Journal Club

Anly Li, PharmD

Cherney DZI, Ferrannini E, Umpierrez GE, et al. Efficacy and safety of sotagliflozin in patients with type 2 diabetes
and stage 3 chronic kidney disease. Diabetes Obes Metab. 2023;25(6):1646-1657. doi:10.1111/dom.15019
Background and Overview
Background1-4  Sodium-glucose co-transporters (SGLTs) are present in the kidney (SGLT2 > SGLT1) and small intestine
 SGLT inhibitors increase glucosuria/natriuresis and decrease albuminuria
 Current SGLT inhibitors have cardiovascular and renal protection
o Dapagliflozin, canagliflozin, and empagliflozin
 SGLT2 inhibitors have an effect in glycemic control up to an eGFR of 20 mL/min/1.73m2 (empagliflozin),
25 mL/min/1.73 m2 (dapagliflozin), 30 mL/min/1.73m2 (canagliflozin)
 Sotagliflozin is a dual SGLT1/2 inhibitor
o Indicated to reduce the risk of CV death, hospitalization for HF, and urgent HF visit in adults with HF
or T2DM, CKD, or other CV risk factors
o SCORED trial showed sotagliflozin may have preserved glucose-lowering effects in type 2 diabetes
and renal impairment
o SOTA-CKD4: HbA1c lowering was not statistically significant
Funding  Funded by Lexicon pharmaceuticals (manufacturer of sotagliflozin)

