Metabolic, Intestinal, and Cardiovascular Effects of Sotagliflozin Compared With Empagliflozin in Patients With Type 2 Diabetes: A Randomized, Double-Blind Study

Design

Exploratory phase 2a, single-center, randomized, double-blind, double-dummy, active-control, parallel-group study

N= 41

Objective

To compare sotagliflozin with empagliflozin, the sodium–glucose cotransporter (SGLT) 2 inhibitor most selective for SGLT2, in patients with type 2 diabetes (T2D) and hypertension to assess changes in multiple intestinal, metabolic, and cardiovascular parameters

Study Groups

Empagliflozin (n= 20)

Sotagliflozin (n= 21)

Inclusion Criteria

Patients ages 18-74 with T2D, body mass index (BMI) 18.0-38.0 kg/m², hypertension grades 1 or 2 by European Society of Hypertension/European Society of Cardiology (BP 140/90 - 179/109 mmHg), HbA_1c  6.5% - 11.0% , eGFR ≥60 mL/min/1.73 m², currently on a stable dose of metformin, and monotherapy with either an angiotensin-converting enzyme inhibitor (ACE) or angiotensin II receptor blocker (ARB)

Exclusion Criteria

Severe anemia, cardiovascular disease, stage 3 or higher chronic kidney disease, New York Heart Association stage III or IV heart failure, or a myocardial infarction within the past 12 months

Methods

After screening and a washout period, all patients were confined at a study unit for 6 days at baseline at week 8. Ambulatory BP monitoring and continuous glucose monitoring were recorded throughout both periods; 48 h feces and 24 h urine samples were collected twice at the end of each period; and transthoracic echocardiograms and pulse wave velocity were evaluated once each during the periods. Timed blood samples were obtained for the measurement of plasma glucose, insulin, intact proinsulin, C-peptide, glucagon, active GLP-1 (aGLP-1), total GLP-1 (tGLP-1), PYY, and GIP. 

Subjects were randomly assigned to sotagliflozin 400 mg (given as two 200-mg tablets) or empagliflozin 25 mg, taken once daily at 8:00 a.m. for 8 weeks.

Duration

March 2018 - April 2019

Treatment was given for 8 weeks

Outcome Measures

Primary outcome: Change from baseline in laboratory values from urine, fecal, and mixed-meal tolerance tests (MMTT) collections

Secondary outcome: Change in baseline from cardiovascular and renal parameters

Baseline Characteristics

Sotagliflozin (n= 21)

Empagliflozin (n= 20)

Age, years

Female

HbA_{1c, %}

BMI, kg

Total daily dose of metformin, mg

ACEi use

ARB use

Results

Sotagliflozin (n= 21)

Empagliflozin (n= 20)

LS mean difference, sotagliflozin vs. empagliflozin (95% CI); p-value

Glucose, h·mmol/L

p-Value

−4.0 (−5.5 to −2.3)

<0.0001

−2.5 (−4.0 to −0.9)

0.0028

Insulin, h·pmol/L

p-Value

−533 (−666 to −399)

<0.0001 

−280 (−414 to −147)

0.0002 

Proinsulin, h·pmol/L

p-Value

−18 (−27 to −8)

0.0008

−8 (−17 to 1)

NS

C-peptide, h·nmol/L

p-Value

−1.5 (−2.1 to −0.9)

<0.0001 

−0.5 (−1.1 to 0.1)

NS

aGLP-1, h·ng/L

p-Value

16 (9–23)

<0.0001

−6 (−13 to 1)

NS

tGLP-1, h·ng/L

p-Value

87 (56–117)

<0.0001 

−15 (−45 to 15)

NS 

PYY, h·ng/L

p-Value

96 (30 to 163)

0.0057

33 (−35 to 102)

NS

GIP, h·ng/L

p-Value

−336 (−444 to −229)

<0.0001 

−173 (−280 to −65)

0.0025 

−164 (−317 to −11); 0.0368

All results are presented as least squares (LS) mean change from baseline at the 0-5 hour time interval (95% CI), unless otherwise specified.

