Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of drugs primarily used in the treatment of type 2 diabetes mellitus (T2DM). These inhibitors work by prolonging the action of incretin hormones, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). While DPP-4 inhibitors are not primarily weight loss medications, understanding their mechanism of action and impact on weight is crucial for diabetes management. This article delves into the mechanisms, therapeutic uses, adverse effects, and the nuanced relationship between DPP-4 inhibitors and weight.
Mechanism of Action
DPP-4 inhibitors function by inhibiting the dipeptidyl peptidase IV (DPP-IV) enzyme. This enzyme is responsible for breaking down incretin hormones like GLP-1 and GIP. By inhibiting DPP-IV, these drugs increase the concentration of active GLP-1 and GIP in the bloodstream.
When blood glucose levels are normal or elevated, GLP-1 and GIP enhance insulin synthesis and release from pancreatic beta cells through intracellular signaling pathways involving cyclic AMP. GLP-1 also reduces glucagon secretion from pancreatic alpha cells, which leads to reduced hepatic glucose production, and it slows gastric emptying time. This glucose-dependent mechanism ensures that GLP-1 does not increase insulin secretion when glucose levels are low (less than 90 mg/dL), reducing the risk of hypoglycemia.
Therapeutic Use
DPP-4 inhibitors are approved by the FDA for use as monotherapy in type 2 diabetes and can also be added to existing treatments like metformin, sulfonylureas, thiazolidinediones, or insulin. When adding DPP-4 inhibitors to sulfonylurea or insulin therapy, it's important to consider reducing the sulfonylurea or insulin dose to minimize the risk of hypoglycemia.
These inhibitors are often recommended as second- and third-line therapy for T2DM. First-line therapy depends on comorbidities, patient-centered factors, and management needs. For patients with T2DM and a high risk for atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or chronic kidney disease (CKD), initial therapy with a sodium-glucose co-transporter 2 (SGLT2) inhibitor or GLP-1 receptor agonist (GLP-1 RA), with or without metformin, is more appropriate based on glycemic needs.
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DPP-4 inhibitors are well-tolerated, have a neutral effect on weight, and have a minimal risk of hypoglycemia when used as monotherapy, making them suitable for special populations like the elderly, patients with renal or hepatic impairment, and those at risk of hypoglycemia.
Dosage and Administration
Several DPP-4 inhibitors are available, each with specific dosing guidelines:
- Sitagliptin: The typical dose is 100 mg once daily. Dosage adjustments are needed for patients with impaired renal function. For example, GFR ≥ 30 to < 45 mL/min requires a dose of 50 mg daily, and GFR < 30 mL/min or patients on hemodialysis require 25 mg daily.
- Saxagliptin: The standard dose is 2.5 or 5 mg once a day, taken with or without food. A reduced dose of 2.5 mg once daily is recommended for patients with GFR < 45 mL/min or those on hemodialysis, administered following hemodialysis.
- Linagliptin: The recommended dose is 5 mg once a day, and it does not require dosage adjustment for renal impairment.
- Alogliptin: Typically, 25 mg is administered once daily. Dosage adjustments are necessary for patients with impaired renal function. For instance, GFR ≥30 to < 60 mL/minute requires 12.5 mg once daily, and GFR ≥15 to < 30 mL/minute or ESRD (GFR < 15 mL/minute or requiring hemodialysis) requires 6.25 mg once daily.
Adverse Drug Reactions
While DPP-4 inhibitors are generally well-tolerated, some adverse reactions have been reported. These include:
- Hypoglycemia, especially when used with sulfonylureas or insulin
- Nasopharyngitis or upper respiratory tract infections
- Headache
- Nausea, diarrhea, abdominal pain
- Urinary tract infections
- Peripheral edema
- Acute pancreatitis
- Hypersensitivity skin reactions like Stevens-Johnson syndrome, urticaria, and exfoliative dermatitis
- Anaphylaxis and angioedema
- Rhabdomyolysis
- Acute renal failure
- Bone fractures (specifically with saxagliptin)
- Lactic acidosis (with Janumet, due to the metformin component)
- Severe arthralgia and disabling joint pain
DPP-4 inhibitors are contraindicated in patients with hypersensitivity reactions to sitagliptin, saxagliptin, linagliptin, or alogliptin. They should not be used in diabetic ketoacidosis or as therapy for type 1 diabetes mellitus.
Drug Interactions
DPP-4 inhibitors can interact with other medications. For instance, sitagliptin can cause a small increase (11%) in the AUC and plasma Cmax (18%) of digoxin. Although a dose adjustment of digoxin is not generally recommended, close monitoring is advised.
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Pharmacokinetics
The pharmacokinetic properties of DPP-4 inhibitors vary:
- Sitagliptin: Has 87% bioavailability, with a peak concentration time of 1-4 hours, is hepatically metabolized, and has 87% renal and 13% fecal excretion. The half-life is 12.4 hours, and the volume of distribution (Vd) is 2.8 L/kg.