Objective Assess the efficacy and safety of sotagliflozin to placebo in adults with type 2 diabetes and stage 3 CKD
Methods
Study design Phase 3, multicentered, randomized, double-blind, placebo controlled study
 150 sites across North and South America, Europe, and Asia
Inclusion & Inclusion Exclusion
Exclusion  Adults > 18 years  BMI less than 20 kg/m2 or more than 45 kg/m2
 Diagnosis of T2DM with HbA1c between 7-11%  SBP > 180 mmHg or DBP > 100 mmHg
 eGFR between 30-60 mL/min/1.73m2  History of diabetic ketoacidosis (DKA) within 12
weeks before screening
 Renal failure
 Severe hypoglycemia within 6 months of
screening
 Use of systemic glucocorticoids for >10 days
within 90 days of screening
 Use of selective SGLT2 inhibitor within 12
months of trial
Outcomes Primary Endpoint
 Change in HgA1c at week 26 of sotagliflozin 200 and 400 mg vs placebo
Secondary Endpoints
 Change from baseline to week 26 in FPG (mmol/L)
 Change from baseline to week 26 in body weight (kg)
 Change from baseline to week 12 in SBP in patients with a SBP of > 130 mmHg at baseline
 Change from baseline to week 12 in SBP in all patients
 UACR in patients with a baseline UACR of > 3.4 mg/mmol at week 26
 Proportion of patients with an HbA1c < 6.5% and < 7% at week 26
 Change from baseline to weeks 26 and 52 in SBP
 Change from baseline to week 52 in HbA1c, FPG, body weight, and eGFR
Treatment Plan  2 week single-blind, run-in period and those with > 80% adherence were randomized 1:1:1 to sotagliflozin
200 mg, 400 mg, or placebo once daily for 52 weeks
o 26 week treatment + 26 week extension period
 Randomization was stratified by:
o A1c (< 8.5% or >8.5%),
o Mean systolic blood pressure (<130 mmHg or >130 mmHg), and
o CKD3A (eGFR > 45 and < 60 mL/min/1.73m2) or 3B (eGFR > 30 and < 45 mL/min/1.73m2)
 Changes to diabetes treatment plan were permitted and at the discretion of the investigator
Statistical  Sample size calculation:
Analysis o Assumed at standard deviation of 1.2% and a two-sided test at an alpha of 0.05
o 130 patients in each CKD stratum in each treatment group would provide 99% power in the overall
group and 98% in each CKD subgroup to detect a treatment difference of 0.5% between sotagliflozin
 200 mg and placebo and 0.6% between sotagliflozin 400 mg and placebo
 Primary endpoint analyses were performed on the ITT (The intention to treat (ITT) population included all
patients randomized to a treatment group) with an ANCOVA model using HbA1c values at baseline and
week 26
o Primary endpoint was evaluated sequentially: treatment compared to placebo in overall population,
then in subgroups CKD3A and 3B, first in sotagliflozin 400 mg and then in sotagliflozin 200 mg
 Missing data imputed by multiple imputation methods
 Changes in UACR were reported as percentage changes based on geometric means estimated from the
ANCOVA model
 Once the primary endpoint null hypothesis was rejected, the secondary endpoint hypotheses were tested in a
hierarchical order. Statistical testing continued among these secondary endpoints provided that statistical
significance was achieved. Once a non-significant test was observed, formal hypothesis testing stopped
 Comparisons after week 26 and safety data were summarized descriptively
o Safety population included all subjects exposed to study medication
o Four patients originally randomized to sotagliflozin 400 mg received sotagliflozin 200 mg due to
changes in eGFR; these patients were included in the 200 mg group for safety analyses.
Results
Baseline  787 patients were randomized
Characteristics o Sotagliflozin 200 mg: 263
o Sotagliflozin 400 mg: 264
o Placebo: 260
 Stated that baseline characteristics were similar across treatment groups
o Mean age of 69 + 7.9 years
o 43.6% Female
o 84.6% White, 25.2% Hispanic/Latino, 5.2% Black, 2.5% Asian, 5.6% Native American
o BMI 32.4 + 5.4
o HbA1c of 8.3% + 1%
o T2DM duration of 17.1 + 9 years
o Mean eGFR was 45 mL/min/1.73m2
o 52% had albuminuria
 CKD3B had a lower eGFR, higher UACR, and greater use of diuretics and CCB than CKD3A
Primary & Primary Endpoint: change in HgA1c at week 26 of sotagliflozin 200 and 400 mg vs placebo
Secondary  Placebo: –0.22% ± 0.06%
Endpoints  Sotagliflozin 200 mg: –0.32% ± 0.06%, p = 0.2095
o HbA1c was not significantly reduced in the CKD3A or CKD3B group
 Sotagliflozin 400 mg: –0.46% ± 0.06%, p = 0.0021
o HbA1c was also significantly reduced in the CKD3A group but not CKD3B group
Secondary Endpoints
 Change from baseline to week 26 in FPG (mmol/L)
o Placebo: -0.4 + 0.2
o Sotagliflozin 200 mg: –1.0 ± 0.2, p = 0.0144
 Also significant for CKD3A subgroup
o Sotagliflozin 400 mg: –0.9 ± 0.2, p = 0.0436
 Also significant for CKD3A subgroup
 Change from baseline to week 26 in body weight (kg)
o Placebo: -0.4 + 0.3
o Sotagliflozin 200 mg: –1.7 ± 0.2, p < 0.0001
o Sotagliflozin 400 mg: –1.2 ± 0.3, p = 0.0155
 Change from baseline to week 12 in SBP in patients with a SBP of > 130 mmHg at baseline
o No significant differences
 UACR in patients with a baseline UACR of > 3.4 mg/mmol at week 26
o Sotagliflozin 200 mg: UACR decreased by 30.7%, p = .002
o Sotagliflozin 400 mg: UACR decreased by 36.2%, p < .001
 Proportion of patients with an HbA1c < 7% at week 26
o Placebo: 23.5%
o Sotagliflozin 200 mg: 19.4%, p = 0.0614
 9.1% more patients with CKD3B achieved HbA1c < 7%, p = 0.047
o Sotagliflozin 400 mg: 20.8%, p = 0.023
 Change from baseline to week 52 in HbA1c, FPG, body weight, and eGFR
 o Change in HbA1c was not significantly different
o Change in FPG was significantly different in both treatment groups as well as CKD3A/sotagliflozin
400 mg subgroup
o Both sotagliflozin groups had an initial eGFR decrease of 3-4 mL/min/1.73m^2 that partly rebounded
at week 4, then remained stable for the remainder of the study
 Over the 26-week core treatment period, rescue therapy was required by 29 (11.2%), 23 (8.7%) and 18
(6.8%) patients in the placebo and sotagliflozin 200 and 400 mg groups, respectively. Over the 52-week
treatment period, rescue therapy was required by 46 (17.7%), 45 (17.1%) and 31 (11.7%) patients in the
placebo and sotagliflozin 200 and 400 mg groups, respectively
Adverse Events Placebo:
 Any AE = 78.1%, any treatment-related AE = 14.2%, AE leading to treatment discontinuation = 5%
 Genital mycotic infections: 0.8% (n = 2)
 Urinary tract infections: 10.4% (n = 27)
 Volume depletion: 1.5% (n = 4)
 Amputation: 1.2% (n = 3)
 Diarrhea: 5.8% (n = 15)
Sotagliflozin 200 mg:
 Any AE = 76.8%, any treatment-related AE = 18.4%, AE leading to treatment discontinuation = 6.7%
 Genital mycotic infections: 1.5% (n = 4)
 Urinary tract infections: 12.7% (n = 34)
 Volume depletion: 3% (n = 8)
 Amputation: 0.4% (n = 1)
 Diarrhea: 7.1% (n = 19)
Sotagliflozin 400 mg: 74.2%
 Any AE = 74.2%, any treatment-related AE = 16.9%, AE leading to treatment discontinuation = 11.9%
 Genital mycotic infections: 1.9% (n = 5)
 Urinary tract infections: 10.8% (n = 28)
 Volume depletion: 3.8% (n = 10)
 Amputation: 0.8% (n = 2)
 Diarrhea: 9.2% (n = 24)
Overall: more AEs in CKD3B than CKD3A; all patients who had amputations had history of amputations &
multiple risk factors
Author’s  After 26 weeks of treatment, sotagliflozin 400 but not 200 mg treatment significantly reduced HbA1c
Conclusion 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 the
changes were not sustained at week 52
 Safety findings were as expected
 Critique
Journal: Diabetes, Obesity and Metabolism
 Peer-reviewed journal
 Open-access journal
 Authors are endocrinologists or nephrologists
Study Subjects:
Baseline demographics seemed to be evenly distributed between the treatment groups
 43.6% female
 Minority representation: Hispanic/Latino: 25.2%, Black: 5.2%, Asian: 2.5%
Baseline characteristics
 UACR slightly higher in sotagliflozin 200 mg group (4.6 mg/mmol) vs 400 mg (3.2) and placebo (3.5)
o Less patients in the A1 albuminuria group (44.4%) compared to 400 mg (50.8%) and placebo (48.4%)

