Elsevier Logo

English

DrugClassOverview

TRANSFORM HOW YOU USE DRUG INFORMATION

Learn more about Elsevier's Drug Information today! Get the drug data and decision support you need, including TRUE Daily Updates™ including every day including weekends and holidays.

Mar.01.2019

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

Summary

  • 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.
  • DPP-4 inhibitors are used as initial monotherapy or part of combination therapy to treat type 2 diabetes mellitus (DM).
  • Efficacy and safety of the drugs in this class appear similar; however, linagliptin is the only DPP-4 inhibitor that does not require dose adjustment for renal impairment. Alogliptin is not involved in CYP450 system or drug-transport based drug interactions.
  • DPP-4 inhibitors reduce postprandial glucose with minimal risk of hypoglycemia and gastrointestinal adverse effects; they are also weight neutral.
  • Secondary to the widespread use of these medications, there is concern regarding certain adverse effects, such as heart failure and arthralgia.

Pharmacology/Mechanism of Action

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.[32810][32811] 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.[32810]

Therapeutic Use

  • Dipeptidyl-peptidase-4 (DPP-4) inhibitors, in general, are recommended as second- and third-line therapy for type 2 diabetes mellitus (T2DM).
  • Metformin is first-line in the treatment of type 2 DM. In patients with established cardiovascular (CV) disease, heart failure (HF), or chronic kidney disease (CKD), a sodium-glucose co-transporter 2 (SGLT2) inhibitor or glucagon-like peptide-1 receptor agonist (GLP-1 RA) with proven CV benefit and reduction of CKD progression is recommended for add-on therapy, independent of baseline A1C or individualized A1C target. In patients without indicators of high-risk or established CVD, HF, or CKD, the DPP-4 inhibitors are a therapeutic option which are generally well tolerated, have a neutral effect on weight, and have minimal risk of hypoglycemia when used as monotherapy.[50321][64933][64926][60608]
  • Because of their favorable efficacy/safety profile, DPP-4 inhibitors are well suited for special populations of T2DM patients such as the elderly, patients with renal or hepatic impairment, and patients at risk of hypoglycemia.[62978][62980]
  • Except for linagliptin, the DPP-4 inhibitors require dose adjustments for renal impairment.
  • Only alogliptin requires caution in hepatic impairment; no alogliptin dosage adjustments are necessary for mild to moderate hepatic impairment, but the drug has not been studied in severe liver disease.

 

Dosage Comparison of DPP-4 inhibitors (Adults)

 

Oral Dosage

Adjust Dose for Renal Impairment*

Alogliptin

25 mg once daily

Yes

(CrCl less than 60 mL/minute)

Linagliptin

5 mg once daily

No

Saxagliptin

2.5 to 5 mg once daily

Yes

(eGFR less than 45 mL/minute/1.73 m2)

Sitagliptin

100 mg once daily

Yes

(eGFR less than 45 mL/minute/1.73 m2)

Abbreviations: CrCl= Creatinine clearance; eGFR = estimated glomerular filtration rate

*Parentheses note the threshold at which dosage adjustment is first initiated

Comparative Efficacy

  • Dipeptidyl-peptidase-4 (DPP-4) inhibitors significantly reduced A1C at 24 weeks by 0.6% (0.5% to 0.7%) when compared with placebo; they showed a similar efficacy in monotherapy and in combination with other agents.[62978]
  • In a systematic review and meta-analyses of trials comparing the safety and efficacy of all DPP-4 inhibitors, there were no differences in mean change from baseline in A1C or body weight, or the proportions of patients achieving A1C less than 7% or experiencing a hypoglycemic event, apart from in patients on alogliptin plus metformin, who achieved A1C less than 7% more frequently than those treated with saxagliptin plus metformin.[62985]

 

DPP-4 inhibitors Comparative Efficacy Trials

CitationDesign/RegimenResultsConclusion
Comparative Efficacy

Craddy P, et al.

Diabetes Ther.2014;5:1-41.

[62985]

Systematic review and meta-analyses of 83 trials to compare the safety and efficacy of DPP-4 inhibitors in patients with type 2 DM and inadequate glycemic control.

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

 

Similar efficacy and safety for DPP-4 inhibitors as treatment for type 2 DM, either as monotherapy or combination therapy.
Safety Trials

Scirica BM, et al.

N Engl J Med 2013;369:1317-26.