- Saxagliptin: Reaches peak concentration in about 2 hours, is hepatically metabolized, and has 60% renal and 22% fecal excretion. Its half-life is 2.5 hours, and Vd is 2.7 L/kg. The AUC increases by 27% when taken with a meal.
- Linagliptin: Is rapidly absorbed, reaching peak concentration in 1.5 hours, is not extensively metabolized, and has a half-life of 12 hours. Its Vd is 1110 L, and 70-80% is protein-bound.
- Alogliptin: Has 100% bioavailability regardless of food intake, is not extensively metabolized, and has a half-life of 21 hours. Its Vd is 417 L, and 20% is protein-bound.
DPP-4 Inhibitors and Weight: A Nuanced Relationship
DPP-4 inhibitors are generally considered weight-neutral. This characteristic sets them apart from other diabetes medications like sulfonylureas and thiazolidinediones, which are associated with weight gain, and GLP-1 receptor agonists, which typically lead to weight loss.
Clinical Trial Observations
Clinical trials have shown that DPP-4 inhibitors do not typically cause significant weight changes. Some studies have reported modest weight loss with vildagliptin, particularly in patients with relatively low baseline glycemia. The weight neutrality of these drugs is likely due to their low risk of hypoglycemia, which prevents the "defensive eating" often seen with other diabetes medications.
- A1C Reduction: Overall A1C reduction for maximum dose sitagliptin (100 mg daily) as monotherapy is only about 0.6% after 18 weeks. When added to metformin, A1C reduction was 0.9% with sitagliptin 100 mg daily. Similar A1C reductions are observed with other DPP-IV inhibitors.
- Monotherapy vs. Combination Therapy: A systematic review and meta-analysis of trials comparing the safety and efficacy of DPP-4 inhibitors found no differences in mean change from baseline in A1C or body weight.
Potential Mechanisms for Weight Neutrality
Several mechanisms may explain the weight neutrality associated with DPP-4 inhibitors:
- Glucose-Dependent Insulin Secretion: DPP-4 inhibitors enhance insulin secretion in a glucose-dependent manner, reducing the risk of hypoglycemia and subsequent compensatory eating.
- Limited Impact on Gastric Emptying: Unlike GLP-1 receptor agonists, DPP-4 inhibitors do not significantly affect gastric emptying.
- Potential Effects on Lipid Metabolism: Some studies suggest that DPP-4 inhibitors, particularly vildagliptin, may influence postprandial lipid and lipoprotein metabolism by inhibiting triglyceride absorption from the gut and promoting lipid mobilization and catabolism.
Impact of Bariatric Surgery on DPP-4 Activity and its Relationship to Weight Loss
Research indicates that weight loss induced by bariatric surgery is associated with decreased circulating DPP4 activity. A study involving 68 non-diabetic patients who underwent bariatric surgery showed that serum DPP4 activity decreased significantly after a median follow-up period of 12 months. This decrease in DPP4 activity was correlated with decreases in BMI, improved cholesterol levels, and reduced hepatic injury markers.
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The study also found that the decrease in DPP4 activity was significantly correlated with changes in BMI, total cholesterol, LDL cholesterol, and liver parameters. This suggests that reduced DPP4 activity after weight loss may contribute to improvements in metabolic markers.
The Role of GLP-1
GLP-1, an incretin hormone, plays a significant role in glucose-dependent insulin secretion, suppression of glucagon secretion, and delayed gastric emptying. DPP-4 inhibitors increase the concentrations of active GLP-1, improving β-cell responsiveness to glucose and suppressing glucagon secretion. This mechanism helps lower both fasting and postprandial glucose concentrations.
However, unlike GLP-1 receptor agonists, DPP-4 inhibitors do not directly affect gastric emptying. This difference may explain why GLP-1 receptor agonists are often associated with weight loss, while DPP-4 inhibitors are generally weight-neutral.
Cardiovascular Safety
Cardiovascular safety data for DPP-4 inhibitors have been investigated in several trials:
- SAVOR-TIMI 53 Trial (Saxagliptin): Reported no difference compared to placebo in the rate of ischemic events. However, the rate of hospitalization for heart failure was increased.
- TECOS Study (Sitagliptin): Showed that sitagliptin did not increase the risk of major adverse cardiovascular events or hospitalization for heart failure in patients with type 2 diabetes and known cardiovascular disease.
- EXAMINE Trial (Alogliptin): Showed that major adverse cardiovascular events were not increased with alogliptin compared to placebo among patients with type 2 diabetes and a recent acute coronary syndrome.
These findings suggest that while some DPP-4 inhibitors may have cardiovascular risks, others do not increase the risk of major adverse cardiovascular events.
Other Considerations
- Pancreatitis Risk: A previous analysis suggested a 2-fold increased odds of hospitalization for acute pancreatitis in patients using sitagliptin or exenatide. However, subsequent studies have not consistently reported similar findings, and the association remains unclear.
- Combination Therapy: Current guidelines do not support the combination therapy of GLP-1 agonists and DPP-4 inhibitors due to a lack of added clinical benefit.