The β-cell preserving properties of short courses of metformin and insulin glargine evaluated in ever-growing population of patients who have diabetes.
It is becoming increasingly common to see type 2 diabetes in younger patients, specifically those between the ages of 10–19. Additionally, younger patients typically have an increased risk of initial treatment failure as well as an increased rate of disease progression and β-cell loss of function compared to their adult counterparts. Therefore, the concept of β-cell preservation, in these patients, becomes increasingly important. In adults, both insulin and metformin have demonstrated β-cell-preserving properties. This study compares short courses of metformin vs insulin glargine followed by metformin on β-cell function over time.
This study is an open label, multi-center, randomized controlled trial. It utilizes a hyperglycemic clamp (method used to determine the amount of insulin secretion or resistance) to evaluate and compare β-cell function at baseline, 12, and 15 months (primary outcome). β-cell function was quantified by calculating insulin sensitivity (derived by dividing the average glucose infusion rate by the steady state insulin concentration at given times during the clamp) as well as the initial C-peptide response to glucose, steady state C-peptide response, and maximum C-peptide response to arginine (an insulin secretagogue). Secondarily, the difference in BMI percentile, fasting glucose, oral glucose tolerance test, and HbA1c were compared between trial groups.
Participants were considered for inclusion if they were: between 10 and 19 years of age, had a BMI of ≥ 85th percentile for age and gender but < 50 kg/m2, recently diagnosed with type 2 diabetes or impaired glucose tolerance, negative IA2 and GAD autoantibody tests, HbA1c ≤ 8% if treatment naive (≤ 7.5% or 7.0% if previously taking metformin for < 3 months or > 3 months respectively), and ≥ 80% compliance with placebo regimen during assessment period. Of the 236 patients who were assessed for inclusion, 91 were deemed eligible and randomized into their respective groups to achieve a reported power of ≥ 80%. Baseline characteristics between groups were equivalent with the exception of a slight variance with regards to average age (14.9 vs 13.9).
The control group received 12 months of metformin, which was titrated to a target dose of 1000 mg twice daily. The intervention group received 3 months of insulin glargine (titrated to achieve a fasting blood glucose between 4.4 to 5 mmol/L) immediately followed by metformin, which was titrated to a target dose of 1000 mg twice daily. β-cell function was evaluated at baseline, 12, and 15 months. The purpose of the 15-month (3 months after treatment discontinuation) measurement was to determine the durability of any observed effect on β-cell function that the treatments might have. The difference between groups was assessed via ANCOVA statistical test, whereas the difference within each group, from baseline, was assessed via ANCOVA repeated measures statistical test.
Once the data was collected and analyzed via ANCOVA, it was determined that, for the primary outcome, there was no statistically significant difference between the metformin group and the insulin glargine followed by metformin group at either the 12- or 15-month data collection points. Interestingly, the data indicated that there was no preservation of β-cell function in either group. Instead, a progressive and statistically significant decline of β-cell function was observed at both the 12-month and 15-month mark. With regards to the secondary outcomes, there was no significant difference between groups at the 12- and 15-month data collection points.
This study was designed to determine which short-course regimen (metformin or insulin glargine followed by metformin) provides superior β-cell preservation in youth with newly diagnosed type 2 diabetes or impaired glucose tolerance. The study design assumes that of these regimens, the β-cell preserving benefit observed in adults would also apply to youth. Ultimately, one regimen was not seen to be any more effective than the other. Surprisingly, the data seems to suggest that these medications may not be an effective means of preserving β-cell function in youth. However, further study is warranted to assess the significance of these findings.
- Metformin and insulin glargine have been shown to preserve β-cell function in adults.
- Neither metformin nor insulin glargine followed by metformin demonstrate any superiority to the other with regards to β-cell preserving effect in youth with type 2 diabetes or impaired glucose tolerance.
- Metformin and insulin glargine may not be an effective means of preserving β-cell function in youth with type 2 diabetes or impaired glucose tolerance.
“Impact of Insulin and Metformin Versus Metformin Alone on β-Cell Function in Youth With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes.” Diabetes Care, vol. 41, no. 8, 2018, pp. 1717–1725., doi:10.2337/dc18-0787.
“A Clinical Trial to Maintain Glycemic Control in Youth with Type 2 Diabetes.” New England Journal of Medicine, vol. 366, no. 24, 2012, pp. 2247–2256., doi:10.1056/nejmoa1109333.
Weng Jianping, et al. “Effect of intensive insulin therapy on β-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial”. 24 May 2008, pp. 1753-1760.
Michael Zaccaro, Pharm. D. Candidate 2019, LECOM School of Pharmacy