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Dipeptidyl-peptidase-4 (DPP-4) inhibitors potentiate the effects of the incretin hormones glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) by inhibiting their breakdown by DPP-4. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells leading to reduced hepatic glucose production, and GLP-1 slows gastric emptying time. By increasing concentrations of incretin hormones in the bloodstream, DPP-4 inhibitors reduce fasting and postprandial glucose concentrations in a glucose-dependent manner; GLP-1 does not increase insulin secretion when the glucose concentration is less than 90 mg/dL.
Dosage Comparison of DPP-4 inhibitors (Adults)
Adjust Dose for Renal Impairment*
25 mg once daily
(CrCl less than 60 mL/minute)
5 mg once daily
2.5 to 5 mg once daily
(eGFR less than 45 mL/minute/1.73 m2)
100 mg once daily
Abbreviations: CrCl= Creatinine clearance; eGFR = estimated glomerular filtration rate
*Parentheses note the threshold at which dosage adjustment is first initiated
DPP-4 inhibitors Comparative Efficacy Trials
Craddy P, et al.
There were no differences between DPP-4 inhibitors in the 4 key efficacy and safety outcomes:
1) A1C mean change from baseline
2) Mean change in body weight
3) Proportion of patients achieving A1C less than 7%
4) Number of patients with hypoglycemic events
Scirica BM, et al.
N Engl J Med 2013;369:1317-26.
HR for MACEs:
1 [95% CI, 0.89 to 1.12] (p = 0.99)
HR for MI:
0.95 [95% CI, 0.80 to 1.12] (p = 0.52)
HR for Stroke:
1.11 [95% CI, 0.88 to 1.39] (p = 0.38)
HR for CV Mortality:
1.03 [95% CI, 0.87 to 1.22] (p = 0.72)
HR for All-cause mortality:
1.11 [95% CI, 0.96 to 1.27] (p = 0.15)
HR for Heart Failure Hospitalization:
1.27 [95% CI, 1.07 to 1.51] (p = 0.007)
HR for Renal Outcomes:
1.08 [95% CI, 0.88 to 1.32] (p = 0.46)
Green JB, et al.
N Engl J Med 2015; 373:232-42.
A 3-year, randomized, double-blind non-inferiority study to assess the risk of MACEs, i.e., CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina with sitagliptin (n = 7,332) or placebo (n = 7,339) in addition to existing therapy in patients with type 2 DM and CV disease.
0.98 [95% CI, 0.89 to 1.08] (p is less than 0.001)
0.95 [95% CI, 0.81 to 1.11] (p = 0.49)
0.97 [95% CI, 0.79 to 1.19] (p = 0.76)
1.03 [95% CI, 0.89 to 1.19] (p = 0.71)
1.01 [95% CI, 0.90 to 1.14] (p = 0.88)
1 [95% CI, 0.83 to 1.20] (p = 0.98*)
White WB., et al.
N Engl J Med 2013;369:1327-35.
0.96 (less than or equal to 1.16)**
1.08 [95% CI, 0.88 to 1.33] (p = 0.47)
0.95 (less than or equal to 1.14)***
0.85 [95% CI, 0.66 to 1.10] (p = 0.21)
0.88 [95% CI, [0.71 to 1.09] (p = 0.23)
Abbreviations: CI, confidence interval; CV, cardiovascular; DM, diabetes mellitus; HR, hazard ratio; MACE, major cardiovascular events; MI, myocardial infarction; OR, odds ratio
*The p value is for the noninferiority of sitagliptin, as compared with placebo, which was calculated by determining whether the upper boundary of the two-sided 95% confidence interval of the hazard ratio exceeded 1.30.
