Satish K. Garg, United States of America

Moderator Of 1 Session

PARALLEL SESSION Webcast
Session Type
PARALLEL SESSION
Channel
Paris
Date
22.02.2020, Saturday
Session Time
08:30 - 10:00

Presenter Of 3 Presentations

SGLT inhibitors for type 1 diabetes - Introduction

Session Type
PARALLEL SESSION
Date
21.02.2020, Friday
Session Time
09:00 - 10:00
Channel
Auditorium A
Lecture Time
09:00 - 09:20

Abstract

Background and Aims

Since the majority of people with T1D do not achieve target A1cs (<7 or 6.5%) and more than 2/3 of the patients with T1D are getting overweight or obese, it is important to find adjunctive therapies for patients with T1D, which might help achieving target A1cs without any increase in weight[1]. Several molecules (like metformin, GLP analogs, coleselvelam, and DPP-4 inhibitors) have been evaluated as adjunctive therapeutic options for T1D[2],[3]. Unfortunately, none of them have been successful in significantly improving glucose control or weight loss; and thus, are not approved for their use in patients with T1D. The only FDA-approved option for adjunctive therapy for patients with T1D is pramlintide, which is rarely used because of GI side-effects and risk of severe hypoglycemia[4].

Background and Aims

Since the majority of people with T1D do not achieve target A1cs (<7 or 6.5%) and more than 2/3 of the patients with T1D are getting overweight or obese, it is important to find adjunctive therapies for patients with T1D, which might help achieving target A1cs without any increase in weight[1]. Several molecules (like metformin, GLP analogs, coleselvelam, and DPP-4 inhibitors) have been evaluated as adjunctive therapeutic options for T1D[2],[3]. Unfortunately, none of them have been successful in significantly improving glucose control or weight loss; and thus, are not approved for their use in patients with T1D. The only FDA-approved option for adjunctive therapy for patients with T1D is pramlintide, which is rarely used because of GI side-effects and risk of severe hypoglycemia[4].

Methods

SGLT 2 inhibitors have been successfully used for patients with T2D with a significant reduction in cardiovascular disease and renal failure. Since this class of drugs have insulin-independent effect and in early phase 1 and 2 clinical trials for patients with T1D showed significant benefits. Several Phase 3 trials were reported in the last two years with SGLT 1 and/or 2 inhibitors used adjunctively with insulin in patients with T1D[1]. DEPICT[2] (dapagliflozin) in T1D showed improvement in A1c, Time-in-Range (TIR), and weight loss with a small but significant increase in diabetic ketoacidosis (DKA). The second trial (replicating real-life use) using a dual SGLT 1 and 2 inhibitor (inTandem 3-Sotagliflozin in T1D)[3] showed significant reduction in A1c, hypoglycemia, especially severe (<55mg/dL) and weight loss. The other two large trials done in the USA and Europe using Sotagliflozin (in Tandem 1 and in Tandem 2) also showed similar results[4],[5]. Similarly, there was a small, but significant, increase DKA, which is now known with all SGLT 2 inhibitors. It’s important to keep in mind that the background risk of DKA is ~5% in the USA (T1D Exchange data—see reference 3) and is increasing significantly in Europe with or without the use of these medications[1]. Lastly, EASE 2 and 3 trials[2] using Empagliflozin in T1D and showed similar benefits and risks like Dapa and Sota except the authors recommended a smaller dose of 2.5mg a day to be considered for T1D (due to no increase in DKA risk, but efficacy on A1c was about 50%) based on a small sample size in EASE 3.

