By Dr. Geoffrey Modest
JAMA recently had a study comparing the A1c effects of uptitrating basal insulin vs using a combo of basal insulin and a GLP-1 agonist (glucagon-like peptide-1) — see JAMA. 2016;315(9):898.
Details:
- 26-week randomized study at 75 centers in 10 countries from Sept 2013 to Nov 2014 of patients with uncontrolled diabetes treated with glargine (20-50 U) and metformin (>=1500mg/d) and had A1c of 7-10% and BMI<40
- 557 patients (mean age 58.8, 49.7% women, 95% white, 40% Latino, BMI 31.7, duration of diabetes 11.5 years, mean basal insulin dose of 31 U, 75% with hypertension, 61% with dyslipidemia, 44% on statins, 27% b-blockers, 65% of RAS inhibitors), randomized to stopping the glargine and substituting degludec/liraglutide (titrating to max dose of 50 U degludec/1.8mg of liraglutide) vs glargine (no max dose) and titrated twice-weekly to glucose target of 72-90 mg/dL. Drug-company sponsored. (Degludec is a newly FDA-approved basal insulin)
- After titration, the mean dose of degludec/liraglutide was 41U degludec/1.48 mg liraglutide and for glargine was 66U.
Results:
- Degludec/liraglutide: baseline A1c of 8.4% decreased 1.81 percentage points; 71.6% achieved A1c <7% and 55.4% achieved A1c <6.5%
- Glargine: baseline A1c of 8.2% decreased 1.13 percentage points; 47.0% achieved A1c <7% and 30.8% achieved A1c <6.5%
- Estimated treatment difference of -0.59 percentage points (-0.74 to-0.45 percentage points), meeting criteria for non-inferiority (p<0.001) and also for statistical superiority (p<0.001)
- Degludec/liraglutide also associated with weight loss of -1.4 kg, vs weight gain with glargine of 1.8kg: estimated treatment difference of -3.20 kg (-3.77 to -2.64 kg, p<0.001) and fewer hypoglycemic episodes/patient-yr of exposure (2.23 vs 5.05, corresponding to 28.4% on degludec/liraglutide and 49.1% on glargine), with estimated hypoglycemia rate ratio of 0.43 (0.30-0.61, p<0.001)
- Adverse events: overall events similar at 343.3 per 100 patient-year of exposure with degludec/liraglutide and 286.4 with glargine; serious events were 3.9 for degludec/liraglutide vs 6.7 for glargine. But degludec/liraglutide had much more minor GI adverse effects (9.4% with nausea vs 1.1% with glargine)
- Overall score on SF-36 patient questionnaire, assessing patient’s sense of their physical and mental well-being, improved with degludec/liraglutide from baseline 47.4 to 49.0, but got worse with glargine, from 47.7 to 47.2, which was statistically significant at p<0.001. I’m not sure these are really clinically significant, but at least the GI adverse effects did not translate into a worsening of the SF-36
So, this trial used a fixed dose combination injection (degludec/liraglutide). The price in the UK is about the same or slightly less than the meds if bought individually. From my searching around, the combo drug is being considered by the FDA this year. Who knows what our price will be?? This is a drug-company sponsored study, but there are several attractive features of this combo injection:
- It seems to work well, and my experience using the combo of a GLP-1 agonist with basal insulin (mostly glargine) has been really pretty dramatically positive. I have been prescribing either weekly exenatide (advantage of being weekly injection, disadvantage of being big needle injecting viscous material in order to slow absorption, and patients having bumps under their skin for a while) or daily liraglutide (may work slightly better, is daily, but very small needle).
- As mentioned in prior blogs, the GLP-1 agonists are the only of the new meds that I am using (other than occasional pioglitazone, esp in those who are needle-averse, and pioglitazone is not really a new med). But GLP-1 agonists seem to be pretty target-specific (vs DPP-4 antagonists, which are oral and block degradation of GLP-1, but are not targeted and degrade other proteins in the body) and restore a normal physiologic insulin response to meals (the incretin effect), which is decreased for some reason in diabetics but is restored with injectable GLP-1 analogs.
- It is noteworthy that the average person in the study above had diabetes for 11.5 years. GLP-1 agonists rely on the pancreas to secrete insulin, and a concern is that patients with long-standing diabetes could have burnt-out pancreases. I have also had several patients with close to 20 years of diabetes who have responded well (though I have checked C-peptide levels in several of them with very long-standing diabetes prior to initiating GLP-1 agonists, just to make sure the pancreas is working).
- There are some pretty useful advantages for the combo treatment: the A1c decreased (though we do need studies seeing if this translates into important clinical outcomes) and there was a reasonably big difference in weight loss vs gain with glargine.
- And, if there really is no price difference, it would be a lot easier to have one injection/day.
For other blogs on diabetes/meds, see https://stg-blogs.bmj.com/bmjebmspotlight/category/diabetes/
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