SAN FRANCISCO -- Interventions intended to boost β-cell function during active treatment did not lead to persistent benefits after treatment withdrawal in type 2 diabetes, a researcher reported here.

In a four-armed intervention study of adults with impaired glucose tolerance or newly diagnosed type 2 diabetes, 12 months of active treatment was associated with a significant reduction in HbA1c levels compared with placebo. This was seen in those on metformin alone, on insulin glargine followed by metformin, and on liraglutide plus metformin, according to Kieren Mather, MD, chair of the Restoring Insulin Secretion (RISE) Consortium.

Significant drops in BMI were also seen across all three treatments after 12 months when compared with placebo. However, during the 3 months after treatments were stopped, HbA1c levels and BMI increased across all treatments group.

After 12 months of active treatment, all treatment groups saw significant increases in glucose-stimulated β-cell responses, which was most pronounced in the liraglutide plus metformin group. However, arginine-stimulated incremental C-peptide response was lower only in the liraglutide plus metformin group at month 12, which was an unexpected result, according to the researchers.

All β-cell responses also disappeared within 3 months of treatment withdrawal, he reported at the American Diabetes Association (ADA) annual meeting. RISE results were simultaneously published in Diabetes Care.

A subanalysis of RISE also was presented at ADA, and published in Diabetes Care, demonstrated that habitual daily physical activity was tied to greater insulin sensitivity.

RISE Details

"The question we're addressing in RISE is whether it's possible to prevent the progressive loss of β-cell function in individuals with dysglycemia," said Mather, who is at the Indiana University School of Medicine in Indianapolis, during an ADA press conference. "There is a general expectation of a progressive loss. It's been described that up to 50% is lost at the time of diabetes."

"Because we wanted to intervene on people who had risk for diabetes but still had some opportunity to improve in function, we identified a group that the threshold between impaired glucose tolerance and new diabetes as the target population for our study," Mather added.

The multicenter analysis included 267 adults with obesity mean age 53.9 (mean BMI 35) with impaired glucose tolerance or type 2 diabetes diagnosed within the year who had never been on pharmacological therapy.

Those on metformin alone begin treatment with one 500-mg tablet daily, which was increased to a maximum dose of two tablets, twice a day. The insulin glargine (Lantus Solostar, Toujeo SoloStar, Basaglar KwikPen) group received 3 months of the therapy twice a week with a target fasting glucose of 4.4-5.0 mmol/L, which was then stopped and followed by 9 months of metformin, titrated up to 1,000 mg twice daily. The liraglutide (Victoza, Saxenda) plus metformin group first received liraglutide, with a weekly titration 0.6 to 1.2 to 1.8 mg daily; thereafter 1,000 mg of twice daily metformin was added.

Diabetes was previously present (median duration 17 days) or newly diagnosed during screening in 26% of the cohort. The mean HbA1c in the whole cohort at study entry was 39.3 mmol/mol.

Blinded tablet adherence ranged from 90% to 93% in the metformin arm and 92% to 94% in the placebo arm during quarterly visits over 12 months of treatment.

The authors reported that serious adverse events occurred in 17 participants, but none were determined to be related to randomized study medications or study procedures.

"All on-treatment effects disappeared 3 months after treatment was stopped, arguing against an ongoing effect of any of the tested treatment approaches to alter underlying β-cell function," they stated.

Study limitations included the fact that RISE did not study every available class of medication, such as thiazolidinedione. But the authors noted that "lack of efficacy following treatment withdrawal does not imply lack of efficacy during active treatment, and in fact the current data demonstrate on-treatment benefits that can be used to inform the design of future studies."

RISE Physical Activity

Karla Temple, PhD, RDN, LDN, of the University of Chicago in Illinois, and colleagues, performed a cross-sectional analysis of data obtained during the run-in and baseline phase of RISE.

The multicenter study included 230 ethnically-diverse adults with obesity who had impaired glucose tolerance, measured with a 3-hour oral glucose tolerance test and hyperglycemia clamp, or diagnosed type 2 diabetes, diagnosed within the year, who were never treated on pharmacological therapy.

Individuals with a fasting plasma glucose 95-125 mg/dL, along with an elevated 2-hour glucose ≥140 mg/dL and HbA1c ≤7.0% were included. About 75% of the cohort had impaired glucose tolerance, while a quarter had recently diagnosed type 2 diabetes.

Physical activity was measured by an accelerometer wore on the wrist for 7 consecutive days that measured both patterns of sleep and physical activity. This was then computed into total physical activity counts (daily mean 233,460; about 50th percentile for age).

At baseline, HbA1c levels were similar across the different levels of physical activity. Fasting glucose levels at baseline were 111.29 mg/dL and 110.02 mg/dL according to the oral glucose tolerance test and hyperglycemic clamp, respectively.

As measured by an oral glucose tolerance test, insulin sensitivity -- measured by 1/fasting insulin (x 10-3 1/[pmol/L]) -- was 7.92 among the most active quartile of adults compared with 10.80 for the least active adults (P=0.033).

However, the authors found that greater amounts of physical activity were not associated with several other markers of ß-cell response:

  • Fasting plasma glucose: 109.47 mg/dL (least active) vs 111.90 mg/dL (most active)
  • 2-hour glucose: 173.63 mg/dL vs 180.46 mg/dL
  • Glucose incremental area under the curve (G-iAUC): 9,923.13 mg/dL-min vs 10,454.87 mg/dL-min

Similar findings were reported when measured according to the hyperglycemic clamp versus the oral glucose tolerance test. Higher insulin sensitivity -- measured as M/I (x 10-5mmol/kg/min per pmol/L) -- was significantly associated with greater amounts of physical activity: 2.32 (0.61-8.78) among the least active versus 3.90 (0.8-19.06) for the most active adults.

As seen with the oral glucose tolerance findings, fasting plasma glucose, 2-hour glucose, and G-iAUC were not tied to physical activity when measured by the clamp.

Study limitations included the cross-sectional design, which limits causality, and the possibility that a larger sample size would have revealed a significant association between physical activity and clamp- or oral glucose test tolerance-based measures of β-cell response.

Temple and colleagues concluded that "our data emphasize the potential for physical activity as an adjunct to weight loss to prevent or delay the onset of type 2 diabetes or its complications."

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