GLP-1's and DPP-4 inhibitors

Incretins are hormones that are released in the gut in response to a meal.

The incretins promote insulin secretion and inhibit glucagon.

Some will slow emptying of the stomach.

Finally, all will reduce appetite.

The result of these effects is to lower sugar levels in the morning and after eating a meal.

The insulin-secreting effects of the incretins depend on blood sugar levels. They have their greatest effects at high sugar levels, when increased insulin secretion is needed.

When sugar levels are normal, they have minimal effects, thus avoiding hypoglycemia (low sugar).

Although these benefits were first noted over 50 years ago, incretins were not previously available as therapy since the hormones lasted less than 10 minutes in your circulation.

Researchers however recently identified technologies that allowed the incretins to last for longer periods of time.

This allowed physicians to use the incretins to treat people with Type 2 Diabetes, in whom incretin related actions are typically reduced.

The first class of incretin related drugs developed were the "incretin mimetics" or glucagon-like receptor agonists (the GLP-1's).

Exenatide (Byetta) and liraglutide (Victoza) were the first drugs available in this class. 

Exenatide was approved by the FDA in 2005, liraglutide in 2010. Exenatide extended release (Bydureon) was introduced in 2012. All are delivered by injection.

Exenatide is a synthetic formulation of exendin 4, a hormone found in the Gila monster. It is very similar to the human incretin (53% homology), but much more resistant to breakdown. It thus lasts for more than 2 hours (compared to 10 minutes!).

The initial formulation required two injections per day.

Bydureon is an extended release form of exenatide. It is injected once weekly.

All of the GLP-1 agonists are available in easy to use pens.

Once weekly formulations used more frequently include dulaglutide (Trulicity), semaglutide (Ozempic) and the combination GLP1-GIP tirzepatide (Mounjaro)

Semaglutide is also available in daily pill form as Rybelsus.

Given its relatively short duration of action, and twice daily meal-time dosing, the short-acting formulation of exenatide is most effective at lowering after-meal blood sugars.

Liraglutide has been chemically modified to resist breakdown. It lasts for 11-13 hours, and is injected once per day. It is thus considered a long-acting GLP-1 agonist. It has 97% sequence homology with native GLP-1.

Given its longer duration of action, liraglutide is most effective at lowering morning sugars.

This is also true of the other long acting incretins such as exenatide extended release, dulagultide, semaglutide and tirzepatide. 

Reductions in gastric emptying are most pronounced with the short-acting GLP-1 agonists.

The choice of a GLP-1 agonist may thus be influenced by your pattern of sugar elevations.

On average, all GLP-1's will lower after meal sugars by ~50 mg/dl, and lower fasting sugars by ~25 mg/dl. HA1c reductions average 1.5%.

A1c reductions are slightly more with liraglutide compared with extended release exenatide followed by regular exenatide. In clinical trials, the longer-acting GLP-1 agonists lower the HA1c levels more than the shorting acting agents.

All are associated with reduced appetite and an average weight loss of 6 pounds after 6 months. At one year, the average weight loss is 10 pounds.

Semaglutide has been associated with greater weight loss.

When prescribed for weight loss, semaglutide is marketed as Wegovy with 0.25 mg, 0.5 mg, 1mg, 1.7 mg and 2.4 mg pens.

Doses are titrated upwards monthly as tolerated.

The average weight loss is 10-12%.

Tirzepatide is more effective re weight loss, with an average loss of 20%.

Both drugs are covered in more detail in the weight loss discussion section (

The weight-loss benefits associated with this class of drugs are typically described as an early sense of "fullness" while eating a meal.

GLP-1's have also been associated with small reductions in blood pressure.

All drugs in this class reduce glucagon secretion.

Cardiovascular risk reduction with a GLP-1 was first reported in liraglutide users in the LEADER trial.

Subjects treated with liraglutide had a significant reduction in heart-related and any cause death compared to those treated with liraglutide.

