When Steve and Andrew got back from the ADA’s 74th Scientific Sessions in San Francisco, we put together an awesome overview of some of the new research and studies on GLP-1. Now that we have had some time to review the entire program we are providing you with more of what they found….
- A study by RAVI RETNAKARAN, CAROLINE K. KRAMER, et al showed that liraglutide induced ~50% enhancement of beta-cell function beyond that achieved with short-term intensive insulin therapy, and this was accompanied by lower A1c and BMI with no effect on insulin sensitivity. In summary, it appears that liraglutide provides robust enhancement of beta-cell function that is sustained over 1 year in early T2DM, and seems to continue for as long as the patient remains on the medication.
- ANDREW J. AHMANN, HELENA W. RODBARD, JULIO ROSENSTOCK, et al, presented information on the use of liraglutide with basal insulin in type 2 patients. After 26 weeks, patients taking LIRA had a greater decrease in HbA1c from baseline than PLAC, and more LIRA patients reached HbA1c <7.0%. Patients taking LIRA also achieved greater decreases from baseline in fasting plasma glucose, body weight and systolic blood pressure (-5.78 mmHg) vs PLAC (-0.76 mmHg).
- Effectiveness and Tolerability with Liraglutide among Patients with Type 2 Diabetes: Two-Year Data from EVIDENCE. This prospective, follow-up, post-marketing Study, from PIERRE GOURDY, ALFRED PENFORNIS, et al, suggests that the effectiveness of liraglutide in real world clinical practice is similar to that observed in randomized clinical trials (RCTs) (up to -1.5% A1c reductions and -3.24 kg weight loss). The incidence of gastrointestinal events was lower than that reported in RCTs (up to 26.5%). In summary, 2-year results from the EVIDENCE study suggest that clinical trial data for liraglutide translate into therapeutic benefits in clinical practice.
- GLP-1 receptors (GLP-1R) have been found in the brain and it has been hypothesized that GLP-1R agonists could improve brain glucose metabolism.
A study by GIUSEPPE DANIELE, MARJORIE MOLINA-WILKINS, et al, shows that a GLP-1 agonist, in this case exenatide, modulates CGMR by increasing glucose uptake in multiple areas of the brain but reduces glucose uptake in the hypothalamus. These results provide a previously unrecognized mechanism via which EX-mediated changes in glucose metabolism can influence the regulation of glucose absorption and hepatic/peripheral glucose metabolism.
Many of the studies compared the effects of insulin to GLP-1 Agonists on A1c and weight but how the two therapies compared when trying to elicit a long-lasting protective effect on beta-cell function was also studied.
- A study by SHIZUKA KANEKO, YUMIKO TAHARA, and YUICHI SATO followed patients with T2DM who had a short-term, 2-3 week course of either basal insulin therapy (n=147) or liraglutide therapy (n=51) to achieve a target two hours postprandial glucose of less than 140mg/dL, then were discontinued. They found fasting CPR/PG*100 was improved from 1.5 +/- 0.7 to 2.1 +/- 0.8 in the liraglutide group which compared favorably to the improvement in basal insulin group (from 1.1 +/- 0.6 to 2.0 +/- 0.6).
Moreover, liraglutide also improved two hours postprandial CPR/PG*100 from 2.6 +/- 1.7 to 4.8 +/- 2.3, insulinogenic index from 0.19+/- 0.23 to 0.50+/- 0.40, and urinary CPR from 96.6+/- 57.3 to 67.6+/- 38.3μg/day. Blood glucose levels stayed within a good range at the sixth month after discontinuance of liraglutide therapy, and 43 out of 51 subjects were under good glycemic control for more than two years. After discontinuance of liraglutide over one year, only 8 subjects needed to restart insulin or liraglutide therapy because of the failure of diet therapy.
