Short‐term intensive insulin as induction and maintenance therapy for the preservation of beta‐cell function in early type 2 diabetes (RESET‐IT Main): A 2‐year randomized controlled trial

Abstract

Aim: To test the hypothesis that the addition of periodic courses of short-term intensive insulin therapy (IIT) could enhance the effect of metformin (MET) maintenance therapy on preservation of beta-cell function following induction IIT.Methods: In this multicentre, randomized controlled trial, 108 adults with type 2 diabetes (median 1.3 years' duration; HbA1c 6.6% ± 0.6%) were randomized to 3 weeks of induction IIT (glargine, lispro) followed by MET maintenance, either with or without periodic 2-week courses of IIT every 3 months for 2 years. Beta-cell function was assessed by the Insulin Secretion Sensitivity Index-2 (ISSI-2) at an oral glucose tolerance test every 3 months.Results: In both arms, induction IIT increased ISSI-2, improved whole-body insulin sensitivity and reduced hepatic insulin resistance (all P ≤ .0004). The primary outcome of baseline-adjusted ISSI-2 at 2 years was not improved by the addition of intermittent IIT (MET + IIT) and was slightly higher in the MET arm (baseline-adjusted difference À35 [95% CI: À66, -3]), with three additional beta-cell measures showing no significant differences. Baseline-adjusted HbA1c at 2 years did not differ between MET and MET + IIT (6.3% ± 0.1% vs. 6.4% ± 0.1%, P = .46), with 32.6% of participants in each arm maintaining HbA1c of 6.0% or less at 2 years. Conclusion:Although initial induction IIT induces metabolic improvement, subsequent repeat courses of IIT every 3 months do not further enhance the effect of MET maintenance therapy on beta-cell function.

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

“…A limitation of this trial is that beta-cell function was assessed with OGTT-based surrogate indices rather than direct measurement on clamp studies, which potentially might have provided greater capacity for detecting subtle differences. Conversely, the four OGTT-based indices of beta-cell function yielded fully consistent findings and are validated measures that have been widely used in previous studies 15 , 21 , 26 – 28 . The distinct nature of the three interventions in this study dictated the need for an open-label design.…”

“…in the absence of pharmacologic effects) holds particular importance in the clinical context of the current trial. Specifically, when administering short-term insulin therapy in early T2DM, an underlying goal of the intervention is to ameliorate the reversible component of beta-cell dysfunction that exists early in the natural history of diabetes 15 . Ideally, the resultant recovery of beta-cell function may then facilitate the capacity to maintain glucose homeostasis after stopping the short-term intervention, thereby enabling the possibility of achieving diabetes remission.…”

“…ISSI-2 is defined as the product of (i) insulin secretion measured by the ratio of area-under-the-insulin-curve to area-under-the-glucose-curve on the OGTT and (ii) insulin sensitivity measured by Matsuda index. Additional measures of beta-cell function included (i) insulinogenic index/HOMA-IR, (ii) ΔCpep 0-120 /Δgluc 0-120 ×Matsuda index and (iii) ΔISR 0-120 /Δgluc 0-120 × Matsuda index (where ISR is the pre-hepatic insulin secretion rate determined by C-peptide deconvolution) 15 .…”

“…However, in practice, the implementation of early insulin therapy can be limited by patient and provider fear of the risks of hypoglycemia and weight gain 14 . Furthermore, the degree of beta-cell functional recovery in response to this intervention can be heterogeneous and the induced remission of diabetes is not permanent, ultimately waning over time 10 , 15 .…”

“…Since it is believed that short-acting GLP1-RAs act preferentially on post-prandial glycemia through their inhibitory effect on gastric emptying (in contrast to long-acting formulations that have more pronounced effects on fasting and post-absorptive glycemia) 2 , 16 – 18 , we reasoned that combining the short-acting GLP1-RA exenatide with basal insulin may provide optimal complementarity in metabolic coverage. Indeed, recognizing that the postprandial glucose-lowering effect of exenatide correlates with the magnitude of its inhibitory effect on the rate of gastric emptying 17 , this short-acting GLP1-RA should reduce the insulin secretory demands placed on the beta-cells, thereby inducing a degree of beta-cell rest (akin to the effect of bolus insulin in short-term intensive insulin therapy) 10 , 15 .…”