What are DPP-4 Inhibitors?
DPP-4 inhibitors are a class of medications widely used to treat Type 2 diabetes. They are commonly referred to as “gliptins.” Some well-known brands include:
These medications work by enhancing incretin hormone levels (GLP-1 and GIP), which reduce glucagon release, increase insulin secretion, slow gastric emptying, and ultimately, lower blood glucose levels.
One of the advantages of DPP-4 inhibitors is their balance of efficacy and safety, making them suitable for individuals with kidney or liver conditions, as well as those at risk of hypoglycemia.
These medications reduce HbA1c levels by 0.5% to 1.0%, varying with the specific drug and its dosage. This effect, while modest, is achieved with fewer side effects compared to other classes, supporting their use as either monotherapy or in combination with metformin.
However, individuals with type 1 diabetes, pregnant women, and those with a history of pancreatitis should avoid this class of medications.
How DPP-4 Inhibitors Work
When you eat, your body breaks down the food into sugar (glucose). This sugar enters your bloodstream, causing blood sugar levels to increase.
To counteract this rise in blood sugar, your body releases hormones, GLP-1 and GIP. GLP-1 tells your pancreas to release insulin, a hormone that helps transfer glucose from your blood into your cells. GIP also helps stimulate insulin release.
However, your body also contains an enzyme known as DPP-4, which quickly breaks down GLP-1 and GIP. This breakdown diminishes their ability to effectively control blood sugar levels.
This is where DPP-4 inhibitors come into play. They work by blocking the activity of the DPP-4 enzyme. As a result, GLP-1 and GIP remain in the body longer, enhancing their ability to control blood sugar levels.
To summarize, DPP-4 inhibitors enhance the action of incretin hormones essential for lowering blood sugar levels by inhibiting the DPP-4 enzyme, which is responsible for their breakdown. This action increases the hormones' presence and activity, helping to manage blood sugar levels more effectively.
Comparing DPP-4 Inhibitors
DPP-4 inhibitors work by increasing incretin levels (GLP-1 and GIP), which in turn inhibit glucagon release, increase insulin secretion, decrease gastric emptying, and decrease blood glucose levels. While their efficacy in lowering A1C levels, mechanisms of action, and side effects are somewhat similar across the class, there are differences in terms of specific active ingredients and costs.
Sitagliptin (JANUVIA, ZITUVIO)
- A1C Reduction: 0.5 to 1%
- Strengths: 25, 50, 100 mg
- Side Effects: Upper respiratory tract infection, headache, and nasopharyngitis. Pancreatitis and joint pain are rare but serious side effects
- Interactions: Beta-blockers (Metoprolol, Propranolol), Timolol (glaucoma eye drops)
- FDA Approval: JANUVIA: October 2006, ZITUVIO: October 2023
Sitagliptin was the first of the DPP-4 inhibitor class to be approved for use, setting the stage for this category of diabetes treatment.
The approval of ZITUVIO in 2023 is significant due to recent findings by the FDA in 2022, which revealed the presence of nitrosamine impurities, specifically Nitroso-STG-19 (known as NTTP), in select samples of sitagliptin. This discovery raised concerns about potential shortages of sitagliptin-based medications. ZITUVIO underwent rigorous quality testing to ensure it remained free from these potential carcinogens before its approval in October 2023.
At the same time Zydus the manufacturer of ZITUVIO got the first generic sitagliptin approved, providing patients with an affordable alternative. The only sitagliptin generic is exclusively available through Marley Drug for $80/month.
However, although JANUVIA and ZITUVIO have the same active ingredient, it is important to keep in mind that these medications are not considered to be interchangeable due to the use of different salt forms of sitagliptin in each drug.
Saxagliptin (KOMBOLYZE)
- A1C Reduction: 0.5 to 1%
- Strengths: 2.5, 5 mg
- Side Effects: Upper respiratory tract infection and urinary tract infection. There is a warning for heart failure risk.
- Interactions: Antibiotics (Ciprofloxacin, Moxifloxacin)
- FDA Approval: July 2009
It is not always the first-choice treatment for Type 2 diabetes. This is due to its potentially less consistent effectiveness in lowering blood sugar levels, especially when used as a standalone therapy, compared to other diabetes medications.
Linagliptin (TRADJENTA)
- A1C Reduction: 0.5 to 0.8%
- Strengths: 5 mg
- Side Effects: Hypoglycemia (when combined with other treatments), headache, and nasopharyngitis. It has a low risk of pancreatitis.
- Interactions: Antibiotics (Rifampin), beta-blockers (Metoprolol, Atenolol)
- FDA Approval: May 2011
Linagliptin is unique among DPP-4 inhibitors for its selective binding to the DPP-4 enzyme. This specificity allows for once-daily dosing without the need for renal dose adjustment, making it a convenient option for patients with kidney issues.
