Preservation of Beta-cell Function: Daily Metformin vs. Intermittent Intensive Insulin Therapy

4 Apr, 18

Background

Type-2 diabetes mellitus (T2DM) is characterized by a progressive decline of pancreatic beta cell function that leads to loss of glycaemic control and this creates a need for intensification of antihyperglycemic therapy. Short course of intensive insulin therapy (IIT) has shown to improve reversible beta-cell dysfunction and thereby induce diabetes remission. However, these effects are temporary as beta cell function deteriorates over time after the therapy is stopped.

Aim

To evaluate the impact of a short induction IIT followed by a maintenance therapy of either daily metformin or intermittent short term insulin therapy every 3 months on beta cell function and glycaemic control over 2 years.

Patient Profile

T2DM patients (≤5 year duration, age: 30-80 years) treated with metformin or lifestyle modification only (n=24).
Screening HbA1c: 6.0%-9.5% (in case patients did not receive any antidiabetic medications) or 5.5%-9.0% (in case patients were treated with metformin)

Method

Study Design

The REmission Studies Evaluating Type 2 Diabetes- Intermittent Insulin Therapy Pilot (RESET IT Pilot) was an open label, parallel arm, randomized controlled trial

Treatment Strategy

Assessments

Serial assessment of glucose homeostasis using oral glucose tolerance test (OGTT) at baseline, after induction IIT, and every 3-months thereafter during the 2-year maintenance phase.

Outcomes

Primary Outcome

Assessment of beta cell dysfunction measured by Insulin Secretion Sensitivity Index-2 (ISSI-2) at the end of 2 years

Secondary Outcomes

Baseline adjusted HbA1c
Fasting glucose levels and different measures of beta cell function such as C- peptide concentration and insulin secretion rate

Results

The patients enrolled in this study had a mean diabetes duration of 2 years and a mean HbA1c of 6.4%
The ISSI-2 (a measure of beta-cell function) was significantly higher in metformin group compared to intermittent IIT group (245 vs. 142.2, p=0.008) at 2 years (Figure 1A)
As compared to intermittent IIT, metformin therapy showed significantly lower HbA1c (7.3% vs. 6.0%, p=0.006; Figure 1B) and fasting glucose levels (136.8 vs. 102.6 mg/dL, p= 0.0002)
More number of patients had HbA1c ≤6% in metformin group compared to intermittent IIT group (66.7% vs. 8.3%, p=0.009; Figure 1C)

Figure 1: Insulin secretion sensitivity index-2 (ISSI-2), HbA1c and patients achieving HbA1c<6% with metformin and IIT at 2 years

None of the patients in metformin group had loss of glycaemic control (HbA1c> 8.0% on 2 consecutive assessments) whereas 41% of patients in intermittent IIT group had a loss of glycaemic control, over 2 years
No difference in insulin sensitivity between the two groups was observed; this suggests that the improvement in glycaemic control is attributable to improvement in beta-cell function
This glycaemic control was achieved without any increased risk of hypoglycaemia or other adverse events

Conclusion

In early type-2 diabetes patients who undergo short-term initial intensive insulin therapy, maintenance therapy with metformin is superior to intermittent intensive insulin therapy for preservation of beta cell function and glycaemic control for over 2 years.

‎Diabetes Obes Metab. 2018 (Published Online); doi: 10.1111/dom.13236.