported outcomes
DTSQ score LSM difference from placebo at Week 24 ± SE (P-value)	-	2.5±0.40 (P<0.001)	2.5±0.40 (P<0.001)
DDS2 score LSM difference from placebo at Week 52 ± SE (P-value)	-	-0.4±0.15 (P=0.003)	-0.5±0.15 (P<0.001)
DDS2, two-item Diabetes Distress Screening Scale (positive scores indicate improvement); DKA, diabetic ketoacidosis; DTSQ, diabetes treatment satisfaction questionnaire; FPG, fasting plasma glucose; LSM, least squares mean; mITT, modified intent-to-treat; SD, standard deviation; SE, standard error; SH, severe hypoglycemia; SOTA, sotagliflozin; TEAE, treatment emergent adverse events. ¹Positively-adjudicated events (defined as an adjudicator assessment of yes/certainly or yes/probably); ²Discontinuation of drug due to diarrhea was: 0.4% placebo, 0% SOTA 200 mg, and 0.4% SOTA 400 mg.

Author Disclosures: J.B. Buse: Other Relationship; Self; ADOCIA, AstraZeneca, Dexcom, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Fractyl Laboratories, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Metavention, NovaTarg, Novo Nordisk A/S, Sanofi, VTV Therapeutics. Research Support; Self; Boehringer Ingelheim GmbH, Johnson & Johnson Services, Inc., Theracos, Inc.. Other Relationship; Self; Shenzhen Hightide Biopharmaceutical, Ltd.. Research Support; Self; National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences. Other Relationship; Self; National Institute of Diabetes and Digestive and Kidney Diseases, American Diabetes Association. Research Support; Self; Patient-Centered Outcomes Research Institute. Other Relationship; Self; National Institute of Environmental Health Sciences. S.K. Garg: Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Sanofi US. Advisory Panel; Self; Sanofi US. Research Support; Self; MannKind Corporation, Diasome Pharmaceuticals, Inc., Labstyle Innovations, Lexicon Pharmaceuticals, Inc., Medtronic. Advisory Panel; Self; Novo Nordisk A/S. J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc. T.S. Bailey: Research Support; Self; Abbott. Consultant; Self; Abbott. Speaker's Bureau; Self; Abbott. Research Support; Self; Ambra BioScience, Ascensia Diabetes Care, Becton, Dickinson and Company. Consultant; Self; Becton, Dickinson and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Calibra Medical. Consultant; Self; Calibra Medical. Research Support; Self; Companion Medical, Dexcom, Inc., Glooko, Inc., GlySens Incorporated, Lexicon Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Medtronic MiniMed, Inc.. Consultant; Self; Medtronic MiniMed, Inc.. Speaker's Bureau; Self; Medtronic MiniMed, Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Senseonics. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Versartis, Inc., Xeris Pharmaceuticals, Inc., MannKind Corporation. P.L. Banks: Employee; Self; Lexicon Pharmaceuticals, Inc. B.W. Bode: Research Support; Self; Abbott. Advisory Panel; Self; ADOCIA. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Research Support; Self; GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk Inc., Diasome Pharmaceuticals, Inc., Sanofi US, Eli Lilly and Company, MannKind Corporation, Dexcom, Inc., OmniPod, Senseonics. T. Danne: Speaker's Bureau; Self; A. Menarini Diagnostics. Advisory Panel; Self; Abbott, AstraZeneca, Bayer AG, Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Dexcom, Inc.. Research Support; Self; Eli Lilly and Company. Stock/Shareholder; Self; DreaMed Diabetes, Ltd.. Research Support; Self; Insulet Corporation. Speaker's Bureau; Self; Menarini Group. J.A. Kushner: Advisory Panel; Self; Lexicon Pharmaceuticals, Inc.. Consultant; Self; KNOW Foods, Inc. W. Lane: Advisory Panel; Self; Novo Nordisk A/S, Insulet Corporation, Intarcia Therapeutics, Inc., Sanofi. Research Support; Self; Novo Nordisk A/S, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Sanofi, Dexcom, Inc.. Speaker's Bureau; Self; Novo Nordisk A/S, Insulet Corporation. P. Lapuerta: Employee; Self; Lexicon Pharmaceuticals, Inc.. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc., Merck & Co., Inc. D.K. McGuire: Consultant; Self; AstraZeneca, Sanofi-Aventis, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi-Aventis, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Lexicon Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Esperion Therapeutics. A.L. Peters:Advisory Panel; Self; Abbott, Bigfoot Biomedical. Research Support; Self; Dexcom, Inc.. Advisory Panel; Self; Eli Lilly and Company, Insulin Algorithms, JDRF, Lexicon Pharmaceuticals, Inc., Livongo Health. Research Support; Self; MannKind Corporation. Other Relationship; Self; Medscape. Advisory Panel; Self; Merck & Co., Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Omada Health, Inc., Optum Rx, Inc., Sanofi. Research Support; Self; T1D Exchange. Advisory Panel; Self; The Endocrine Society. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust. Advisory Panel; Spouse/Partner; Johnson & Johnson Diabetes Institute, LLC.. J.H. Reed: None. S. Sawhney: Employee; Self; Lexicon Pharmaceuticals, Inc.. Stock/Shareholder; Spouse/Partner; GlaxoSmithKline plc., AstraZeneca, Pfizer Inc., Eli Lilly and Company, Novartis Pharmaceuticals Corporation. P. Strumph: Employee; Self; Lexicon Pharmaceuticals, Inc.. Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc.. Board Member; Self; College Diabetes Network.

Press Office in Orlando
June 22 - 26, 2018
407-685-4010

Contact:
Michelle Kirkwood
(703) 299-2053
[email protected]

SOURCE American Diabetes Association