CI = confidence interval, NS = not significant

Results for other parameters were primarily displayed as a graph. There were no differences between treatments for HBa1c values and most cardiovascular parameters (hemoglobin, baseline blood pressure). Most urine parameters showed no significant difference between the treatment groups, besides an decreased albumin excretion rate for empagliflozin and increased magnesium and calcium excretion rate for sotagliflozin. No signifcant changed were obeserved from fecal samples. 

Adverse Events

Common Adverse Events: Sotagliflozin: Genital fungal infection (10%), Urinary tract infection (5%)

Serious Adverse Events: None

Percentage that Discontinued due to Adverse Events: None

Study Author Conclusions

Sotagliflozin and empagliflozin did not show any major differences in overall glycemic and BP control or in selected metabolic, urinary, and intestinal parameters.

InpharmD Researcher Critique

Efficacy And Safety Of Sotagliflozin In Patients With Type 2 Diabetes And Stage 3 Chronic Kidney Disease

Design

Phase 3, randomized, placebo-controlled trial

N= 787

Objective

To assess the efficacy and safety of sotagliflozin, a dual inhibitor of sodium-glucose co-transporters 1 and 2, in adults with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD3)

Study Groups

Placebo (n= 260)

Sotagliflozin 200 mg (n= 263)

Sotagliflozin 400 mg (n= 264)

Inclusion Criteria

Age ≥ 18 years old with T2D, HbA1C ≥ 7% and < 11%, estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m² and < 60 ml/min/1.73 m²

Exclusion Criteria

Body mass index (BMI) ≤ 20 kg/m² or > 45 kg/m², systolic blood pressure (SBP) of more than 180 mmhg or diastolic blood pressure of more than 100 or without any antihypertensive therapy, history of diabetic ketoacidodis within 12 weeks before screening

Methods

After a run-in period in which patients were randomized (1:1:1) to receive placebo, sotagliflozin 200 mg or sotagliflozin 400 mg administered as two tablets once daily before breakfast with concomitant antihyperglycemic treatment for 52 weeks. 

Duration

Enrollment: September 2017 to October 2019

Intervention: 52 weeks

Follow-up: 52 weeks

Outcome Measures

Primary: superiority of week 26 HbA1c reductions

Secondary: change from baseline to week 26 in fasting plasma glucose (FPG) and body weight; change from baseline to week 12 in in patients with SBP of ≥ 130 mmHg; urine albumin-creatinine ratio (UACR) in patients with baseline UACR of > 3.4 mg/mmol at week 26; and the proportions of patients with an HbA1c of ≤ 6.5% and of ≤7.0% at week 26. Other endpoints included change from baseline to weeks 26 and 52 in SBP and change from baseline to week 52 in HbA1c, FPG, body weight and eGFR.

Baseline Characteristics

Placebo (n= 260)

Sotagliflozin 200 mg (n= 263)

Age, years

Female

White

Duration of diabetes, units

HbA1c, %

SBP, mmHg

BMI, units

eGFR, units

UACR, mg/mmol (IQR)

Antihyperglycemic medications

Insulin

Sulfonylurea

Metformin

Other oral agent

GLP-1RA

170 (65.4)

83 (32.4)

134 (52.3)

55 (21.5)

18 (7.0)

170 (64.6) 

94 (36.7)

138 (53.9)

47 (18.4)

27 (10.5)

166 (62.9) 

93 (37.1)

138 (55.0)

50 (19.9)

19 (7.6)

GLPA-1RA, glucagon-like peptide-1 receptor agonist

Results

Endpoint

Placebo (n= 260)

Sotagliflozin 200 mg (n= 263)

 Sotagliflozin 400 mg (n= 264)