[62981]

A 2-year, randomized, double blind, placebo-controlled trial to study to assess the risk of major adverse cardiovascular events (MACEs), i.e., CV death, MI, or ischemic stroke with saxagliptin (n = 8,280) or placebo (n = 8,212) in patients with type 2 DM who had a history of, or were at risk for, CV events.

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)

 

Saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased.

Green JB, et al.

N Engl J Med 2015; 373:232-42.

[62982]

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.

 

HR for MACEs:

0.98 [95% CI, 0.89 to 1.08] (p is less than 0.001)

 

HR for MI:

0.95 [95% CI, 0.81 to 1.11] (p = 0.49)

 

HR for Stroke:

0.97 [95% CI, 0.79 to 1.19] (p = 0.76)

 

HR for CV Mortality:

1.03 [95% CI, 0.89 to 1.19] (p = 0.71)

 

HR for All-cause mortality:

1.01 [95% CI, 0.90 to 1.14] (p = 0.88)

 

HR for Heart Failure Hospitalization:

1 [95% CI, 0.83 to 1.20] (p = 0.98*)

 

Among patients with type 2 DM and established CV disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse CV events, hospitalization for heart failure, or other adverse events.

White WB., et al.

N Engl J Med 2013;369:1327-35.

[62983]

A 40-month, randomized, double-blind, placebo-controlled, non-inferiority study to assess CV outcomes with alogliptin (n = 2,701) or placebo (n = 2,679) in addition to existing antihyperglycemic and CV drug therapy in patients with type 2 DM and either an acute MI or unstable angina requiring hospitalization within the previous 15 to 90 days

HR for MACEs:

0.96 (less than or equal to 1.16)**

 

HR for MI:

1.08 [95% CI, 0.88 to 1.33] (p = 0.47)

 

HR for Stroke:

0.95 (less than or equal to 1.14)***

 

HR for CV Mortality:

0.85 [95% CI, 0.66 to 1.10] (p = 0.21)

 

HR for All-cause mortality:

0.88 [95% CI, [0.71 to 1.09] (p = 0.23)

 

Among patients with type 2 DM who had had a recent acute coronary syndrome, the rates of major adverse CV events were not increased with alogliptin as compared with placebo.

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.

Adverse Reactions/Toxicities

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.[62984]

Hypoglycemia and weight

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.[62979][62984]

Hypersensitivity and dermatologic reactions

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.[62984][62988] 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.[62984][62987]

Arthralgia

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.[62984][60132][62986]

Heart Failure and cardiovascular issues

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.[62981][62982][62983][62990] 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.[62984][62990] 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.[62984][62981][62991] 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.[62984] 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.[62981][62982][62983][62984] CV outcome studies with linagliptin are in progress.[62984]

Pancreatitis

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.[62981][62982][62983] 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.[62992] 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.[62984] 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.[53573][56778] The risk of pancreatic cancer, if anything, appears to be reduced rather than increased in T2DM patients treated with DPP-4 inhibitors.[62984][62993][62994] These data are reassuring, although further postmarketing surveillance is still recommended.[62984][62992]

Renal impairment

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.[62984][62993] 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.[62979]

Infection

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.[62978][62995] 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.[36111]

Hepatic effects

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.[52999][62984]

Drug Interactions

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.[62853][62996]

Drugs that are strong CYP3A4/5 inhibitors

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.[36111][62996]

Drugs that affect P-glycoprotein (P-gp)

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.[36111][41966][62853][62996]

 

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.[31240][62853][62996]

Safety Issues

The safety issues listed are considered relevant to all dipeptidyl-peptidase-4 (DPP-4) inhibitors.

Hypersensitivity and serious dermatologic reactions

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.[62984]

Arthralgia

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.[60132][62984]

Heart failure

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.[62984][62981][62982][62990]

Pancreatitis

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.[53573][56778][62984][62992]

[31240]Tradjenta (linagliptin) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc.; 2020 Mar.

[32810]Triplitt C, Wright A, Chiquette E. Incretin mimetics and dipeptidyl peptidase-IV inhibitors: potential new therapies for type 2 diabetes mellitus. Pharmacotherapy 2006;26:360-74.

[32811]Miller SA, St. Onge EL. Sitagliptin: a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Ann Pharmacother 2006;40:1336-43.

[36111]Onglyza (saxagliptin) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2019 Jun.

