Glp-1 agonists – The Complete Guide


What does GLP 1 do?


It is one of two incretin hormones which are meant to boost glycemic control, when incretin effect is reduced or lacking in type 2 diabetic patients, therapeutic intervention with doses of GLP becomes necessary to stimulate insulin secretion 


Why LGP 1 is especially important for people with type 2 diabetes? Because: 


  1. It enhances the secretion of insulin 
  2. Slows down the release of glucagon provided that glucose levels are raised
  3. Slows the transit of food from the stomach into the intestines
  4. Helps with weight loss

According to a number of preclinical studies, LGP1 may enhance the proliferation of beta cells but since GLP 1 is very short-acting and can easily be inactivated by the DPP-4 enzyme, patients should receive LGP 1 doses around the clock.


To overcome such a major drawback, researchers had to work on developing derivatives of GLP 1 that are both long-acting and resistant to the effect of the DPP 4 enzyme. As a result, 2 types of therapies which are incretin-based came into existence, one of them is GLP 1 receptor agonists that are our concern here


A brief on the approved GLP-1 receptor agonist medicines:

These medicines are prescribed for the treatment of type 2 diabetes and are  also known as incretin mimetics

What is the GLP 1 receptor agonist action mechanism

The action mechanism of this medicine depends primarily on copying the function of the native incretin (GLP-1) hormone responsible for enhancing the production of insulin from the pancreas. The function of GLP 1 receptor agonist here is to prolong the effect duration of GLP 1 which has a very short duration span, thereby helps in maintaining blood sugar level within the desired limit.  GLP-1 receptor agonists can be injectable (one to two injections per day or once a week depending on the used medicine). They may be used alone or in combination with other diabetes drugs


List of approved GLP 1 receptor agonist medicines:


Europe, U.S, and japan have currently approved 2 types of GLP-1 receptor agonists for the treatment of type 2 diabetes:

  1. Exenatide                               B.Liraglutide



This medicine shares 53% sequence identity with the native GLP-1, an exendin-4 mimetic is now licensed in the United States for treating patients with type 2 diabetes either alone or combined with other diabetes medicines. The administration is two times a day as its half-life reaches 2.4 hours. It was suggested that Exenatide helps with lowering blood glucose levels if combined with certain diabetes medicines, and contributes to weight loss is associated with metformin

Tolerance: Well tolerated

Side effects: Nausea (especially at the beginning of administration) and may cause recurrent hypoglycemia if used alongside with sulfonylurea 



A derivative of native GLP 1 which shares  97% of its characteristics, one dose per day is administered since the added C 16 fatty acid side chain prolongs the effect of liraglutide to more than 24 hours. Liraglutide  was found to significantly help in the treatment of diabetes type 2 as it promotes glycemic control- whether consumed alone or along with specific diabetes medicines, reduces body weight if combined with metformin ± sulfonylurea, and reduces systolic blood pressure

Tolerance: Well tolerated

Side effects: Moderate gastrointestinal disorders namely nausea (especially at the beginning of treatment) and increase in hypoglycemia recurrency when associated with metformin and sulfonylurea


A comparison between long  and short-acting GLP-1 receptor agonists


Once-daily liraglutide Twice-daily exenatide
  • More effective in reducing A1C (percentage of type 2 diabetes patients who achieved  A1C goal set by ADA reached 54%)
  • Fasting plasma glucose was reduced to −1.61 mmol/L
  • Weight loss estimated by -3.24 kg (78% of patients)
  • Less recurrent hypoglycemia 
  • Less effective in reducing A1C (percentage of type 2 diabetes patients who achieved  the A1C goal set by ADA is 43%)
  • Fasting plasma glucose was reduced to −0.60  mmol/L
  • Weight loss estimated by -2.87 kg (76% of patients)
  • Well tolerated with minor to moderate side effects most prominent of which is nausea (mild and less recurrent here )
  • Well tolerated with minor to moderate side effects most prominent of which is nausea (more frequent here)
  • The duration of this clinical trial study exceeds 26 weeks and was conducted on 464 patients
  • An extended study followed, where liraglutide treated patients continued to use liraglutide and exenatide treated patients started to use a mono-dose of liraglutide. Patients who replaced exenatide by liraglutide experienced a decrease in A1C reached  6.9%, fasting plasma glucose −0.9 mmol/L, weight loss −0.9 kg and Systolic Blood Pressure−3.8 mmHg, in addition to lower hypoglycemia rates. On the other hand, 3.2% of patients suffered from nausea after they started to receive treatment with liraglutide against 1.5% of the patients who were given liraglutide from the beginning. 


