Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus

Authors:: Kathleen Dungan, MD; Anthony DeSantis, MD
Section Editor:: David M Nathan, MD
Deputy Editor:: Katya Rubinow, MD

Literature review current through: Jan 2024.

This topic last updated: Apr 27, 2023.

INTRODUCTION — Glucagon-like peptide 1 (GLP-1)-based therapies (eg, dipeptidyl peptidase 4 [DPP-4, DPP4] inhibitors, GLP-1 receptor agonists) affect glycemia through several mechanisms, including enhancement of glucose-dependent insulin secretion, slowed gastric emptying, and reduction of postprandial glucagon and food intake (table 1).

This topic will review the mechanism of action and therapeutic utility of DPP-4 inhibitors for the treatment of type 2 diabetes mellitus. GLP-1 receptor agonists are discussed separately. General discussions of the initial management of blood glucose and the management of persistent hyperglycemia in adults with type 2 diabetes are also presented separately.

●(See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)

●(See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)

●(See "Management of persistent hyperglycemia in type 2 diabetes mellitus".)

MECHANISM OF ACTION — Glucagon-like peptide 1 (GLP-1) is produced from the proglucagon gene in L cells of the small intestine and secreted in response to nutrients (figure 1) [1]. GLP-1 exerts its main effect by stimulating glucose-dependent insulin release from the pancreatic islets [2]. It has also been shown to slow gastric emptying [3], inhibit inappropriate post-meal glucagon release, and reduce food intake (table 1) [1,4]. GLP-1-based therapies, including the dipeptidyl peptidase 4 (DPP-4) inhibitors, do not usually cause hypoglycemia unless combined with therapies that can cause hypoglycemia [5]. GLP-1 is considered an incretin and is one of a family of naturally occurring gut hormones that is released in response to oral food ingestion, but not to intravenous carbohydrate, and stimulates insulin synthesis and secretion. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Gastrointestinal peptides'.)

DPP-4 inhibitors are a class of oral diabetes drugs that inhibit the enzyme DPP-4 [6]. DPP-4 is a ubiquitous enzyme expressed on the surface of most cell types that deactivates a variety of bioactive peptides, including GLP-1 and glucose-dependent insulinotropic polypeptide (GIP); therefore, its inhibition could potentially affect glucose regulation through multiple effects [7]. However, DPP-4 inhibitors have a modest effect on GLP-1 levels and activity compared with GLP-1 receptor agonists. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)

SUGGESTED APPROACH

Patient selection

●Add-on therapy – Dipeptidyl peptidase 4 (DPP-4) inhibitors may be used as add-on therapy for patients with type 2 diabetes who need modest, additional glucose lowering. They are not the preferred agents for patients with cardiovascular or kidney disease, because they do not impart protective effects on cardiovascular and kidney outcomes. (See 'Cardiovascular effects' below and 'Kidney outcomes' below.)

DPP-4 inhibitor therapy is safe and effective in combination with any of the following:

•Metformin.

•A thiazolidinedione.

•Basal insulin.

•A sulfonylurea.

•A sodium-glucose cotransporter 2 (SGLT2) inhibitor [8,9].

Inadequate data are available to support the efficacy of DPP-4 inhibitors in combination with prandial insulin. Combination therapy with glucagon-like peptide 1 (GLP-1) receptor agonists and DPP-4 inhibitors should be avoided as this combination does not provide additive glucose-lowering effects. (See 'Glycemic efficacy' below.)

DPP-4 inhibitors may be a good option for glucose-lowering therapy particularly in patients at high risk of hypoglycemia, including older patients and those with chronic kidney disease. (See 'Efficacy in chronic kidney disease' below and 'Hypoglycemia and body weight' below.)

Therapeutic options for the management of persistent hyperglycemia in type 2 diabetes are discussed in detail separately. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'.)

