Incretins in Diabetes

Incretins are hormones that are released in the gut in response to a meal. The incretins promote insulin secretion, inhibit glucagon, and slow emptying of the stomach. The result of these effects is to lower sugar levels in the morning and after eating a meal. Incretins also appear to promote the growth and survival of beta cells (the cells that release insulin).

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). This is a significant advantage when these hormones are used for treatment.

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 has 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". Currently available drugs in this class are Byetta and Victoza. Both are delivered by injection. Byetta 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 formulation which is currently available requires two injections per day. Victoza has been chemically modified to resist breakdown. It lasts for 11-13 hours, and is injected once per day.

Bydureon, a once weekly version of Byetta, was approved by the FDA in January 2012.

On average, Byetta and Victoza reduce HA1C levels by 1-2%, lower after meal sugars by ~50 mg/dl, and lower fasting sugars by ~25 mg/dl. Both drugs are associated with reduced appetite and an average weight loss of 2-6 pounds after 7 months. At one year, the average weight loss is 10 pounds.

Victoza appears to be more effective in HA1c reduction, with the greatest benefits in people with the highest sugar levels.

The weight-loss benefits associated with this class of drugs are typically described as an early sense of "fullness" while eating a meal. Byetta and Victoza have also been associated with small reductions in blood pressure. New retrospective data suggests a potential role for incretins in the reduction of heart-related risk.

Prospective clinical trials regarding heart disease reduction are now underway. Incretin related side effects include nausea, and rarely, vomiting. Gastrointestinal complaints are typically dose-related, and lessen with time (typically within 6-8 weeks).

Nausea appears to be more common with Byetta.

A gradual increase in dose reduces the frequency and duration of nausea in many patients.

Recently, cases of acute pancreatitis have been described in people treated with Byetta and Victoza. A causal relationship has not been definitively identified.

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

Until further information is available, you should not use these medications if you have a history of pancreatitis, or are judged to be at high risk for this disease.

Thyroid tumors were seen in mice and rats treated with Victoza in pre-clinical trials. These findings were not observed in monkeys. There were no reported cases of medullary thyroid cancer in human clinical trials.

Nonetheless, Victoza should not be used if you have a history of medullary thyroid cancer, or if anybody in your family has medullary thyroid cancer.

The second class of incretin related drugs are the "DPP-4 inhibitors".

The DPP-4 inhibitors inhibit the breakdown of the incretins, thereby increasing circulating levels of these hormones. Currently available drugs in this class include Januvia, Onglyza and Tradjenta. All are once daily oral medications.

The DPP-4 inhibitors reduce HA1C levels by 0.8% on average. Fasting and after-meal blood sugar levels are also reduced. They 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.

These drugs are an interesting addition to the treatment options available to people with Diabetes.

Before you begin therapy, remember to discuss all potential risks with your physician.

Michael A. Dempsey, M.D.