Is There an Ongoing Effect After Beta-cell Function Treatment Withdrawal? — ADA

Evidence has shown diabetic treatment options to improve beta-cell function and/or insulin sensitivity, but do these effects persist upon beta-cell function treatment withdrawal?

Slowing the progression from prediabetes to type 2 diabetes or slowing the loss of β-cell function plays a role in the treatment of diabetes. Previous studies have demonstrated post-withdrawal effects in patients with type 2 diabetes being treated with intensive insulin therapy. However, with the popularity of metformin for treatment and prevention of diabetes, studies have not tested the durability of efficacy upon withdrawal for longer than 2 weeks.

The current study used data from the Restoring Insulin Secretion (RISE) Adult Medication Study to determine the durability of efficacy upon withdrawal of treatment. The RISE Adult Medication Study was a three-center, randomized controlled trial consisting of 4 arms to compare treatments to improve β-cell function. The first arm was composed of 67 randomized patients, to receive insulin glargine for 3 months, followed by metformin for 9 months (G/M). The second arm consisted of 68 patients receiving liraglutide with metformin (L+M), the third, 65 patients treated with metformin monotherapy, and 67 patients receiving placebo. Patients underwent baseline measurements, including a hyperglycemic clamp, HbA1c (then measured quarterly), glucose, C-peptides, and insulin. Active treatment was given for a total 12 months before withdrawal. 3 months post-withdrawal measurements were repeated to report durability. The hyperglycemic clamp was performed at baseline, month 12 (M12), and month 15 (M15) to quantify insulin sensitivity (M/I: mean glucose infusion rate divided by the mean steady-state plasma insulin concentration) and β-cell response (3 recorded measures: steady-state C-peptide [SSCP], acute C-peptide response to arginine at maximal glycemic potentiation [ACPRmax], and acute C-peptide response to glucose [ACPRg]).

In the analyses, only 2 measures of β-cell function served as co-primary outcomes, SSCP and ACPRg, each evaluated with insulin sensitivity to determine treatment arm differences. Data was run at both 15 (primary) and 12 months (secondary). ANOVA was used to compare means across treatments at specific time points. To analyze changes within each treatment arm over time, paired t tests were used.

Over the 12 months of treatment, adherence was recorded quarterly based on the percent of total expected pills taken. In the metformin arm, adherence ranged from 90% to 93%, in the placebo arm, 92% to 94%, the G/M arm, 85% of patients were >80% adherent, and liraglutide was 92%. Patient withdrawals did occur during the 12 months of active intervention, the highest occurring in the L+M group and the lowest in the G/M group.

From the hyperglycemic clamp data, the L+M group at M12 had significantly higher C-peptide concentration at all time points (P < 0.01). At M15, both the metformin and G/M groups displayed improved insulin sensitivity (P = 0.027, P = 0.018) whereas the other 2 groups didn’t. In terms of β-cell response, all groups, except the placebo group, showed consistent changes in SSCP and insulin sensitivity. Due to decreases in SSCP being proportional to increases in insulin sensitivity, the researchers noted it represents no change at M15 in β-cell function compared to baseline. ACPRmax and insulin sensitivity at M15 compared to baseline, exhibited a decreased secretion response in the metformin, G/M, and the placebo groups (P = 0.025, P = 0.002, P = 0.050). However, across the groups, the changes seen were not statistically significant (P = 0.81). Lastly, ACPRg with insulin sensitivity at M15 compared to baseline was only different in the G/M group (P = 0.013), but again, across the groups there was no significant difference (P = 0.81). Altogether, at M15 compared to baseline, a small increase in insulin sensitivity was observed along with declines in β-cell responses, but the data across the 4 arms was not statistically significant. This indicates at M15, there was no change in underlying β-cell function.

At M12 compared to baseline, insulin sensitivity was significantly increased in the metformin group alone (P = 0.0002) and unchanged in the G/M and placebo groups. The L+M group displayed changes but weren’t statistically significant (P = 0.060). Looking at the joint measure of SSCP with insulin sensitivity, at M12 a change was seen in the metformin and placebo group (P = 0.0007, P = 0.034), with a much larger change in the L+M group (P < 0.0001). Furthermore, these changes across the 4 arms differed significantly (P < 0.0001). Comparing M12 to baseline, only the L+M group changes signified improved β-cell function. The joint change in arginine-stimulated incremental C-peptide response with insulin sensitivity at M12 in the L+M group, diminished compared to baseline (P < 0.0001).

Throughout the study, the interventions had different patterns of change in BMI and glycemia. At M12 compared to baseline, BMI was reduced in all 3 active intervention groups (P < 0.0001), but not placebo. Upon withdrawal, BMI increased in the same 3 groups, however, it was still lower than baseline. HbA1c was found to be reduced in the G/M group (P < 0.05) and lowest in the L+M group (P < 0.0001) at M12. Again, at M15, levels returned to baseline or above.

After 12 months of treatment, significant increases were seen in β-cell function, with the greatest in the L+M group. This signifying during active treatment there is efficacy of the medications, specifically the combination of liraglutide with metformin. Upon discontinuation of treatment, after 3 months, results returned to baseline, meaning there is no ongoing effect from the treatments upon discontinuation. RISE did not study all medication classes available and future studies could expand.

Practice Pearls:

• Metformin is most often used as first line in prevention and treatment of prediabetes, impaired glucose tolerance, and newly diagnosed type 2 diabetes.
• Combination of liraglutide with metformin had the best impact on β-cell response.
• Upon withdrawal of medications, any altered β-cell function during treatment should not be expected to persist.

Reference for Is There an Ongoing Effect After Beta-cell Function Treatment Withdrawal?:

Ehrmann, David, et al. Lack of Durable Improvements in β-Cell Function Following Withdrawal of Pharmacological Interventions in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes. Diabetes Care. 2019 June 9.

Emma Kammerer, L|E|C|O|M Bradenton School of Pharmacy, PharmD Candidate