●Monotherapy – DPP-4 inhibitors are not used as initial therapy for most patients with type 2 diabetes. Rather, initial therapy usually entails dietary change, weight reduction, exercise, and metformin (in the absence of contraindications). In patients who cannot tolerate or have contraindications to metformin (and to other glucose-lowering medications if indicated for cardiovascular or kidney benefit), DPP-4 inhibitors may be considered as monotherapy. Therapeutic options for the initial management of type 2 diabetes are reviewed in detail separately. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Choice of initial therapy'.)

Contraindications and precautions — The following contraindications and precautions should be considered when initiating DPP-4 inhibitor therapy:

●DPP-4 inhibitors should not be initiated in patients with a history of pancreatitis. (See 'Pancreas' below.)

●Alogliptin and vildagliptin have been associated with liver toxicity and require additional monitoring during treatment. For patients with underlying liver disease, an alternative DPP-4 inhibitor should be selected. (See 'Monitoring' below and 'Liver' below.)

●Patients who develop a hypersensitivity reaction to any DPP-4 inhibitor should not be treated with another agent in this class. (See 'Skin' below.)

●Saxagliptin and alogliptin have been associated with an increased risk of hospitalization for heart failure. In patients with existing cardiovascular disease (CVD) or high cardiovascular risk, other glucose-lowering medications with cardiovascular benefit (eg, sodium-glucose cotransporter 2 [SGLT2] inhibitors or GLP-1 receptor agonists) are preferred. If circumstances require use of DPP-4 inhibitor therapy, an alternative DPP-4 inhibitor (ie, sitagliptin, linagliptin) should be selected. If a patient develops heart failure while taking saxagliptin or alogliptin, the DPP-4 inhibitor should be discontinued. Substitution of an alternative agent should be guided by subsequent monitoring of glycemia. (See 'Heart failure' below.)

Choice of DPP-4 inhibitor — Sitagliptin, saxagliptin, linagliptin, and alogliptin are the dipeptidyl peptidase 4 (DPP-4) inhibitors available for the treatment of type 2 diabetes in the United States and many other countries (table 2). Vildagliptin is available in many countries but not in the United States. Few head-to-head trials have been conducted to guide selection of a specific DPP-4 inhibitor, but available data suggest that DPP-4 inhibitors generally have comparable, modest glucose-lowering efficacy [8]. Patient preference and payer coverage are often considerations for selecting a specific agent. (See 'Glycemic efficacy' below.)

If the decision is made to use DPP-4 inhibitor therapy for glucose lowering, we typically choose either sitagliptin or linagliptin based on data showing the neutral effects of these agents on cardiovascular outcomes including hospitalization for heart failure. (See 'Heart failure' below.)

If DPP-4 inhibitors are used in patients with severe chronic kidney disease (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²), we prefer linagliptin because it is primarily eliminated via the enterohepatic system. (See 'Patients with chronic kidney disease' below and 'Efficacy in chronic kidney disease' below.)

Dosing

Patients with normal kidney function — Dosing for specific DPP-4 inhibitors can be found in the table (table 2) [10]. All of the DPP-4 inhibitors are also available in combined formulations [11-14].

The DPP-4 inhibitors saxagliptin and linagliptin are metabolized by cytochrome P450 (CYP) enzymes. For patients taking strong CYP3A4/5 inhibitors (eg, ketoconazole) (table 3), the lowest dose (2.5 mg) of saxagliptin is recommended [15]. In patients taking medications that induce CYP3A4 or P-glycoprotein (eg, rifampin), linagliptin should be avoided (table 3 and table 4).

Patients with chronic kidney disease — For patients with an eGFR <30 mL/min/1.73 m² in whom a decision has been made to use a DPP-4 inhibitor, we suggest linagliptin. Linagliptin is primarily eliminated via the enterohepatic system, and no dose adjustment is necessary in patients with kidney impairment.

Other DPP-4 inhibitors may also be used in the setting of chronic kidney disease with proper dose adjustment (table 2) [10,16].

Monitoring

●Kidney – Prior to initiation of any DPP-4 inhibitor, serum creatinine should be measured for calculation of eGFR. Thereafter, calculated eGFR should be monitored every three to six months in patients with eGFR ≤45 mL/min/1.73 m² and approximately every 6 to 12 months in those with eGFR >45 mL/min/1.73 m². (See "Assessment of kidney function", section on 'eGFR from creatinine (primary approach)'.)