Least squares mean change in HbA1C, %

Difference vs. placebo, % (95% CI); p-value

-0.22 ± 0.06

N/A

-0.32 ± 0.06

-0.10 (-0.25 to 0.05); 0.2095

-0.46 ± 0.06

-0.24 (-0.39 to 0.09); 0.0021

 Number of patients (%) achieving HbA1c < 6.5%

      Difference from placebo, % (95% CI);              P value

11 (4.2)

 N/A

15 (5.7) 

1.5 (–2.2 to 5.2); 0.433

15 (5.7)

 1.5 (–2.2 to 5.2); 0.433

 Number of patients (%) achieving HbA1c < 7.0%

     Difference from placebo, % (95% CI);              P value

35 (13.5)

N/A 

51 (19.4)

6.0 (–0.2 to 12.2); 0.0614 

55 (20.8)

7.4 (1.1 to 13.7); 0.0230

 FPG, mmol/L

     Difference from placebo, week 26 (95% CI); P value

 9.2 ± 3.3

N/A

 9.1 ± 2.7

0.6 (-1.1 to -0.1); 0.0144

 9.0 ± 2.9

-0.5 (-0.9 to -0.01); 0.0436

 Body weight (kg)

    Difference from placebo, week 26 (95% CI); P value

 89.1 ± 16.6

N/A

 89.8 ± 18.0

1.3 (-1.9 to -0.6); P < 0.0001

 89.5 ± 18.1

-0.8 (-1.5 to -0.2); 0.0155

Adverse Events

Common Adverse Events: hypoglycemia (38.1% vs. 41.9% vs. 35.4%), urinary tract infections (% vs. % vs. %), diarrhea ( )

Serious Adverse Events: cardiovascular events (3.5% vs.3.4% vs. 3.5%), bone fractures (2.3% vs. 0.7% vs. 1.9%)

Percentage that Discontinued due to Adverse Events: 5% vs. 6.7% vs. 11.9%

Study Author Conclusions

After 26 weeks, HbA1c was significantly reduced with sotagliflozin 400 but not 200 mg compared with placebo in this CKD3 cohort. UACR in patients with at least A2 albuminuria was reduced with each of the two doses at 26 weeks, but changes were not sustained at week 52.

InpharmD Researcher Critique

The study did not compare Sotagliflozin to other medication in the class of SGLT2 inhibitor, most participants were white and study should have been variety of races.

Sotagliflozin In Patients With Diabetes And Chronic Kidney Disease

Design

Phase 3, randomized, double-blind, placebo-controlled trial 

N= 10,584

Objective

To examine whether sotagliflozin would reduce the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure in patients with diabetes mellitus and chronic kidney disease, regardless of the degree of albuminuria 

Study Groups

Sotagliflozin (n=5292)

Placebo (n=5292)

Inclusion Criteria

Pateints ≥18 years of age with type 2 diabetes mellitus with a glycated hemoglobin level of 7% or higher, chronic kidney disease (eGFR, 25 to 60 ml per minute per 1.73 m² of body surface area)

Exclusion Criteria

Methods

Patients were randomized with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m² of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo

Duration

Outcome Measures

Primary: composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure

Secondary: Total number of hospitalizations for heart failure and urgent visits for heart failure; deaths from cardiovascular causes; the total number of deaths from cardiovascular causes, death from any cause, and total no. of deaths from cardiovascular causes, nonfatal myocardial infarctions, and nonfatal strokes

Baseline Characteristics

Sotagliflozin (N=5292)

Placebo (N=5292)

Age, years

Female

White

Hemoglobin

BMI

eGFR

MI

Glucose lowering medication

Ejection Fraction

Results

Endpoint

Sotagliflozin
(N=5292)

Placebo
(N=5292)

Hazard Ratio
(95% CI)

p-Value

Primary end point: total no. of deaths from cardiovascular causes, hospitalizations for HF, and urgent visits for HF

Adverse Events

Common Adverse Events: diarrhea, diabetic ketoacidosis, and volume depletion

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events.