Liraglutide continues to have the greatest CV reductions reported in the GLP1 CVOT's (ELIXA, LEADER, SUSTAIN 6, EXCEL, HARMONY and REWIND)

Heart related benefits were subsequently reported with semaglutide injections and pills (the SUSTAIN-6 and PIONEER 6 Trials) as well as with dulaglutide (the REWIND Trial).

The class has the greatest impact on the reduction of atherosclerotic CV events with a 14% relative risk reduction for major CVE.

They are neutral with respect to HF risk (a 7% relative risk reduction in HF hospitalizations compared with 31% for the SGLT2's).

The 2019 ESC/CVE guidelines recommend liraglutide, semaglutide or dulaglutide in people with T2DM and CVD, or at very high/high CV risk.

The guidelines recommend liraglutide in these groups to reduce the risk of death.

The 2023 ADA guidelines recommend either the GLP-1 agonsits or the GLT2 inhibitors in people with T2DM where CVD predominates, vs the GLT2 inhibitors if HF or CKD predominates.

Incretin related side effects include nausea, and rarely, vomiting.

Gastrointestinal complaints are typically dose-related, and lessen with time.

Exenatide extended release has the lowest rate of stomach upset. Regular release exenatide has the highest.

In general, the longer-acting GLP-1 agonists are associated with less stomach upset.

Injection site reactions are seen most commonly with the once weekly GLP-1's.

Satisfaction is similar among the GLP-1's, with studies reporting most improvements arising from changing from twice daily exenatide to one of the weekly formulations.

Recently, cases of acute pancreatitis have been described in people treated with exenatide and liraglutide.

Risk assessment is complicated since pancreatitis risk is already increased in people who are obese and who have Type 2 Diabetes.

A 2013 statement from the FDA and the European Medicines Association stated, "available data do not confirm recent concerns over an increased risk for pancreatic side effects with glucagonlike peptide-1 (GLP-1)-based diabetes therapies".

This is a link to the article:

More recent studies have supported the lack of a signal for pancreatitis in multiple randomized clinical trials.

This class of drugs should nonetheless not be used if you have a history of pancreatitis.

Thyroid tumors were seen in mice and rats treated with liraglutide in pre-clinical trials.

These findings were not observed in monkeys.

There were no reported cases of medullary thyroid cancer in multiple human clinical trials.

Nonetheless, this class of drugs shouldn't be used if you or anyone in your family has a history of medullary thyroid cancer or Multiple Endocrine Neoplasia Type 2 (MEN 2).

Incretins also appear to promote the growth and survival of beta cells (the cells that release insulin).

The LIBRA Trial (Diabetes Care 2014; 37:3270-3278) reported preservation of beta cell function at 48 weeks in 51 people with Type 2 diabetes of 2.6 +/- 1.9 years duration treated with liraglutide. Benefits were lost when therapy was discontinued.

The clinical relevance of this is unknown pending further long-term trials.

The second class of incretin related drugs are the "DPP-4 inhibitors" (also known as the DPP-4's).

The DPP-4's inhibit the breakdown of the incretins, thereby increasing circulating levels of these hormones.

The most commonly used drugs in this class are sitagliptin (Januvia), saxagliptin (Onglyza) and linagliptin (Tradjenta). All are once daily oral medications.

The DPP-4 inhibitors reduce HA1C levels by an average of 0.8%.

Fasting and after-meal blood sugar levels are reduced, albeit to a lesser degree than with the GLP-1's. The DPP-4's are "weight-neutral" without an effect on appetite.

The DPP-4 inhibitors are very well tolerated due to simple once daily dosing and rare side effects.

Linagliptin does not require dose alteration in the setting of kidney disease.

Two studies published in 2013 noted an increased incidence of congestive heart failure among users of saxagliptin and alogliptin.

Although results from subsequent trials have been inconsistent, with some showing no risk (EXAMINE) and others reporting risk in combination with metformin, caution should be exercised in people with, or at high risk for, congestive heart failure.

Sitagliptin (Januvia) was shown to be heart neutral in the TECOS trial. We were one of the investigator sites for this trial.

We have been investigators in many of the pivotal incretin trials.

Despite a lack of heart benefits, the DPP-4's continue to be the most commonly prescribed of the newer oral diabetes agents.

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