**Upper boundary of the one-sided repeated confidence interval, 1.16; p is less than 0.001 for noninferiority
***The parenthetical value is the upper boundary of the one-sided repeated CI, at an alpha level of 0.01.
The dipeptidyl-peptidase-4 (DPP-4) inhibitors are generally well-tolerated in everyday use. Headache was a common adverse effect in clinical trials of these agents vs. placebo. When compared with other active glucose-lowering agents, both in randomized-controlled trials and in real-life observational studies, DPP-4 inhibitors were shown to exert less GI side effects than metformin, acarbose, and GLP-1 receptor agonists.
The dipeptidyl-peptidase-4 (DPP-4) inhibitors are generally considered weight neutral and to have a low risk of hypoglycemia. When compared with other active glucose-lowering agents in randomized-controlled trials and in real-life observational studies, DPP-4 inhibitors are associated with a lower incidence of hypoglycemia than sulfonylureas and insulin and less weight gain than sulfonylureas, thiazoladinediones, and insulin. When a DPP-4 inhibitor is used with an insulin secretagogue or insulin, the dose of these agents may need to be reduced to decrease the risk for hypoglycemia. In specific analyses, the addition of a DPP-4 inhibitor to insulin therapy improved A1C levels without increasing the incidence or severity of hypoglycemia.
Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with dipeptidyl-peptidase-4 (DPP-4) inhibitors. These reactions have typically occurred within 3 months of drug initiation, with some occurring after the first dose. Angioedema is theorized to be a result of simultaneous pharmacological inhibition of 2 enzymes, DPP-4 and angiotensin-converting enzyme (ACE), due to the accumulation of vasoactive kinins. Other serious events that have been reported include serious skin reactions. Bullous pemphigoid or pemphigus requiring hospitalization has occurred. A careful analysis of the French Pharmacovigilance Database showed a strong signal for an increased risk of bullous pemphigoid during DPP-4 inhibitor exposure (OR 67.5; 95% CI, 47.1 to 96.9). Serious exfoliative skin conditions, including Stevens-Johnson syndrome, as well as urticaria, vasculitis, stomatitis and mouth ulceration, have also been reported postmarketing with the various DPP-4 inhibitors. These adverse drug reactions have been suggested to be a class effect.
Dipeptidyl-peptidase-4 (DPP-4) inhibitors have been reported to cause severe arthralgia and disabling joint pain, possibly requiring hospitalization. Arthralgia symptoms can occur from 1 day to several years after the start of therapy with a DPP-4 inhibitor. Symptoms typically resolve with discontinuation of therapy, usually in less than a month; however, some patients experience a recurrence of joint pain when restarting the same drug or switching to another DPP-4 inhibitor. The incidence of these adverse events and the underlying mechanism remain unknown. It has been suggested that such adverse events might be related to cytokine-induced inflammation.
An increased risk of hospitalization for heart failure (hHF) was reported with saxagliptin in the SAVOR trial; however, this adverse event was not confirmed with sitagliptin in the TECOS trial, even in high-risk patients. In EXAMINE, a non-significant trend for a higher rate of hospitalization due to heart failure was observed in alogliptin-treated patients vs. placebo in a high-risk population with a recent acute coronary syndrome. A systematic review concluded that the relative effect of dipeptidyl-peptidase-4 (DPP-4) inhibitors on the risk of heart failure (HF) is uncertain, although the risk for events due to heart failure may be increased in patients with existing cardiovascular disease (CV), recent acute coronary syndromes, or chronic kidney disease. Numerous observational studies focusing on this possible adverse reaction were unable to evidence an increased risk of HF or hHF in type 2 diabetes mellitus (T2DM) patients treated with DPP-4 inhibitors compared to patients treated with other glucose-lowering agents. None of CV outcome trials used echocardiography at baseline to provide a precise diagnosis of HF; therefore, few precise data are available in T2DM patients with well-diagnosed HF and treated with DPP-4 inhibitors. The risk for heart failure due to DPP-4 agents in patients with T2DM does not appear to be increased versus the use of other agents, such as the sulfonylureas, even in T2DM patients with underlying heart disease. The SAVOR, EXAMINE, and TECOS trials showed that saxagliptin, alogliptin, and sitagliptin were not associated with any increase in the number of major cardiovascular events (MACEs) in high cardiovascular (CV) risk patients. These events included CV-related death, non-fatal myocardial infarction (MI), and non-fatal ischemic stroke. In observational studies, CV outcomes were more favorable in T2DM patients treated with DPP-4 inhibitors than in those treated with sulfonylureas or active glucose-lowering agents. CV outcome studies with linagliptin are in progress.