InpharmD Researcher Critique

Loss of funding is a major risk factor and it can led to inability to complete the intended duration of follow up. 

Effects of sotagliflozin added to insulin patients with type 1 diabetes

Design

Multicenter, randomized, double-blind, placebo-controlled trial

N= 1,402

Objective

To evaluate the safety and efficacy of sotagliflozin, an oral inhibitor of sodium–glucose cotransporters (SGLTI) 1 and 2, in combination with insulin treatment in patients with type 1 diabetes

Study Groups

Placebo (n= 703)

Sotagliflozin (n= 699)

Inclusion Criteria

Exclusion Criteria

Methods

After a 2-week, single-blind run-in period where all patients received placebo, patients were randomized 1:1 ratio to either sotagliflozin or placebo for 24 weeks. Efficacy and safety were assessed at prespecified times during the treatment period, and a final safety assessment was performed 30 days after the last dose of the trial regimen was administered.

The sotagliflozin group received 400-mg dose of sotagliflozin daily, as two 200-mg oral tablets taken before the first meal of the day.

The placebo group took two matching placebo tablets in the same manner.

Patients' existing regimens with any approved insulin were continued. Insulin doses were individualized and adjusted to meet target blood glucose levels during self-monitoring.

Duration

October 2015 - April 2017

Interventions were given for 24 weeks

Outcome Measures

Primary outcome: Percentage of patietns with glycated hemoglobin level > 7.0% at week 24 and no severe hypoglycemia or diabetic ketoacidosis

Secondary: mean change in the glycated hemoglobin level, weight, and daily bolus insulin from baseline to week 24, and systolic blood pressure from baseline to week 16

Baseline Characteristics

Placebo (n= 703)

Sotagliflozin (n= 699)

Age, years

Female

White

Glycated hemoglobin, %

BMI, kg

Basal insulin dose, IU/day

Results

Placebo (n= 703)

Sotagliflozin (n= 699)

Difference (95% CI)

p-Value

Patients with glycated hemoglobin <7.0% and no severe
hypoglycemia or diabetic ketoacidosis

Patients with glycated hemoglobin ≥ 7.0%

≥ 1 episode of severe hypoglycemia

≥ 1 episode of diabetic ketoacidosis

13 (1.8%)

4 (0.6%)

16 (2.3%)

18 (2.6%)

0.4 (-1.0 to 1.9)

2.0 (0.7 to 3.3)

0.56

0.003 

Week 24 change from baseline

Glycated hemoglobin

Weight, kg

*Systolic blood pressure values are reported as a change at 16 weeks

Adverse Events

Common Adverse Events: Severe hypoglycemia (3.0% vs 2.4%), diarrhea (4.1% vs 2.3%), urinary tract infections (3.6% vs 3.8%), general mycotic infections (6.4% vs 2.1%)

Serious Adverse Events: Sotagliflozin (6.9%), Placebo (3.3%)

Percentage that Discontinued due to Adverse Events: Sotagliflozin (6.3%), Placebo (2.3%)

Study Author Conclusions

The proportion of patients who achieved a glycated hemoglobin level lower than 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. The use of sotagliflozin was also associated with significant decreases in glycated hemoglobin level, fasting plasma glucose level, insulin dose, weight, and systolic blood pressure.

InpharmD Researcher Critique

The interventions of this study were given for 24 weeks, which is not long enough to establish long term saftey and efficacy results. The design of this study also used more stringent protocol to reduce the risk of DKA, which may have affected the number of patients who could have potentially developed DKA. The study collected the patient's SGBM values but they were not included within the results of this study.

Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: the North American inTandem1 study

Design

Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study

N= 793

Objective

To evaluate the efficacy and safety of the dual sodium–glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor sotagliflozin in combination with optimized insulin in type 1 diabetes (T1D)

Study Groups

Placebo (n= 268)

Sotagliflozin 200 mg (n= 263)

Sotagliflozin 400 mg (n= 262)

Inclusion Criteria

Patients aged ≥ 18 years with T1D using either multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) for insulin delivery, HbA1c 7.0–11.0% at screening

Exclusion Criteria

β-hydroxybutyrate (BHB) levels > 0.6 mmol/L, use of SGTIs or antidiabetic agent other than insulin or insulin analog at the time of screening, chronic systemic corticosteroid use, type 2 diabetes mellitus (T2D), or severely uncontrolled T1D 

Methods

There were two double-blind periods: a 24-week treatment period, followed by a 28-week double-blind extension. 6 weeks before randomization, insulin therapy was optimized by adjusting basal and bolus doses to maintain fasting or preprandial blood glucose between 4.4 and 7.2 mmol/L (80 and 130 mg/dL) and 1- to 2-h postprandial glucose < 10 mmol/L (< 180 mg/dL)

Patients were randomly assigned 1:1:1 to sotagliflozin 200 mg, sotagliflozin 400 mg, or placebo once daily before the first meal of the day. Insulin doses were adjusted according to self-monitoring bllod glucose (SMBG) data to meet study targets. 

Duration

March 2015 - February 2017

Outcome Measures

Primary outcome: Placebo adjusted change in HbA1c from baseline to week 24

Secondary outcomes: A composite of the proportion of patients with HbA1c <7.0% and no severe hypoglycemia or DKA at week 24, change from baseline to week 24 in body weight, bolus insulin dose, fasting plasma glucose (FPG), and scores on the Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) and the 2-item Diabetes Distress Screening Scale (DDS2) 

Baseline Characteristics

Placebo (n= 268)

Sotagliflozin 200 mg (n= 263)

Age, years

Female

White

Hemoglobin A1c, %

Body weight, kg

Baseline total daily insulin dose, IU/kg

Results

Sotagliflozin 200 mg (n= 263)

Sotagliflozin 400 mg (n= 262)

Placebo (n= 268)

A1c, %

95% CI

p-Value

-0.36

-0.41 

Body weight, kg 

95% CI

p-Value

-3.35

-3.45 

Total daily insulin dose, %

95% CI

p-Value

-6.16 

-9.70 

Patients with HbA1c <7.0% and no severe hypoglycemia or DKA at week 24

All end points are given as the change in least square means (LSM) from baseline at week 24 from placebo

CI = confidence interval

Adverse Events

Common Adverse Events:

Hypoglycemia: Placebo (9.7%), Sotagliflozin(6.5% for both groups)

General mycotic infections: Placebo (3.4%), Sotagliflozin 200 mg (9.1%), Sotagliflozin 400 mg (13.0%)

Diarrhea: Placebo(6.7%), Sotagliflozin 200 mg (8.4%), Sotagliflozin 400 mg (10.3%)

Serious Adverse Events: Placebo (7.46%), Sotagliflozin 200 mg (10.27%) , Sotagliflozin 400 mg (11.07%)

Percentage that Discontinued due to Adverse Events: Placebo (4.1%), Sotagliflozin 200 mg (4.9%), Sotagliflozin 400 mg (6.5%) 

Study Author Conclusions

In a 1-year T1D study, sotagliflozin combined with optimized insulin therapy was associated with sustained HbA1c reduction, weight loss, lower insulin dose, fewer episodes of severe hypoglycemia, improved patient-reported outcomes, and more DKA relative to placebo.

InpharmD Researcher Critique

The rate of DKA was higher in the sotagliflozin group but still typical of those with type 1 diabetes. The results of the study may have been affected by the more frequent monitoring of blood glucose levels and insulin adjusments made by the patients and researchers. Overall, the adverse events associated with the treatment group were not as serious, and therapy was resumed shortly after. 