Methods

SGLT 2 inhibitors have been successfully used for patients with T2D with a significant reduction in cardiovascular disease and renal failure. Since this class of drugs have insulin-independent effect and in early phase 1 and 2 clinical trials for patients with T1D showed significant benefits. Several Phase 3 trials were reported in the last two years with SGLT 1 and/or 2 inhibitors used adjunctively with insulin in patients with T1D[1]. DEPICT[2] (dapagliflozin) in T1D showed improvement in A1c, Time-in-Range (TIR), and weight loss with a small but significant increase in diabetic ketoacidosis (DKA). The second trial (replicating real-life use) using a dual SGLT 1 and 2 inhibitor (inTandem 3-Sotagliflozin in T1D)[3] showed significant reduction in A1c, hypoglycemia, especially severe (<55mg/dL) and weight loss. The other two large trials done in the USA and Europe using Sotagliflozin (in Tandem 1 and in Tandem 2) also showed similar results[4],[5]. Similarly, there was a small, but significant, increase DKA, which is now known with all SGLT 2 inhibitors. It’s important to keep in mind that the background risk of DKA is ~5% in the USA (T1D Exchange data—see reference 3) and is increasing significantly in Europe with or without the use of these medications[1]. Lastly, EASE 2 and 3 trials[2] using Empagliflozin in T1D and showed similar benefits and risks like Dapa and Sota except the authors recommended a smaller dose of 2.5mg a day to be considered for T1D (due to no increase in DKA risk, but efficacy on A1c was about 50%) based on a small sample size in EASE 3.

Results

More recently, a meta-analysis of inTandem studies showed significant reduction in hypoglycemia (<70mg/dL) and severe hypoglycemia (defined as <54mg/dL)[1]. SGLT inhibitors have been approved in Europe and Japan as adjunctive therapy for patients with T1D whose BMI is >27kg/m2 and whose insulin requirements are 0.5 units/kg/day. In the USA, no SGLT inhibitor has been approved for patients with T1D and the FDA has issued a complete response letter (CRL) for both sota- and dapagliflozin. If and when these drugs are approved for patients with T1D in the USA, the risk of DKA will need to be mitigated by proper education for patients and providers following the STICH and STOP DKA protocols[2],[3],[4].

Results

More recently, a meta-analysis of inTandem studies showed significant reduction in hypoglycemia (<70mg/dL) and severe hypoglycemia (defined as <54mg/dL)[1]. SGLT inhibitors have been approved in Europe and Japan as adjunctive therapy for patients with T1D whose BMI is >27kg/m2 and whose insulin requirements are 0.5 units/kg/day. In the USA, no SGLT inhibitor has been approved for patients with T1D and the FDA has issued a complete response letter (CRL) for both sota- and dapagliflozin. If and when these drugs are approved for patients with T1D in the USA, the risk of DKA will need to be mitigated by proper education for patients and providers following the STICH and STOP DKA protocols[2],[3],[4].

Conclusions

Finally, the use of SGLT inhibitors as adjunctive therapy for T1D may allow many more patients to achieve target A1cs without any further weight gain and may in fact have long-term cardiovascular and renal benefits as have been shown in patients with T2D.

[1] Garg SK, et al. Diabetes Technol Ther. 2019 Feb;21: 66-72. PMID: 30657336.

[2] Garg et al. Endocrine Practice, 2013;19:19-28.

[3] Garg SK et al, Diabetes Obesity and Metabolism, 2011; 13:137-43.

[4] Weyer et al. Diabetes Care 2003; 26:3074–3079.

[5] Garg SK. Diabetes Technol Ther, 19 (10):549-551, 2017. PMID: 28891680.

[6] Dandona P et al. Lancet DE 2017; 5:864-876.

[7] Garg SK, et al. N Engl J Med. 2017;377:2337-2348.

[8] Buse JB, Garg SK et al. Diabetes Care 2018;41:1970−80.

[9] Danne T, et al. Diabetes Care 2018;41:1981−90.

[10] Zhong et al. Diabetes Care 2018;41:1870.

[11] Rosenstock J, et al. Diabetes Care. 2018 Dec;41(12):2560-2569. PMID: 30287422.

[12] Danne T, Garg SK, et al. Diabetes Care Jun 2019 (42). PMID: 31335194.

[13] Garg SK, et al. Diabetes Technol Ther. 2018 (20): 571-575. PMID: 30129772.

[14] Danne T, Garg SK, et al. Diabetes Care Jun 2019 (42). PMID: 31335194.

[15] Goldenberg RM, et al. Diabetes Obes Metab. Jun 2019. ePub ahead of print. PMID: 31183975.

