A Fixed Combination of Long-Acting Insulin and GLP-1 Receptor Agonist

Summary and Comment |
March 8, 2016

A Fixed Combination of Long-Acting Insulin and GLP-1 Receptor Agonist

  1. Allan S. Brett, MD

In a 6-month study, this combination, compared with long-acting insulin alone, improved glycemic control with less hypoglycemia.

  1. Allan S. Brett, MD

Long-acting basal insulin can be given with a glucagon-like peptide-1 receptor agonist (GLP-1RA) for treating patients with type 2 diabetes. In this industry-sponsored, open-label trial, 557 diabetic adults who had been taking glargine plus metformin were randomized to once-daily injection of basal insulin (glargine) alone or once-daily injection of a fixed-ratio combination of basal insulin degludec plus the GLP-1RA liraglutide. Fixed-combination degludec/liraglutide is not yet FDA approved; the two components are available separately as Tresiba and Victoza, respectively.

At baseline, mean age was 59 years, mean diabetes duration was 11 years, and mean glycosylated hemoglobin (HbA1c) was 8.3%. Both glargine and combination degludec/liraglutide were adjusted to achieve fasting blood glucose levels of 72 to 90 mg/dL. At 26 weeks, these statistically significant differences were noted:

  • Mean HbA1c had fallen by 1.8% with degludec/liraglutide and by 1.1% with glargine.

  • Mean daily insulin dose was 41 units with degludec/liraglutide and 66 with glargine.

  • Mean weight was 1.4 kg lower with degludec/liraglutide and 1.8 kg higher with glargine.

  • Hypoglycemia was less common with degludec/liraglutide than with glargine (2.2 vs. 5.0 episodes per patient-year), although only one episode was serious.

  • Nausea was more common in degludec/liraglutide patients than in glargine patients (9% vs. 1%).


This study suggests that achieving tight glycemic control (e.g., target fasting glucose, <100 mg/dL; target HbA1c, <7%) while minimizing hypoglycemia can be accomplished more readily with basal insulin plus a GLP-1RA than with basal insulin alone. But an important question, not discussed by the authors, is whether this degree of glycemic control is worthwhile for patients like those in this trial — middle-aged or older adults with longstanding type 2 diabetes. Notably, the ACCORD, ADVANCE, and VADT trials did not convincingly demonstrate overall clinical benefit from tight control in this patient population (NEJM JW Gen Med Jul 1 2008 and N Engl J Med 2008; 358:2560 and 2545; NEJM JW Gen Med Jan 15 2009 and N Engl J Med 2009; 360:129).

Editor Disclosures at Time of Publication

  • Disclosures for Allan S. Brett, MD at time of publication Nothing to disclose


Reader Comments (3)

albert dehaan

Thought-provoking commentary - I learned a lot from the specifics . Does anyone know where my company would be able to acquire a blank IRS W-3 example to fill in ?

thomas kline md phd

The drug company/JAMA study above pushes the flawed glycemic control hypothesis yet again.

Two, and only two, studies are quoted in nearly all papers supporting current glycemic control treating all other aspects of this multi-organ disease. The two studies are familiar: DCCT and UKPDS 33 with 18,000 citations.

DCCT was type 1, not type 2. It was not controlled for 20% of young diabetics with MODY, and was not replicated. It showed the same outcome effects years later after switching back to less stringent regimens. Although interpreted as a newly invented "legacy effect" more logically it might indicate accidental selection bias tainting the original DCCT potentially invalidating this "landmark" $100,000,000 study - not a pleasant thought.

The second pillar to justify excessive treatment: the UKPDS 33 claimed longer life but only with metformin. No other metformin study before or since has shown impact on outcomes much less lifespan, leaving UKPDS 33 unsupported. Insulin was not involved positively in the UKPDS conclusions.

Remove these two "landmark" studies and add back the 3 larger studies mentioned by Dr. Brett showing excessive glucose reductions to be dangerous and ineffective, one is left with little support for the glycemic control hypothesis at all.

Two years ago the French researcher Remy Boussageon concluded there was no support for the "millions of prescriptions" written for type 2 anti-diabetic drugs. Why does this poor risk/benefit ratio, expensive, idealogy to lower, lower, lower --continue?

Thomas F. Kline MD, PhD

JOSEPH CHEMPLAVIL, MD, FACE Physician, Endocrinology, Private Office

It is about time that we should start practicing value based medicine. Embracing what is new and throwing away the old drugs with proven track records on safety and effectiveness should not be our new mantra.

Guideline committees and prescribers must compare the cost of the drugs to bring down HbA1c by 1% or part there of, in the treatment of diabetes. If not, we can't blame anybody else for the health care cost keep going through the roof!

Of course, we should try our best not to waste valuable resources in diabetes care especially with no proven benefit!

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