Design

N= 782

Objective

Study Groups

Inclusion Criteria

Patients aged ≥ 18 years with T1D using either multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) for insulin delivery, HbA1c 7.0–11.0% at screening

Exclusion Criteria

β-hydroxybutyrate (BHB) levels > 0.6 mmol/L

Methods

Duration

May 2015 - June 2017

Outcome Measures

Primary outcome: Placebo adjusted change in HbA1c from baseline to week 24

Secondary outcomes: A composite of the proportion of patients with HbA1c <7.0% and no severe hypoglycemia or DKA at week 24, change from baseline to week 24 in body weight, bolus insulin dose, fasting plasma glucose (FPG), and scores on the Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) and the 2-item Diabetes Distress Screening Scale (DDS2) 

Baseline Characteristics

Placebo (n= 258)

Sotagliflozin 200 mg (n= 261)

Age, years

Female

White

Hemoglobin A1c, %

Body weight, kg

Baseline total daily insulin dose, IU/kg

Results

Sotagliflozin 200 mg (n= 261)

Sotagliflozin 400 mg (n= 263)

A1c, %

95% CI

p-Value

Body weight, kg 

95% CI

p-Value

-1.98 

-2.58

Total daily insulin dose, %

95% CI

p-Value

-8.23

-9.47 

All end points are given as the change in least square means (LSM) from baseline at week 24 

CI = confidence interval

Adverse Events

Common Adverse Events: 

Hypoglycemia: Placebo (5.0%), Sotagliflozin 200 mg (5.0%), Sotagliflozin 400 mg (2.3%)

General mycotic infections: Placebo (2.3%), Sotagliflozin 200 mg (9.2%), Sotagliflozin 400 mg (11.0%)

Diarrhea: Placebo(3.5%), Sotagliflozin 200 mg (4.6%), Sotagliflozin 400 mg (7.2%)

Urinary tract infections: Placebo(5.0%), Sotagliflozin 200 mg (4.2%), Sotagliflozin 400 mg (6.8%)

Serious Adverse Events: Placebo (6.6%), Sotagliflozin 200 mg (10.0%), Sotagliflozin 400 mg (8.0%)

Percentage that Discontinued due to Adverse Events: Placebo (3.5%), Sotagliflozin 200 mg (3.8%), Sotagliflozin 400 mg (6.8%)

Study Author Conclusions

InpharmD Researcher Critique

The results of this study are similar to the other inTandem trials that have been conducted. There was no incidence of DKA in placebo compared to the sotagliflozin groups. The more frequent glucose checks and insulin adjusments, compared to actual clinical practive, may also have affected the results of this study. 

Dose‐dependent glycometabolic effects of sotagliflozin on type 1 diabetes over 12 weeks: The inTandem4 trial

Design

Phase 2b, multicentre, randomized, double‐blind, placebo‐controlled, parallel‐group, dose‐ranging study

N= 141

Objective

To assess the dose‐related effects of sotagliflozin, a novel dual inhibitor of sodium‐glucose co‐transporters‐1 and ‐2, in type 1 diabetes (T1D)

Study Groups

Placebo (n = 36)

Sotagliflozin 75 mg (n = 35)

Sotagliflozin 200 mg (n = 35)

Sotagliflozin 400 mg (n = 35)

Inclusion Criteria

Patients aged ≥18 years with T1D whose HbA1c level was 7.0%-10.0%

Exclusion Criteria

Serum beta‐hydroxy‐butyrate (BHB) levels > 0.6 mmol/L, estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m²

Methods

During a 2‐week placebo run‐in period, patients had to be ≥80% adherence to placebo tablets. After, they were randomly assigned 1:1:1:1 to placebo or sotagliflozin 75, 200 or 400 mg administered once daily before the first meal of the day, with randomization stratified by mode of insulin administration. During the 12‐week double‐blind period, investigators adjusted insulin regimens, but the total insulin dose could not exceed the total dose at baseline for patients. Postprandial glucose (PPG), body weight, daily urinary glucose excretion (UGE), and fasting plasma glucose (FPG), HbA1c, were assessed at each visit.