●Liver (vildagliptin and alogliptin only) – Due to reports of liver toxicity with vildagliptin and alogliptin, liver biochemical tests should be evaluated prior to initiation of either agent and at three-month intervals during the first year of therapy [17]. If an increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) of three times the upper limit of normal or greater persists, the drugs should be discontinued. (See 'Liver' below.)

CLINICAL OUTCOMES

Glycemic efficacy — All of the dipeptidyl peptidase 4 (DPP-4) inhibitors appear to have similar glycemic efficacy [8] and result in modest improvement in glycated hemoglobin (A1C). They can be used in combination with most other diabetes medications except glucagon-like peptide 1 (GLP-1) receptor agonists due to lack of additive glucose-lowering effects. The efficacy of combined treatment with DPP-4 inhibitors and prandial insulin is uncertain due to limited data.

Efficacy as monotherapy or combination therapy — Across trials, DPP-4 inhibitor treatment as monotherapy or in combination with other agents resulted in placebo-adjusted A1C reductions of approximately 0.4 to 0.9 percentage points [8], without substantial differences among specific DPP-4 inhibitors.

●Monotherapy – When used as monotherapy, all DPP-4 inhibitors reduce A1C compared with placebo [18-26], with placebo-adjusted A1C reductions of approximately 0.6 to 0.75 percent [8].

Few DPP-4 inhibitor trials have used an active comparator. In studies of treatment-naïve patients with type 2 diabetes, vildagliptin had similar A1C-lowering efficacy as rosiglitazone but was less effective than metformin [27,28]. For example, in a 52-week trial that compared vildagliptin (100 mg daily) with metformin (titrated to 2000 mg daily) in 780 patients with previously untreated type 2 diabetes, metformin led to greater A1C reduction (between-group difference 0.4 percentage points, 95% CI 0.28-0.65) [28]. Goal A1C (<7 percent) was achieved by 45 and 35 percent of participants who received metformin and vildagliptin, respectively.

●Combination therapy – DPP-4 inhibitors have been tested in combination with metformin [28-38], thiazolidinediones [39-43], sodium-glucose cotransporter 2 (SGLT2) inhibitors [44-46], and sulfonylureas [47-50]. Across trials, add-on therapy with a DPP-4 inhibitor led to placebo-adjusted reductions in A1C of approximately 0.4 to 0.9 percentage points [8]. Alogliptin and vildagliptin also have been tested in combination with insulin therapy [51,52], including multiple daily insulin injection regimens. For example, in a 24-week trial in 296 patients with type 2 diabetes suboptimally treated with insulin, the addition of vildagliptin (50 mg twice daily) modestly improved A1C relative to placebo (placebo-adjusted reduction of 0.3 percentage points) [51]. Importantly, participants in this trial administered an average of three daily insulin injections, providing evidence of the safety and modest efficacy of DPP-4 inhibitor therapy when combined with prandial insulin.

When baseline A1C is higher, add-on therapy with a DPP-4 inhibitor may not provide sufficient glucose lowering to achieve glycemic targets. For example, among participants with baseline A1C values >8.5 percent, add-on therapy with vildagliptin 50 or 100 mg daily resulted in an A1C of <7 percent in only 7.5 and 16.3 percent of participants, respectively, versus 2.1 percent of participants who received placebo [35].

Few head-to-head trials have directly compared DPP-4 inhibitors with other agents when used in combination therapy [53,54]. In the five-year GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness) comparative effectiveness trial in 5047 patients with type 2 diabetes on metformin monotherapy, add-on therapy with sitagliptin was less effective in achieving and maintaining the A1C goal of <7 percent than liraglutide, glimepiride, or glargine [53]. The GRADE trial is reviewed in detail separately. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Without established cardiovascular or kidney disease'.)

Efficacy in chronic kidney disease — DPP-4 inhibitors are effective in patients with chronic kidney disease [55-59], including those requiring dialysis.