A comparison between Once-weekly exenatide LAR and twice-daily exenatide


Once-weekly exenatide LAR Twice-daily exenatide
Glycemic control
  • Remarkable improvement with A1C  reduced greatly to reach −1.9% (77% of patients achieved the ADA’s A1C goal)
  • Less remarkable improvement with A1C  reduced to −1.5%, ( only 61% of patients  achieved the ADA’s A1C goal)
Fasting plasma glucose
  • −2.3 mmol/L
  • −1.4 mmol/L
Weight loss
  • −3.7 kg from baseline
  • −3.6 kg from baseline
Side effects
  • Nausea 26.4 %
  • Prurigo due to injection 17.6%
  • Hypoglycemic 0% (14.5% if associated with  sulfonylurea) 
  • Nausea 34.5%,
  • Prurigo due to injection1.4%
  • Hypoglycemic 1.1% (15.4%if associated with  sulfonylurea) 
  • The duration of this clinical trial study exceeds 30 weeks, and was conducted on 295 patients who are either experienced with diabetes medicines or naive to the drugs used in the treatment of diabetes
  • In the extended study which followed – where exenatide LAR treated patients continued to use exenatide LAR and  the twice-daily exenatide treated patients started to use the once-weekly exenatide LAR, decrease in A1C and fasting plasma glucose reductions were maintained all through the main study and the extension study
  • Patients who turned from treatment with twice-daily exenatide into the treatment with exenatide LAR experienced more glycemic control enhancement 
  • The body loss ratio was the same in both groups
  • Hypoglycemia was reported in people who used exenatide alongside  with a sulfonylurea only

A brief account on the clinical effectiveness of long-acting GLP-1 receptor agonists:

Due to the lack of data that constitute the basis for the clinical effectiveness assessment of GLP-1 receptor agonists – known up to the moment, we will lay our comparison here on the clinical trial studies outcomes :


  • A1C


No less than 50% of people with diabetes achieved ADA’s A1C target i.e  <7.0% through the administration of long-acting GLP-1 receptor agonists, percentage raised from 53% after 16 weeks from using albiglutide to 81% after 8 weeks from using taspoglutide


  • Weight reduction


All long-acting GLP-1 receptor agonists succeeded in reducing weight from 1.4 kg after 16 weeks from using 30 mg of  albiglutide to 3.87 kg after 15 weeks from using 2.0 mg of exenatide LAR


  • Systolic Blood Pressure (SBP)


Long-acting GLP-1 receptor agonists could reduce Systolic Blood Pressure from −4.7 mmHg after 15 weeks from using exenatide LAR to −6.7 mmHg after 26 weeks from treatment with liraglutide


An overview of the tolerance and safety of long-acting GLP-1 receptor agonists:



  • Gastrointestinal side effects


Gastrointestinal disorders including nausea and vomiting are the most common side effect of using long-acting GLP-1 receptor agonists. These side effects are usually intense in the initial stage of treatment but only for a while that could be as short as one day in the case of taspoglutide



  • Hypoglycemia


Treatment with long-acting GLP-1 receptor agonists may result in the occurrence of hypoglycemic within a limited range (0%-14% of diabetic patients), yet it was noticed that hypoglycemic became more recurrent when the long-acting GLP-1 receptor agonists were associated with sulfonylurea



  • Antibodies


No considerable percentage of antibodies formation caused by the treatment with once-weekly GLP-1 receptor agonists was reported. With  Albiglutide (which shares 95% of native GLP-1 identity) the percentage was limited to 2.5% of patients. With Liraglutide (which shares 97% sequence identity with native GLP-1) the percentage did not exceed  8.6%

On the other hand, the percentage of patients who developed antibodies to Exenatide(which shares less sequence identity with native GLP-1)  reached 61% of patients. However, patients who shifted from exenatide to liraglutide after 26 weeks continued to produce anti-exenatide antibodies after treatment luckily that did not influence consequent treatment with liraglutide




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