DPP-4 inhibitors are now available from various companies. DPP4 inhibitors work by blocking dipeptidyl peptidase IV (DPP-4), an enzyme that breaks down gut peptides, especially GLP-1. Unlike GLP-1 agonists that increase GLP-1 action, DPP-4 inhibitors work indirectly to raise GLP-1. Blocking DPP-4 makes GLP-1 levels rise and increases insulin release after meals and when glucose levels are high. However, inhibition of DPP-4 also causes levels of GLP-2, GIP, and other gut peptides to rise.
DPP-4 inhibitors have a major advantage over other diabetes medications in that glucose control remains stable with little or no rise in A1c levels for long periods of use. With other drugs, a gradual and persistent rise in glucose levels over time is seen. This loss of drug effect has not been seen as yet with DPP-4 inhibitors or GLP-1 agonists which both work by raising GLP-1 levels in the blood. GLP-1 increases insulin levels by increasing beta-cell mass and by decreasing apoptosis or destruction of cells, especially beta cells.
DPP-4 is a key enzyme involved in the breakdown of a variety of gut peptides. These peptides possess a variety of activities and many breakdown products also have their own biological activity. A shift in biological activity will occur because of delayed breakdown and higher levels of several incretins, but also because this delays the appearance of biologically active breakdown products.
The overall consequences of interfering with gut peptide has to this point not been a major problem, but not all of the gut peptides that DPP-4 interacts with are known and some of the known ones, like GLP-2, have biological activities that are poorly understood.
Not all GLP-1 activities are positive. It can raise arterial blood pressure and heart rate through an increase in epinephrine levels, although the overall effect on peripheral blood pressure has been positive. Although the decrease in apoptosis or cell death would generally be considered positive, this effect might not be helpful if some cancer cells also lived longer.
The FDA approved Linagliptin, also known as Tradjenta, tablets in May of 2011. Made by Boehringer Ingelheim and Eli Lilly and Company, it was the first DPP-4 to be approved in one standard dose of 5 mg, regardless of kidney or liver impairment, age, or weight. It’s taken once a day, with or without food.
The FDA has approved the use of linagliptin alone or in combination with other commonly prescribed medications for type (2) diabetes—such as metformin, sulfonylurea, and pioglitazone. The risk of low blood sugar levels is minimal when taken alone, but when combining with other types of medications, the risk is substantially higher.
During the clinical studies, the most common side effects were cold-like symptoms, stuffy nose, sore throat, coughing, high cholesterol, high triglycerides, and weight gain.
Linagliptin should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it is not effective for treating these conditions.
Learn more about Tradjenta at www.tradjenta.com
As a once-a-day tablet, Januvia, also called sitagliptin phosphate, coupled with diet and exercise, allows the body to produce the proper amount of insulin to handle high blood sugars without causing hypoglycemia. It has not been studied with other medicines known to cause low blood sugar, such as sulfonylureas or insulin. Before taking Januvia, be sure your doctor realizes it may not be appropriate if you are taking a sulfonylurea or other medicine that can cause low blood sugar.
During clinical trials, Januvia was examined in a few thousand patients with type 2 diabetes during studies lasting from 12 weeks to more than a year. These studies demonstrated improved blood sugar control when Januvia was used alone in patients not properly managed with Metformin or a PPAR agonist.
Januvia can be taken alone or together with certain other diabetes medicines to help control blood sugar. Take Januvia exactly as your doctor has prescribed. For most people, the recommended dose is:
- one 100-mg pill once a day (anytime)
- by mouth, with or without food
In clinical studies, the most common side effects of Januvia have been a small but insignificant increase in upper respiratory tract infections, sore throats, and diarrhea. These side effects, so far, have appeared to be mild. Weight gain and low blood sugar are often seen with some diabetes medications but do not appear to be an issue with Januvia.
Januvia is not for patients with Type 1 diabetes or for patients with diabetic ketoacidosis (increased ketones in the blood or urine). If you have kidney problems, your doctor may prescribe lower doses of Januvia.
Learn more about Januvia at www.januvia.com.
Onglyza, approved by the FDA in July 2009, is a prescription medicine that is also used along with diet and exercise to lower blood sugar in adults with type 2 diabetes mellitus. Onglyza comes as a tablet that you take with your food. You can take it any time of day; however, it is suggested that you try to take it at the same time every day. For the medication to work properly, it must be taken as prescribed. The dosage that your healthcare provider recommends will vary depending on a number of factors, including your current control level, other medical conditions you may have, and other medications you may currently be taking. Onglyza has not been studied with insulin but it has been studied other oral diabetes medications.
The clinical trials for Onglyza included studies that evaluated the drug at up to 80 times therapeutic clinical doses. The six core Phase III trials assessing the safety and efficacy of saxagliptin involved more than 4,000 patients, including 3,000 who were treated with saxagliptin. During the studies, Onglyza lowered A1c, morning blood sugar (FPG), and after-meal blood sugar (PPG) when added to one of several common oral diabetes medicines. The most common side effects with Onglyza include upper respiratory tract infection, urinary tract infection, and headache.
When Onglyza is used with certain other diabetes medicines to treat high blood sugar, such as a sulfonylurea, low blood sugar (hypoglycemia) may occur. Follow your healthcare provider’s instructions for treating low blood sugar.
If you have allergic (hypersensitivity) reactions, such as rash, hives, and swelling of the face, lips, and throat, stop taking Onglyza and call your healthcare provider right away.
When Onglyza is used with a thiazolidinedione (TZD), such as pioglitazone or rosiglitazone, to treat high blood sugar, peripheral edema (fluid retention) may become worse. If you have symptoms of peripheral edema, such as swelling of hands, feet, or ankles, call your healthcare provider.
Your healthcare provider should test your blood to measure how well your kidneys work. You may need a lower dose of Onglyza if your kidneys are not working well. Tell your healthcare provider if you start or stop taking other medications, including antibiotics, antifungals, or HIV/AIDS medications, as your healthcare provider may need to change your dose of Onglyza. Tell your healthcare provider if you are pregnant or breast-feeding, or plan to become pregnant or breast-feed.
Galvus was approved by the FDA in March of 2006. It blocks dipeptidyl peptidase enzymes (DPP-4) which breaks down the proteins that trigger the release of insulin. This helps your pancreas make more insulin and tells your liver to make less sugar. As a once-a-day tablet, this new medication, coupled with proper diet and exercise, allows the body to produce the proper amount of insulin to handle high blood sugars after meals.
As a once-daily dose, Galvus was studied in more than 4,300 patients worldwide. It was studied as monotherapy and in combination with other prescribed anti-diabetic medicines. During the study, Galvus demonstrated it can reduce blood sugar for up to one year. It was not associated with weight gain.
The most common side effects were cold-like symptoms, headaches, and dizziness.