Gastrointestinal side effects were occasional but tolerable, and a hypoglycemic episode was never observed in the liraglutide group. Short-term GLP-1R agonist and basal insulin therapy induced the same degree of improvement on insulin secretion in type 2 diabetic patients.
A long-lasting protective effect on pancreatic beta-cell function can be expected by short-term GLP-1R agonist therapy.
Although most researchers looked at GLP-1 mimetics to improve glucose levels there were also a few who looked at other effects on the body.
- While looking at the relationship of the gallbladder and diabetes, ULRICH ROHDE, DAVID P. SONNE, MORTEN HANSEN, et al found that that gallbladder emptying stimulates human GLP-1 secretion and that colesevelam and metformin, respectively, would potentiate any GLP-1 secretion by inducing gallbladder emptying. Using this hypothesis they were able to show that a single dose of metformin can elicit robust and additive GLP-1 responses in humans. They speculate that MET’s mode of action includes stimulation of GLP-1 secretion by both bile acid-dependent and independent mechanisms.
- In addition ALIP BORTHAKUR, SUMIT BHATTACHARYYA, and JOANNE K. TOBACMAN discovered that carrageenan (CGN), a sulfated polygalactan, used as a common food additive to improve texture of processed foods inhibits expression and secretion of GLP-1 in intestinal L-cells. This leads to reduced stimulation of Glut-2 expression and this demonstrates that exposure to the common food additive carrageenan may profoundly affect glucose metabolism in human cells.
- DANIELA JAKUBOWICZ, OREN FROY, MONA BOAZ et al, found that the simple addition of a whey protein preload before a high glycemic breakfast enhanced prandial iGLP-1 and tGLP-1 secretion that occurred in a parallel fashion and strongly associated with the insulinotropic effect. These findings suggest that whey protein may contribute to the improvement of the impaired function of GLP-1 as a transmitter in the enteroinsular axis and may represent a novel approach for incretin-based therapy, stimulating GLP-1 and prandial insulin release limiting postprandial glycemia in type 2 diabetes.
- JIANPING XU found that chewing sugarless gum can increase satiety, and decrease the decline of GLP-1 levels. Compared with the control group, by chewing sugarless gum 80 times every 2 minutes, the satiety of the test group increased at 15, 25 and 30 minutes after the beginning (p = 0.043, p = 0.014 and p = 0.018, respectively), blood GLP-1 level of the test group at 30 minutes was 49.6 ± 20.3pmol/l, significantly higher than the control group(38.9 ± 20.9 pmol/l, p = 0.031). The study suggests that fasting chewing sugarless gum can increase satiety, and decrease the decline of GLP-1 levels.
There was even some great research being done with orally-available GLP-1 Agonists. We all face the challenges of convincing our patients to use an injectable drug and the idea of using an oral compound would be awesome.
- TTP273 is an oral formulation that was studied by STEPHANIE GUSTAVSON, AARON BURSTEIN, CARMEN VALCARCE et al. They found that there was no hypoglycemia, and GI AEs, including nausea and vomiting, were infrequent and similar in incidence in TTP273 groups vs. Placebo. TTP273 was rapidly absorbed with a median Tmax of ~2 hrs and a mean terminal t½ of ~6 hrs. Glucose lowering effects were consistent with those of injectable GLP-1 agonists. Dose-responsive decreases in mean daily glucose (reduction of 42 mg/dL in the TTP273 75 mg BID group vs. 11 mg/dL in PBO; p=0.01) and fasting glucose (reduction of 39 mg/dL in the TTP273 75 mg BID group vs. 11 mg/dL in PBO; p<0.01) were observed. Notably, the BID and QPM regimens appear to result in superior glucose lowering compared to QD regimens, with no increase in side effects. Numerical, dose-responsive reductions in blood pressure (systolic and diastolic) and triglycerides were also observed after TTP273 administration.
The future for GLP-1 is gigantic and we are all looking forward to more data and products being released well in advance of next year’s 75th Scientific Sessions.
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