Comment: Sodium-Glucose Cotransporters as Potential Therapeutic Targets in Patients With Type 1 Diabetes Mellitus: An Update on Phase 3 Clinical Trial Data

Objective: To review the pharmacology, pharmacokinetics, safety, and efficacy of teplizumab and evaluate relevant clinical trial data. Data Sources: Searches of MEDLINE, International Pharmaceutical Abstracts, ClinicalTrials.gov, American Diabetes Association scientific posters, and Google Scholar (1966-May 2012) were conducted using the key words teplizumab. anti-CD3 monoclonal antibody, MGA031, and hOKT3γ1 (Ala-Ala). Searches were limited to articles published in English. Study Selection and Data Extraction: Clinical trials evaluating teplizumab for type 1 diabetes mellitus (T1DM) published in English were selected from the data sources. All published relevant abstracts were included. References cited in identified articles were used for additional citations. Data Synthesis: T1DM accounts for up to 10% of all cases of diabetes mellitus, T1DM is characterized as a chronic and progressive autoimmune disease leading to the destruction of insulin-producing β-cells of the pancreas. Teplizumab is a humanized Fc-mutated anti-CD3 monoclonal antibody that alters the function of the T-lymphocytes that mediate the destruction of the insulin-producing β-cells. While clinical data are limited, both Phase 2 and Phase 3 studies have demonstrated preserved C-peptide response as a measure of insulin production, decreased exogenous insulin use, and improved grycemic control following a 12- to 14-day teplizumab infusion in patients diagnosed with T1DM within the previous 6 weeks. However, 1 Phase 3 trial tailed to find the same benefits in those diagnosed with T1DM within the previous 12 weeks when a lower cumulative teplizumab dose was used. Initial studies indicated that teplizumab is well tolerated, with a self-limiting rash as the most commonly reported adverse effect. Conclusions: Teplizumab is an anti-CD3 human monoclonal antibody with promising activity in treatment of patients with T1DM, Results from Phase 3 trials are needed to further determine safety, efficacy, and dosing frequency.

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Sodium-Glucose Cotransporters as Potential Therapeutic Targets in Patients With Type 1 Diabetes Mellitus: An Update on Phase 3 Clinical Trial Data

Annals of Pharmacotherapy ◽

10.1177/1060028019859323 ◽

2019 ◽

Vol 53 (12) ◽

pp. 1227-1237 ◽

Cited By ~ 6

Author(s):

Kajal Patel ◽

Antonia Carbone

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Glucose Transporter ◽

Trial Data ◽

Mitigation Strategies ◽

Phase 3 ◽

Glucose Transporter 2 ◽

Increased Risk

Objective: To review phase 3 trials of sodium-glucose cotransporter (SGLT) inhibitors in type 1 diabetes mellitus (T1DM) patients. Data Sources: A literature search of Ovid MEDLINE databases (1946 through May 17, 2019) limited to English-language human clinical trials was conducted using the following terms: sodium-glucose transporter 2 inhibitors, canagliflozin, dapagliflozin, empagliflozin, sotagliflozin, ertugliflozin, ipragliflozin, or remogliflozin combined with type 1 diabetes mellitus. Results were verified via Google Scholar and clinicaltrials.gov. Study Selection and Data Extraction: Articles were included if they were phase 3 trials in adults with T1DM. Data Synthesis: Phase 3 trials are available for dapagliflozin, empagliflozin, and sotagliflozin. All 3 drugs demonstrated statistically significant reductions in hemoglobin A1C, weight, and total daily insulin dose without an increased risk of hypoglycemia in up to 52 weeks of therapy. The incidence of diabetic ketoacidosis (DKA) was higher in patients on a SGLT inhibitor at all doses, with the exception of empagliflozin 2.5 mg (0.8% vs 1.2% with placebo). Relevance to Patient Care and Clinical Practice: SGLT inhibitors are potential adjuncts to insulin in T1DM patients, providing clinically meaningful benefits. Regulatory bodies have either approved or are reviewing these agents for use in T1DM. Clinicians should be familiar with the DKA risk associated with SGLT inhibitors and utilize DKA risk-mitigation strategies. Empagliflozin 2.5 mg warrants additional investigation given its efficacy without an increased incidence of DKA. Conclusions: Phase 3 trial data of SGLT inhibitors provide evidence for sustained efficacy in T1DM patients. Appropriate patient selection for therapy and routine monitoring are essential to minimize associated risks.

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