●End-stage kidney disease requiring dialysis – In patients with end-stage kidney disease requiring dialysis, DPP-4 inhibitors provide similar glucose-lowering efficacy as sulfonylureas. For example, in a 54-week trial in 129 patients with end-stage kidney disease requiring dialysis, participants were randomly assigned to sitagliptin (reduced dose) or glipizide treatment in place of their usual oral glucose-lowering agents [55]. Reductions in A1C did not differ significantly between the sitagliptin and glipizide groups (-0.72 versus -0.87 percentage points, respectively). Sitagliptin is more expensive than sulfonylureas.

●Chronic kidney disease not requiring dialysis – When used in combination therapy regimens, DPP-4 inhibitor treatment confers comparable glucose-lowering in individuals with chronic kidney disease and those with normal kidney function. For example, in a trial in 133 patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² (but not requiring dialysis), participants were randomly assigned to receive linagliptin or placebo, in addition to their previous background glucose-lowering therapy [56]. At 12 weeks, reduction in A1C was greater with linagliptin than with placebo (-0.76 versus -0.15 percentage points, respectively), and this A1C-lowering effect was sustained over one year.

Cardiovascular effects — Short-term use of a DPP-4 inhibitor in combination with another oral agent does not appear to reduce or increase the risk of adverse atherosclerotic cardiovascular disease (CVD) outcomes [60-66]. However, specific DPP-4 inhibitors may increase the risk of hospitalization for heart failure. The US Food and Drug Administration (FDA) added warnings about the risk of hospitalization for heart failure to the labels of medications containing either saxagliptin or alogliptin [67]. The FDA subsequently added warnings regarding the use of all DPP-4 inhibitors in patients at high risk for heart failure [68,69]. The FDA also recommends discontinuation specifically of saxagliptin and alogliptin in patients who develop heart failure and monitoring to determine if alternative therapy for diabetes is required [70].

Of note, most of the cardiovascular studies to date have been carried out in very high-risk populations to increase the hazard rate for major CVD events and complete the studies in a relatively brief timeframe. Therefore, few data regarding cardiovascular safety or possible benefit are available in lower-risk patients. In one trial in 5047 participants with type 2 diabetes and low baseline CVD risk, the cumulative incidence of prespecified cardiovascular secondary outcomes was generally higher with sitagliptin than with liraglutide but similar to treatment with glargine or glimepiride over a mean follow-up of five years [71]. The details of the trial are reviewed separately. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Without established cardiovascular or kidney disease'.)

Atherosclerotic CVD and cardiovascular mortality — In cardiovascular outcomes trials in patients with type 2 diabetes and high cardiovascular disease (CVD) risk, DPP-4 inhibitors have neither increased nor decreased the risk of major cardiovascular or cerebrovascular events.

In several placebo-controlled trials with a median follow-up of 18 to 36 months in participants with type 2 diabetes and either existing CVD or high CVD risk, the primary cardiovascular endpoint (usually a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke) occurred in a similar proportion of patients who were randomly assigned to add-on therapy with saxagliptin, alogliptin, sitagliptin, or linagliptin compared with those who received placebo [60,62,64,65].

In a cardiovascular outcomes trial that compared linagliptin with glimepiride in 6042 patients with type 2 diabetes and elevated cardiovascular risk (median follow-up 6.3 years), the occurrence of the composite outcome (first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was similar in the two groups (11.8 versus 12 percent in the linagliptin and glimepiride groups, respectively; hazard ratio [HR] 0.98, 95% CI 0.84-1.14) [66].