Alogliptin (NESINA)
- A1C Reduction: 0.5 to 0.8%
- Strengths: 6.25, 12.5, 25 mg
- Side Effects:Nasopharyngitis, headache, and a risk of pancreatitis are noted. It may also cause joint pain.
- Interactions: Antibiotics (Ciprofloxacin, Moxifloxacin), beta-blockers (Metoprolol)
- FDA Approval: January 2013
Combination Pills
DPP-4 inhibitors are not typically considered first-line treatment options for type 2 diabetes. These medications are often used in combination with metformin, or insulin, to achieve optimal glycemic control.
Combining DPP-4 inhibitors with other medications is often done to achieve more comprehensive blood sugar control with type 2 diabetes. This approach targets multiple aspects of the condition, such as insulin production, insulin sensitivity, and glucose absorption, leading to better overall management of blood sugar levels. Additionally, combining medications may allow for lower doses of each drug, potentially reducing the risk of side effects while still providing effective treatment.
| Generic | Brand | Strength |
|---|---|---|
| Sitagliptin + Metformin | JANUMET | 50mg/500mg, 50mg/1,000mg |
| ZITUVIMET | 50mg/500mg, 50mg/1,000mg | |
| Alogliptin + Metformin | KAZANO | 12.5mg/500mg, 12.5mg/1,000mg |
| Linagliptin + Metformin | JENTADUETO | 2.5mg/500mg, 2.5mg/850mg, 2.5mg/1,000mg |
| Saxagliptin + Metformin | KOMBOLYZE XR | 5mg/500mg, 2.5mg/1,000mg, 5mg/1,000mg |
In some cases, your healthcare provider may recommend combining a DPP-4 inhibitor and metformin to help manage your blood sugar levels.
Metformin, classified as a biguanide, works by reducing the release of sugar from the liver into the bloodstream and decreasing the absorption of sugar by the body from the gastrointestinal tract. Additionally, it enhances your body's response to insulin.
Typically, for those with diabetes, metformin is prescribed as the primary medication. If metformin isn’t effective in controlling blood sugar levels, your healthcare provider may recommend adding sitagliptin to your treatment regimen.
It is important to know that medications containing metformin carry a boxed warning indicating a potential risk of lactic acidosis, a rare but serious condition characterized by the accumulation of acids in the body. Stop taking your medication and call your doctor right away if you:
- experience dizziness or lightheadedness
- feel cold in your hands or feet
- feel very weak or tired
- experience abnormal muscle pain
- have difficulty breathing
- experience stomach pains, nausea, or vomiting
Additionally, prolonged use of metformin can lead to a decrease in vitamin B12 levels over time. Your healthcare provider may monitor your B12 levels regularly or initiate supplementation with vitamin B12 to address any deficiencies.
Side Effects
Common Side Effects
- Hypoglycemia: confusion, dizziness, fatigue, increased heartbeat, headache, hunger, irritability, sweating, and/or weakness
- Gastrointestinal problems: nausea, upset stomach, vomiting, diarrhea, and/or constipation
- Skin reactions
- Upper respiratory tract infection: headache, runny nose, and/or sore throat
Serious Side Effects
- Pancreatitis: There have been reports of acute pancreatitis associated with the use of DPP-4 inhibitors. Patients should be monitored for signs and symptoms of pancreatitis, such as severe abdominal pain that may radiate to the back, nausea, and vomiting.
- Severe Skin and Allergic Reactions: Rare cases of serious hypersensitivity reactions, including anaphylaxis, angioedema, rash, blisters, sores, trouble breathing, and swelling have been reported with the use of DPP-4 inhibitors.
- Joint pain:Some may experience joint pain while taking DPP-4 inhibitors. In some cases, this pain may be severe and debilitating.
- Kidney problems: Not urinating, swelling in your legs or ankles, feeling tired, trouble breathing, confusion, or feeling nauseous
- Heart Failure: There have been reports of heart failure exacerbation in patients treated with some DPP-4 inhibitors. Patients with a history of heart failure or at increased risk for heart failure should be monitored closely.
Speak With Your Doctor
Speaking with your doctor about DPP-4 inhibitors and their benefits is important because they can provide guidance based on your health needs and medical history. Your doctor can assess whether DPP-4 inhibitors are appropriate for you and discuss the potential benefits they may offer in managing your type 2 diabetes.
Additionally, your doctor can help you choose the most appropriate DPP-4 inhibitor medication based on factors such as efficacy, safety profile, potential side effects, and any other medications you may be taking. This ensures you receive the most effective and suitable treatment for your condition.