Duration

July 2015 - August 2016

Outcome Measures

Primary outcome: Change in least squares mean (LSM) HbA1c from baseline to week 12

Secondary outcome: Change in least squares mean (LSM) PPG, UGE, and weight from baseline to week 12

Baseline Characteristics

Placebo (n = 36)

Sotagliflozin 75 mg (n = 35)

Age, years

Female

White

Hemoglobin A1c, %

Body weight, kg

2‐h PPG, mg/dL

UGE, g/day

Results

Sotagliflozin 75 mg (n = 35)

Sotagliflozin 200 mg (n = 35)

Sotagliflozin 400 mg (n = 35)

A1c, %

95% CI

p-Value

-0.3

-0.5

-0.4

Body weight, kg 

95% CI

p-Value

-1.3

-2.4

-2.6

2‐h PPG, mg/dL

95% CI

p-Value

-22.2

-28.7

-50.2

UGE, g/day

95% CI

p-Value

41.8

57.7

70.5

All end points are given as the change in least square means (LSM) from baseline at week 12 from placebo

CI = confidence interval

Adverse Events

Common Adverse Events: 

Hypoglycemia:  Placebo (97.2%), 75 mg (94.3%), 200 mg (91.4%), 400 mg (97.1%)

Genital mycotic infection: Sotagliflozin all groups (2.9%)

Urinary tract infection: Placebo (5.6%), 400 mg (2.9%)

Diarrhea: Placebo (8.3%); 200, 400 mg (2.9%)

Serious Adverse Events: Placebo (2.8%), Sotagliflozin (2.9%)

Percentage that Discontinued due to Adverse Events: 4 participants discontinued due to DKA, ketosis, pregnancy, and neurosensory deafness.

Study Author Conclusions

Combined with stable insulin doses, sotagliflozin 200 mg and 400 mg improved glycaemic control and weight in adults with T1D. Sotagliflozin 400 mg reduced PPG levels. UGE increased with all sotagliflozin doses. Rates of severe hypoglycaemia and DKA were low.

InpharmD Researcher Critique

This trial has a smaller population size and shorter duration compared to the other inTandem trials; however, its findings are supported by previous studies. The dual SGLT inhibition was effective in improving PPG and UGE values in this population. It is important to note that several of the authors had conflicts of interests with the manufacturing company.

Sotagliflozin In Patients With Diabetes And Recent Worsening Heart Failure

Design

Multicenter, double-blind trial

N= 1222

Objective

To hypothesized that sotagliflozin would reduce the risks of death from cardiovascular causes, hospitalization for heart failure, and an urgent visit for heart failure among patients with diabetes mellitus and recent worsening of heart failure with either reduced or preserved ejection fraction when administered soon after an episode of decompensated heart failure

Study Groups

Sotagliflozin (n= 608)

Placebo (n= 614)

Inclusion Criteria

Patients aged ≥18 to 85 years and had been hospitalized because of the presence of signs and symptoms of heart failure and received treatment with intravenous diuretic therapy and required to have received a previous diagnosis of type 2 diabetes before the index admission or to have laboratory evidence to support a diagnosis of type 2 diabetes during the index admission

Exclusion Criteria

End-stage heart failure or recent acute coronary syndrome, stroke, percutaneous coronary intervention or coronaryartery bypass surgery, or an estimated GFR of <30 ml per minute per 1.73 m² of bodysurface area

Methods

Patients who met all eligibility and stability criteria were randomly assigned, either before or within 3 days after hospital discharge, to receive 200 mg of sotagliflozin once daily (with a dose increase to 400 mg, depending on side effects) or placebo. 

Follow-up visits were scheduled at 1, 2, and 4 weeks, at 4 months, and every 4 months thereafter.

