Drug Review: GLP-1 Analogues (exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide)

GLP-1 analogues available in the U.S. are exenatide (sold as Byetta and Bydureon), liraglutide (sold as Victoza), albiglutide (Tanzeum), dulaglutide (Trulicity), and lixisenatide (Adlyxin).  They are sometimes referred to as GLP-1 receptor agonists.  They are not considered first-choice drugs, but instead are typically used in combination with other drugs, in conjuction with diet and exercise.

Remember that drug names vary by country and manufacturer.  This is a brief review only; consult your physician or pharmacist for full details.

Fun Fact for the diabetic version of  Trivial Pursuit:

Exenatide  (Byetta and Bydureon) is a synthesized version of a protein initially discovered in the saliva of a lizard, the Gila monster.

How do they work?

It’s complicated.

First off, you need to know that a small intestine hormone, glucagon-like peptide-1 (GLP-1), is produced in response to a meal.  This hormone increases insulin secretion by pancreas beta cells, suppresses glucagon after meals, inhibits emptying of the stomach, and inhibits appetite. Other effects are suppression of glucose production by the liver, and improved glucose uptake by tissues outside the liver.  All this tends to lower blood sugar levels after meals.

The problem is that GLP-1 is quickly destroyed by an enzyme called DPP-4.  We have available to us now chemicals similar to GLP-1, called GLP-1 analogues, that bind to the GLP-1 receptors and are resistant to degradation by the enzyme DPP-4.  They essentially act like GLP-1, and they hang around longer.

GLP-1 levels, by the way, are decreased in type 2 diabetes.

The action of GLP-1 is dependent on blood sugar levels.  If blood glucose is not elevated, GLP-1 doesn’t go to work.  From a practical viewpoint, this means that GLP-1-based therapies rarely cause hypoglycemia.

We know little about long-term outcomes with these drugs, such as diabetic complications, health-related quality of life, or mortality.


Exenatide (Byetta)  is FDA-approved for adults with type 2 diabetes who are not adequately controlled with metformin, sulfonylurea, or a thiazolidinedione (or a combination of these agents).  So it’s an add-on drug, not approved for use by itself.  In October, 2011, the FDA extended approval as an add-on therapy to insulin glargine (for example, Lantus in the U.S.), with or without metformin and/or a thiazolidinedione (TZD), in conjunction with diet and exercise for adults with type 2 diabetes who are not achieving adequate glycemic control on insulin glargine alone.

Once-weely exenatide (Bydureon) was FDA-approved in January, 2012.  Use with insulin has not been studied and is not recommended.  Don’t use along with Byetta.  Surprisingly, I found nothing in the drug package insert Feb.2, 2012, regarding whether it can be used with other diabetes drugs.  See comments in the preceding paragraph regarding standard twice-daily exenatide.  I suspect Bydureon can be used with metformin, sulfonylurea, thiazolidinedione, and insulin glargine (Lantus), but the package insert is not at all clear.

Liraglutide is FDA-approved for treatment of type 2 diabetes but is not recommended as initial therapy, although it does seem to be approved for use by itself.  It has been used alone and also in combination with metformin, sulfonylurea, and/or thiazolidinediones.  It’s not approved for use with insulin therapy.

Albiglutide is a once-weekly subcutaneous injection for type 2 diabetes. It was FDA-approved in 2014. It’s not recommended as initial drug therapy, although it is approved for use by itself. It can be used in combination with metformin, sulfonylurea, thiazolidinediones, and/or insulin.

Dulaglutide is also a once-weekly injection for adults with type 2 diabetes, approved by the FDA in2014.  It’s not a first-line drug, but can be used by itself or with metformin, glimiperide (and presumably other sulfonylureas), pioglitazone, and insulin lisper (e.g., Humalog, a rapid-acting insulin).

Lixisenatide is a daily injection for adults with type 2 diabetes. It can be used alone or in combination with metformin, sulfonylurea, thiazolidinedione (e.g., pioglitazone), or long-acting insulin (insulin glargine). Clinical trials did not include short-acting insulin.

You can assume none of these have been tested for safety in pregnant or nursing mothers.


They are available only as subcutaneous injections.  Exenatide is twice daily, starting at 5 mcg within 60 minutes prior to a meal.  After one month, the dose may be increased to 10 mcg twice daily.

Extended-release exenatide (Bydureon): 2 mg subcutaneous injection every seven days.

Liraglutide is a once daily subcutaneous injection starting at 0.6 mg, increasing to 1.2 mg after one week.  It is given without regard to meals.  Maximum dose is 1.8 mg/day.

Albiglutide is started at 30 mg subcutaneously every seven days and may be increased to 50 mg if needed.

Start dulaglutide at 0.75 mg weekly, increasing to 1.5 mg weekly if needed.

Lixisenatide starts at 10 mcg daily for 14 days then increases to 20 mcg daily.

Side Effects

GLP-1 analogues tend to cause nausea, vomiting, and diarrhea in as many as four in 10 users.  The nausea typically improves over time.  Compared with Byetta, Bydureon seems to cause less nausea.  They tend to cause weight loss.  These drugs might cause pancreatitis, which is life-threatening.  When used with insulin or an insulin secretagogue (like sulfonylureas or meglitinides), hypoglycemia may occur.

Hypoglycemia is rare when GLP-1 analogues are used as the sole diabetes drug, but still possible (0-5% risk?). When it happens, it’s rarely severe.

Liraglutide, albiglutide, and dulaglutide might cause thyroid cancer or thyroid tumors.   

Don’t use if you have . . .

… severe kidney impairment (exenatide), end-stage renal disease (lixisenatide),Multiple Endocrine Neoplasia syndrome (liraglutide), Multiple Endocrine Neoplasia syndrome type 2 (albiglutide, dulaglutide), or family history of medullary thyroid cancer (liraglutide, albiglutide, dulaglutide), or personal history or medullary thyroid cancer (albiglutide, dulaglutide).

Use GLP-1 analogues with caution or avoid entirely if you have a history of pancreatitis or gastroparesis. Don’t use dulaglutide if you have pre-existing severe gastrointestinal disease.

Use liraglutide with caution in patients with kidney or liver impairment. Dulaglutide is risky in the setting of liver impairment.

Don’t use any of these to treat diabetic ketoacidosis.

Steve Parker, M.D.

Last modification date: July 29, 2016

1 Comment

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One response to “Drug Review: GLP-1 Analogues (exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide)

  1. Riya Ghosh

    Thanks for such lucid, graspable and comprehensible explanation of the MOA. Though not too much of technical details are involved in the write up, as an overview and to get an understanding of the overall bigger picture of the interconnection between GLP-1 , DPPiv, GLP Analogues – this is an excellent explanation !!

    Thanks again, would expect another write up explaining the technicalities in a similar simple manner.