Conclusions

Finally, the use of SGLT inhibitors as adjunctive therapy for T1D may allow many more patients to achieve target A1cs without any further weight gain and may in fact have long-term cardiovascular and renal benefits as have been shown in patients with T2D.

[1] Garg SK, et al. Diabetes Technol Ther. 2019 Feb;21: 66-72. PMID: 30657336.

[2] Garg et al. Endocrine Practice, 2013;19:19-28.

[3] Garg SK et al, Diabetes Obesity and Metabolism, 2011; 13:137-43.

[4] Weyer et al. Diabetes Care 2003; 26:3074–3079.

[5] Garg SK. Diabetes Technol Ther, 19 (10):549-551, 2017. PMID: 28891680.

[6] Dandona P et al. Lancet DE 2017; 5:864-876.

[7] Garg SK, et al. N Engl J Med. 2017;377:2337-2348.

[8] Buse JB, Garg SK et al. Diabetes Care 2018;41:1970−80.

[9] Danne T, et al. Diabetes Care 2018;41:1981−90.

[10] Zhong et al. Diabetes Care 2018;41:1870.

[11] Rosenstock J, et al. Diabetes Care. 2018 Dec;41(12):2560-2569. PMID: 30287422.

[12] Danne T, Garg SK, et al. Diabetes Care Jun 2019 (42). PMID: 31335194.

[13] Garg SK, et al. Diabetes Technol Ther. 2018 (20): 571-575. PMID: 30129772.

[14] Danne T, Garg SK, et al. Diabetes Care Jun 2019 (42). PMID: 31335194.

[15] Goldenberg RM, et al. Diabetes Obes Metab. Jun 2019. ePub ahead of print. PMID: 31183975.

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EFFICACY, SAFETY AND IMMUNOGENICITY IN PEOPLE WITH DIABETES ON MDI USING SAR341402 OR INSULIN ASPART TOGETHER WITH BASAL INSULIN GLARGINE (GLA-100): GEMELLI-1 STUDY

Session Name
E-POSTER DISCUSSION 10
Session Type
E-POSTER DISCUSSION
Date
21.02.2020, Friday
Session Time
10:05 - 10:25
Channel
Station 4 (E-Poster Area)
Lecture Time
10:15 - 10:20

Abstract

Background and Aims

SAR341402 (SAR-Asp) was developed as a biosimilar/follow-on to rapid-acting insulin NovoLog®/NovoRapid® (NN-Asp). Efficacy and safety results, including immunogenicity, for SAR-Asp and NN-Asp in patients with type 1 diabetes (T1DM) or type 2 diabetes (T2DM) are similar. Further subgroups analyses were done by baseline factors (age, ethnicity, race, BMI, duration of diabetes and HbA1c).

Methods

GEMELLI-1 (NCT03211858) was a 6-month (with 6-month extension) open-label randomised phase 3 study of SAR-Asp and NN-Asp in people with T1DM or T2DM using insulin glargine 100 U/mL (Gla-100) as basal insulin. Primary endpoint was HbA1c change (non-inferiority margin of 0.3 %) from baseline to Week 26.

Results

597 participants were randomized, with similar baseline characteristics in both treatment groups. The mean change in HbA1c at Week 26 was similar in both treatment groups in the total cohort as well as in subgroup analyses based on baseline BMI (≥30 vs <30 kg/m2), duration of diabetes (≥10 or <10 years), eGFR (≥60 vs <60 mL/min/1.73 m2), and ethnicity (Table). In these subgroups, the incidence of hypoglycaemia, especially severe hypoglycaemia (SAR-Asp 4.0%; NN-Asp 3.4%), was similar in participants who received SAR-Asp and NN-Asp. The immunogenicity data and TEAEs in subgroups were also consistent with the overall population (Table).

table.png

Conclusions

SAR341402 was as effective and well tolerated as insulin aspart in people with T1DM or T2DM regardless of the baseline characteristics.

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Opening words

Session Type
PLENARY SESSION
Date
21.02.2020, Friday
Session Time
13:00 - 14:30
Channel
Auditorium A
Lecture Time
13:00 - 13:03