A slight risk of acute pancreatitis with dipeptidyl-peptidase-4 (DPP-4) inhibitors has been reported in a meta-analysis of the 3 cardiovascular outcome trials (EXAMINE, SAVOR, TECOS) compared with placebo. An absolute increased risk of 0.13% was estimated, which should translate to 1 to 2 additional cases of acute pancreatitis for every 1,000 type 2 diabetes mellitus (T2DM) patients treated for 2 years. Several observational studies in different countries were unable to discern an increased risk of acute pancreatitis related to DPP-4 inhibitor therapy compared with other glucose-lowering agents. After an extensive review of the available data, the FDA and EMA announced a position statement that the data do not support an increased risk of pancreatitis in patients receiving DPP-4 inhibitors. The risk of pancreatic cancer, if anything, appears to be reduced rather than increased in T2DM patients treated with DPP-4 inhibitors. These data are reassuring, although further postmarketing surveillance is still recommended.
Adverse reactions related to renal impairment have been reported with dipeptidyl-peptidase-4 (DPP-4) inhibitors. Decreased creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR), increased serum creatinine, and acute renal failure, sometimes requiring dialysis, have been reported. The risk for worsened renal impairment may be increased in patients of increasing age, with high cardiovascular or renal risk factors, such as those with pre-existing chronic kidney disease. Monitoring of renal function may be advisable in these higher risk patients. In a meta-analysis of 36 placebo-controlled randomized-controlled trials, allowing analyses of 54,664 patients, there was no significant difference in renal failure (RR 1.06; 95% CI, 0.88 to 1.27) with the use of DPP-4 inhibitors compared with placebo. In other analyses, the addition of a DPP-4 inhibitor to insulin therapy improved A1C levels irrespective of renal function without increasing the number of renal adverse events.
An slightly increased risk of infection, specifically upper respiratory tract infections and nasopharyngitis, has been reported in patients receiving DPP-4 inhibitors compared with patients receiving other anti-diabetic drugs. With saxagliptin, a decrease in lymphocyte count (750 cells/microL or less) has been observed infrequently. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured in patients receiving saxagliptin. The lymphopenia is usually reversible with drug discontinuation and does not appear to recur in most patients on drug rechallenge.
There have been postmarketing reports of elevated hepatic enzymes (ALT) fatal and nonfatal hepatic failure in patients taking alogliptin, although some of the reports contain insufficient information necessary to establish the probable cause. If a patient is found to have symptoms suggestive of liver impairment, clinically significant liver enzyme elevations, and if abnormal liver tests persist or worsen, the drug should be interrupted and investigation done to establish the probable cause. Do not restart the drug unless another cause of the abnormalities is determined. In a review of DPP-4 inhibitors, the ability for these drugs to cause hepatic toxicity is questionable, and the DPP-4 inhibitors have been shown to improve fatty liver disease in some studies. Only alogliptin carries a caution regarding use in hepatic disease.
In general, the propensity of the (DPP-4) inhibitors to exhibit drug interactions is low as these drugs are not reported to induce or inhibit the hepatic CYP450 enzyme system. Saxagliptin is the DPP-4 inhibitor with the greatest likelihood for CYP-related drug-drug interactions, as a substrate of CYP3A4/5. Metabolism of sitagliptin and linagliptin is minimal, and for the most part, not clinically significant. Alogliptin is primarily renally excreted and metabolism is negligible; of the DPP-4 inhibitors, it is the agent devoid of potential CYP450 or drug transporter mediated interactions.