Methodology:
Design:
 Inclusion/exclusion criteria are appropriate
 No mention of non-pharmacological actions taken by patients/recommended by providers
 Sample sizes were smaller (~260 patients per group) – the FDA recommends at least 500 patients with stage 3/4 CKD
 26 weeks for efficacy and 52 weeks for assessment of longer durability of effect are both appropriate
o FDA recommends 6 months for efficacy because A1c is reflection of blood glucose over past 2-3 months
 Changes in antihyperglycemic therapy was reported (rescue therapy) but reported as a yes/no rather than a quantitative
measurement (how much was changed, what was changed)
Primary Outcome Measures:
 Change in HbA1c is a reasonable outcome measure for determining effectiveness of diabetes therapy (the recommended
endpoint by the FDA5,6)
Secondary Outcome Measures:
 FPG, HbA1c are appropriate for determining antihyperglycemic effect of sotagliflozin
o A1c < 7% and 6.5% are appropriate for secondary endpoints
 SBP is appropriate for determining impact on blood pressure
 Body weight and eGFR are also appropriate end points in studies with SGLT2i
Statistical Analysis:
 Sample size was met in each subgroup and the set A1c change of 0.5-0.6% are both appropriate
 Alpha of 0.05 is standard for clinical trials
 Appropriate statistical analysis was used (ANCOVA for continuous variable)
 ITT increases external validity
 Addressed missing data methods (multiple imputations)
Results:
 Does not mention in body of paper nonadherence or drop-out rate during trial (no participant flow diagram)
 Statistical analysis was hierarchical/sequential
o Reporting of the endpoints was not very structured – jumped around and not in the sequential order defined
o Reported p-values for endpoints after non-significant test was observed
 Diagram/figures included are appropriate
 Safety outcomes reported in percentages, no p-values reported
Discussion/Conclusion:
 Discussed significance of secondary outcomes even through non-significant test was observed before those secondary outcomes
o “Week 52 decreases in FPG with both doses and in body weight with sotagliflozin 200 mg were associated with P values
of less than .05”
o “Both sotagliflozin 200 and 400 mg significantly reduced FPG and body weight relative to placebo, and significant
decreases in UACR were observed with both doses in the subpopulation of patients with A2 albuminuria at week 26.”
 Discussed limitations of the trial
Overall Strengths:
 Randomized, controlled trial
 Appropriate endpoints that follow FDA guidelines for determining antidiabetic effect of sotagliflozin
 ITT increases external validity
 Power was met
Overall Weaknesses:
 Primary endpoint was not met for sotagliflozin 200 mg group, potentially due to small sample size - no difference found
between sotagliflozin and placebo
 No mention of lifestyle modifications that were undertaken by the patient, if at all
 No discussion of adherence to therapy, drop out rate
Clinical Application:
 Results can be applied to patients with T2DM who have uncontrolled diabetes and CKD3.
 Sotagliflozin is not approved for use in diabetes treatment (even in patients without kidney disease)
Overall Conclusion:
 Sotagliflozin 400 mg is effective in reducing HbA1c over a 6 month period but the effect is not sustained. Diabetes is a chronic
condition and a short term reduction of HbA1c would not be beneficial.

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