[41966]Januvia (sitagliptin) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2020 Dec.

[50321]Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:2669-2701.

[52999]Nesina (alogliptin) package insert. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2019 Jun.

[53573]Food and Drug Administration (US FDA) Drug Medwatch-FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. Retrieved Mar. 14, 2013. Available on the World Wide Web at http://www.fda.gov/Drugs/DrugSafety/ucm343187.htm.

[56778]Egan AG, Blind E, Dunder K, , et al. Pancreatic safety of incretin-based drugs-FDA and EMA assessment. N Engl J Med 2014;370:794—7.

[60132]Food and Drug Administration (US FDA) MedWatch. Drug safety communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. Retrieved August 28, 2015. Available on the World Wide Web at: http://www.fda.gov/Drugs/DrugSafety/ucm459579.htm

[60608]Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by The American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm 2019 Executive Summary. Endocrine Pract 2019;25:69-100.

[62853]Amin M, Suksomboon N. Pharmacotherapy of type 2 diabetes mellitus: an update on drug-drug interactions. Drug Saf. 2014;37:903-919.

[62978]Scheen AJ. A review of gliptins in 2011. Expert Opin Pharmacother 2012;1:81–99.

[62979]Deacon CF. A review of dipeptidyl peptidase-4 inhibitors Hot topics from randomized controlled trials. Diabetes Obes Metab 2018. Epub ahead of print, doi: 10.1111/dom.13135.

[62980]Barzilai N, Guo H, Mahoney EM, et al. Monotherapy in elderly patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Curr Med Res Opin 2011;27:1049-58.

[62981]Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.

[62982]Green JB, Bethel MA, Armstrong PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2015;373:232-42.

[62983]White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35.

[62984]Scheen AJ. The safety of gliptins: updated data in 2018. Expert Opin Drug Saf. 2018 Epub ahead of print, doi: 10.1080/14740338.2018.1444027.

[62985]Craddy P, Palin HJ, Johnson KI. Comparative effectiveness of dipeptidylpeptidase-4 inhibitors in type 2 diabetes: a systematic review and mixed treatment comparison. Diabetes Ther 2014:5:1—41.

[62986]Mascolo A, Rafaniello C, Sportiello L, et al. Dipeptidyl Peptidase (DPP)-4 Inhibitor-Induced Arthritis/Arthralgia: A Review of Clinical Cases. Drug Saf. 2016 May;39(5):401—7.

[62987]Bene J, Moulis G, Bennani I, et al. Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: a case-noncase study in the French Pharmacovigilance Database. Br J Dermatol 2016;175:296-301.

[62988]Byiers S, Carr D, et al. Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema. Hypertension 2009;54:516-23.

[62990]Li L, Li S, Deng K, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ 2016;352:i610.

[62991]Standl E, Erbach M, Schnell O. Dipeptidyl-peptidase-4 inhibitors and heart failure:class effect, substance-specific effect, or chance effect? Curr Treat Options Cardiovasc Med 2014;16:353.

[62992]DeVries JH, Rosenstock J. DPP-4 inhibitor-related pancreatitis: rare but real! Diabetes Care 2017;40:161-63.

[62993]Rehman MB, Tudrej BV, Soustre J, et al. Efficacy and safety of DPP-4 inhibitors inpatients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials. Diabetes Metab 2017;43:48-58.

[62994]Zhang Z, Chen X, Lu P, et al. Incretin-based agents in type 2 diabetic patients at cardiovascular risk: compare the effect of GLP-1 agonists and DPP-4 inhibitors on cardiovascular and pancreatic outcomes. Cardiovasc Diabetol 2017;16:31.

[62995]Willemen, MJ, Mantel-Teeuwisse AK, Straus SM, et al. Use of dipeptidyl peptidase-4 inhibitors and the reporting of infections:a disproportionality analysis in the World Health Organization VigiBase. DiabetesCare 2011;34:369-74.

[62996]Scheen AJ. Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions. Clin Pharmacokinet 2010;49:573-88.

[64926]American Diabetes Association. Standards of Medical Care in Diabetes - 2021. Diabetes Care. 2021; 44(Suppl 1):S1-S232. Available at: https://care.diabetesjournals.org/content/44/Supplement_1

[64933]Buse JB, Wexler DJ, Tsapas A, et al. 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2019. Epub ahead of print, doi: 10.2337/dci19-0066.

;