Saxagliptin is a substrate for the CYP450 isoenzymes 3A4 and 3A5. The adult saxagliptin dose is limited to 2.5 mg/day when coadministered with a strong CYP3A4/5 inhibitor such as atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin. The concomitant use of saxagliptin with a strong CYP3A4/5 inhibitors can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
Sitagliptin and saxagliptin are both P-glycoprotein (P-gp) substrates. Concomitant use of drugs that are P-gp inhibitors or inducers with sitagliptin or saxagliptin in theory would alter the concentrations of these drugs. However, no clinically significant drug interactions related to inhibition of P-gp have been reported; no dosage adjustments are recommended. For patients receiving digoxin (a P-gp substrate) in combination with sitagliptin, monitoring of patients is recommended according to prescribing information as a slight increase in AUC of digoxin was observed in drug-drug interaction studies that was not considered clinically relevant for most patients.
Linagliptin has a low propensity for pharmacokinetic drug interactions. Linagliptin is a P-gp substrate, and CYP3A4 appears to play a minimal role in metabolism. However, administration with a strong P-gp and CYP3A4 inducer (rifampin) decreased linagliptin exposure, suggesting that the efficacy of the drug may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducers. Interactions with CYP3A4 or P-gp inhibitors are not considered clinically significant.
The safety issues listed are considered relevant to all dipeptidyl-peptidase-4 (DPP-4) inhibitors.
Serious hypersensitivity reactions, including angioedema and anaphylaxis have been reported in patients during the first 3 months of therapy with a dipeptidyl-peptidase-4 (DPP-4) inhibitor; some reports occurred after the first dose. Use caution in patients with a history of angioedema or anaphylaxis to DPP-4 inhibitors; it is unknown whether patients who reacted to one agent will be predisposed to serious reactions with another agent in the class. If a hypersensitivity reaction is suspected, discontinue the drug, assess for other potential causes for the event, and institute appropriate treatment, including alternative treatment for diabetes. Postmarketing cases of serious skin reactions, including severe exfoliative dermatitis and bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. If a serious allergic or dermatologic reaction is suspected, discontinue the DPP-4 inhibitor and refer the patient to a dermatologist for diagnosis and appropriate treatment.
Severe arthralgia can occur from 1 day to several years after the start of therapy with a dipeptidyl-peptidase-4 (DPP-4) inhibitor. Symptoms typically resolve with discontinuation of therapy, usually in less than a month; however, some patients experience a recurrence of joint pain when restarting the same drug or switching to another DPP-4 inhibitor. Advise patients not to discontinue therapy but to contact their health care professional immediately if they experience severe and persistent joint pain while taking a DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue the drug if appropriate.
Dipeptidyl-peptidase-4 (DPP-4) inhibitors should be used with caution in patients who have a history of or who have increased risk factors for heart failure, including type 2 diabetes mellitus (T2DM) patients with existing cardiac disease, recent acute coronary syndromes, or chronic kidney disease. Observe patients receiving DPP-4 inhibitors for signs and symptoms of heart failure, and if heart failure develops, consider discontinuing the drug, initiating therapy as per standard of care, and monitoring for diabetic control. There is considerable controversy regarding the ability of DPP-4 inhibitors to increase the risk for hospitalization due to heart failure in patients with and without underlying known risk factors; close postmarketing monitoring is needed to determine these effects, and further studies are needed to determine if any differences exist among agents within the class.
Acute pancreatitis has been reported in the postmarketing setting for dipeptidyl-peptidase-4 (DPP-4) inhibitors and in randomized clinical trials. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using a DPP-4 inhibitor. After initiation of a DPP-4 inhibitor, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, the DPP-4 inhibitor should promptly be discontinued and appropriate management should be initiated. After an extensive review of the available data, the FDA and EMA announced a position statement that the data do not support an increased risk of pancreatitis in patients receiving DPP-4 inhibitors. These data are reassuring, although further postmarketing surveillance is still recommended given that there have been reports of pancreatitis in clinical use.
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