Duration

November 16, 2020

Outcome Measures

Primary: Total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure 

Secondary: Total number of hospitalizations and urgent visits for heart failure; the incidence of death from cardiovascular causes; the incidence of death from any cause; the total number of deaths from cardiovascular causes, hospitalizations for heart failure, nonfatal myocardial infarctions, and nonfatal strokes; the total number of deaths from cardiovascular causes, hospitalizations and urgent visits for heart failure, and events of heart failure during hospitalization

Baseline Characteristics

Sotagliflozin (N=608)

Placebo (N=614)

Age, years (IQR)

Female

White

Median glycated hemoglobin level (IQR) 

Median body-mass index (IQR)

Median estimated GFR (IQR), ml/min/1.73 m²

Results

Endpoint

Sotagliflozin (N=608)

Placebo (N=614)

Hazard Ratio or Difference (95% CI)

p-Value

Hospitalizations and urgent visits for heart failure

 Deaths from cardiovascular causes

Deaths from cardiovascular causes, hospitalizations for heart failure, nonfatal myocardial infarctions, and nonfatal strokes

Deaths from cardiovascular causes, hospitalizations and urgent visits for heart failure, and events of heart failure during hospitalization

Deaths from any cause

Adverse Events

Common Adverse Events: hypotension (6.0% vs. 4.6%), urinary tract infection (4.8% vs. 5.1%), and diarrhea (6.1% vs. 3.4%)

Serious Adverse Events: Severe hypoglycemia was more common with sotagliflozin than with placebo (1.5% vs. 0.3%)

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

In patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo

InpharmD Researcher Critique

Loss of funding from the sponsor that led to the trial being stopped before enrollment of the initial planned sample size

Design

N= 277

Objective

Study Groups

Placebo (n= 93)

Sotagliflozin 200 mg (n= 92)

Sotagliflozin 400 mg (n= 92)

Inclusion Criteria

Exclusion Criteria

Methods

There was a 2 week, single-blind run-in phase prior to randomization, a 26 week, double-blind treatment period, a 26 week, double-blind extension period; and a 4 week, post-treatment follow-up period to collect safety information.

Duration

Outcome Measures

Primary outcome: Least squares mean (LSM) change in HbA1c between baseline and week 26 between sotagliflozin 400 mg and placebo.

Secondary outcome: Least squares mean (LSM) change in HbA1c between baseline and week 26 for sotagliflozin 200 mg and placebo, change from baseline in FPG, body weight, and urine albumin-creatinine ratio (UACR) at Week 26 among groups

Baseline Characteristics

Placebo (n= 93)

Sotagliflozin 200 mg (n= 92)

Age, years

Female

White

Results

Sotagliflozin 200 mg (n= 92)

Sotagliflozin 400 mg (n= 92)

Difference in A1c reduction, %

95% CI

p-Value

0.05 

-0.38 to 0.4

0.812

Mean change in UGE, mmol/L 

95% CI

p-Value

27.0

14.4 to 39.6

< 0.001 

34.8

22.0 to 47.5

< 0.001

Mean change in eGFR, mL/min/1.73 m²

95% CI

p-Value

-1.8

-3.2 to -0.3

0.019 

-1.6

-3.0 to -0.1

0.034

All values listed are results measured at 26 weeks.

Adverse Events

Common Adverse Events: 

Hypoglycemia: Placebo (40.9%), 200 mg (40.4%), 400 mg (38.9%)

Renal events: Placebo (10.8%), 200 mg (13.8%), 400 mg (12.2%)

Urinary tract infections: Placebo (19.4%), 200 mg (17.0%), 400 mg (10.0%)

Serious Adverse Events: Placebo (1.1%), 200 mg (2.1%), 400 mg (1.1%)

Percentage that Discontinued due to Adverse Events: Placebo (12.9%), 200 mg (10.6%), 400 mg (13.3%)

Study Author Conclusions

InpharmD Researcher Critique

This study was powered around A1c changed and not renal parameters. There was also no control SGLT2 to compare sotagliflozin against for overall efficacy in CKD4. The continued use of other therapies, including insulin, could have affected the results of the study.