The metabolic effects of adding exenatide to basal insulin therapy when targeting remission in early type 2 diabetes in a randomized clinical trial

Abstract

Combining a glucagon-like peptide-1 receptor agonist (GLP1-RA) with basal insulin is an emerging option when initiating injectable therapy in longstanding type 2 diabetes (T2DM). Recognizing that short-term insulin therapy can improve beta-cell function and induce glycemic remission in early T2DM, we hypothesized that adding the short-acting GLP1-RA exenatide to basal insulin in early T2DM may enhance the achievability of these outcomes. In this completed, 20-week, open-label, parallel-arm trial at an academic hospital, 103 individuals aged 30–80 years with <7 years duration of T2DM were randomized (by computer-generated sequence) to 8-weeks treatment with (i) insulin glargine (Glar; n = 33), (ii) glargine + thrice-daily lispro (Glar/Lispro; n = 35), or (iii) glargine + twice-daily exenatide (Glar/Exenatide; n = 35), followed by 12-weeks washout. The analyzed population of 102 participants (median 3.5 years of T2DM, A1c 6.6% ±0.7%) consisted of 33 on Glar, 35 on Glar/Lispro and 34 on Glar/Exenatide. Oral glucose tolerance tests at baseline, 4-weeks, 8-weeks and 20-weeks enabled assessment of beta-cell function (Insulin Secretion-Sensitivity Index-2 (ISSI-2)) and glycemic control. Mean ISSI-2 over the 8-week intervention (primary outcome) did not differ across the groups (Glar/Exenatide 237 ± 11; Glar/Lispro 208 ± 11; Glar 223 ± 11; p = 0.19). Baseline-adjusted A1c at 8-weeks (secondary outcome) was lowest in Glar/Exenatide followed by Glar/Lispro and Glar (mean 5.9% vs 6.0% vs 6.2%; p = 0.0007). After 12-weeks washout, however, neither baseline-adjusted A1c nor baseline-adjusted ISSI-2 (secondary outcomes) differed between the groups, nor did (additional outcome) rates of remission (Glar/Exenatide 26.7%, Glar/Lispro 43.8%, Glar 32.1%; p = 0.35). There were no severe hypoglycemia episodes. In conclusion, adding exenatide to basal insulin in early T2DM does not further enhance underlying beta-cell function or the capacity to achieve diabetes remission, despite yielding on-treatment glycemic benefit.

Baseline determinants of remission of type 2 diabetes in response to short‐term insulin‐based therapy: The pivotal role of beta‐cell function

“…The PREVAIL Trial (ClinicalTrials.Gov NCT02194595) was a parallel arm, open‐label trial, in which adult patients with T2D were randomized to 8 weeks of treatment with (a) insulin glargine, (b) glargine + thrice‐daily lispro, or (c) glargine + twice‐daily exenatide, followed by 12 weeks of washout. The study protocol and primary outcome have been described in detail previously 10 . The study was approved by the Mount Sinai Hospital Research Ethics Board and all participants provided written informed consent.…”

“…Participants stopped any oral antidiabetic medications and fasted overnight prior to the baseline visit, at which they completed a 2‐hour 75‐g oral glucose tolerance test (OGTT). At the baseline visit, they received instruction on healthy lifestyle practices for managing T2D, which they were encouraged to follow for the duration of the trial 10 . Participants were randomized (1:1:1) by computer‐generated random allocation sequence to one of the following insulin‐based therapies for 8 weeks: Glargine: participants administered insulin glargine once daily at bedtime, with a starting dose of 0.12 units/kg.…”

“…ISSI‐2 is defined as the product of (a) insulin secretion measured by the ratio of area‐under‐the‐insulin‐curve to area‐under‐the‐glucose‐curve on the OGTT; and (b) insulin sensitivity measured by the Matsuda index. Beta‐cell function was also assessed with the following three measures: (a) insulinogenic index/HOMA‐IR; (b) ΔC‐pep 0‐120 /Δgluc 0‐120 × Matsuda index; and (c) ΔISR 0‐120 /Δgluc 0‐120 × Matsuda index (where ISR is the prehepatic insulin secretion rate determined by C‐peptide deconvolution), as previously described 10 …”

A Scoping Review of Trials Designed to Achieve Remission of Type 2 Diabetes with Lifestyle Intervention Alone: Implications for Sub-Saharan Africa

“…The most well-known category combines LSI with either hypoglycemic medication or bariatric surgery. 9,10 The other category, which is less studied, but would have greater public health impact in Africa are studies of T2D remission using LSI-alone.…”

Concordance of A1C, Fasting Glucose, and Oral Glucose Tolerance Test Criteria for Defining Remission of Diabetes

“…The Preserving b-Cell Function in Type 2 Diabetes with Exenatide and Insulin (PREVAIL) trial was a 20-week, open-label, parallel-arm, randomized controlled trial in which adults with type 2 diabetes of <7 years' duration were treated for 8 weeks with either 1) insulin glargine, 2) glargine plus thrice-daily lispro, or 3) glargine plus twice-daily exenatide, followed by a 12-week washout to assess for remission (4). The study protocol and main findings were recently reported in detail (4).…”