Heart failure — In trials in patients with high CVD risk followed over a median of 18 to 36 months, treatment with saxagliptin and possibly alogliptin [60,63,67] but not sitagliptin or linagliptin [64,72] increased risk of hospitalization for heart failure. For example, in the saxagliptin cardiovascular outcomes trial, patients in the saxagliptin group had a higher frequency of hospitalization for heart failure than those in the placebo group (3.5 versus 2.8 percent, respectively; HR 1.27, 95% CI 1.07-1.51) [60]. Known risk factors for heart failure, including baseline N-terminal pro B-type natriuretic peptide (BNP) elevation, prior heart failure, and chronic kidney disease, were risk factors for heart failure hospitalizations [61]. In a post hoc analysis of the alogliptin cardiovascular outcomes trial, the frequency of hospitalization for heart failure was numerically higher in the alogliptin group than in the placebo group (3.9 versus 3.3 percent, respectively; HR 1.19, 95% CI 0.90-1.58) [63,67].

In contrast, in cardiovascular outcomes trials for sitagliptin and linagliptin, the rate of hospitalization for heart failure did not differ between DPP-4 inhibitor and placebo groups [64,72]. Similarly, in a trial that compared linagliptin with glimepiride in 6042 patients with type 2 diabetes and elevated CVD risk, hospitalization for heart failure did not differ between the two groups over a median follow-up of 6.3 years [66].

In a systematic review and meta-analysis of randomized trials and observational studies examining heart failure outcomes with DPP-4 inhibitor use, the evidence overall demonstrated no increased risk of new-onset heart failure but a slightly increased risk of hospitalization for heart failure in patients with established CVD or multiple CVD risk factors [73]. Whether this risk extends to patients without high CVD risk is unknown.

The specific findings in the meta-analysis were as follows [73]:

●Risk of heart failure – A meta-analysis of 38 trials found no significant difference in risk of heart failure with DPP-4 inhibitor or control (placebo or active comparator) treatment (event rates 0.27 and 0.26 percent, respectively), but the evidence was low quality. Observational studies supported findings from the randomized trials but were limited by heterogeneity (eg, patients with or without baseline CVD, different comparator treatments) and provided very low-quality evidence.

●Risk of hospital admission for heart failure – A meta-analysis of five trials provided moderate-quality evidence that DPP-4 inhibitor therapy increased risk of hospitalization for heart failure compared with placebo (event rate 3.4 versus 3.0 percent; odds ratio [OR] 1.13, 95% CI 1.00-1.26). The patients in the included cardiovascular outcomes trials had established CVD or multiple CVD risk factors. Observational studies supported this finding but with very low-quality evidence. In the observational studies, results varied with the use of an active comparator versus placebo control.

Although these data suggest an increased risk of hospitalization for heart failure with DPP-4 inhibitor use, individual trial data indicate that this risk may not be a class effect. The mechanism(s) underlying this increased risk are unknown but would provide important insight into the likelihood of a class effect.

All-cause mortality — DPP-4 inhibitors do not appear to have any effect on all-cause mortality. In a systematic review and meta-analysis of 189 trials, no difference in all-cause mortality was found between any incretin-based drug (DPP-4 inhibitors and GLP-1 receptor agonists) versus control [74]. The meta-analysis did not distinguish between DPP-4 inhibitor- and GLP-1 receptor agonist-associated mortality, and results were heavily weighted by six large, randomized trials in which 92 percent of all deaths occurred. In a subgroup analysis of the DPP-4 cardiovascular outcomes trials, no difference in all-cause mortality was found between DPP-4 inhibitor and placebo groups (6.1 versus 6.0 percent, OR 1.02, 95% CI 0.91-1.14) [74].

In the subsequent GRADE trial in 5047 patients with type 2 diabetes and low cardiovascular risk, patients who were randomly assigned to sitagliptin had a similar incidence of all-cause mortality over a mean follow-up of five years compared with those who received glimepiride or glargine [71]. The details of the trial are reviewed separately. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Without established cardiovascular or kidney disease'.)

Kidney outcomes — DPP-4 inhibitors appear to have an overall neutral effect on risk of diabetes-related kidney disease.

●Patients without preexisting kidney disease – DPP-4 inhibitors neither increase nor decrease risk of incident kidney disease relative to other glucose-lowering therapies. The strongest evidence for these neutral effects over longer-term therapy derives from the GRADE trial. In this trial in 5047 patients with type 2 diabetes on metformin monotherapy and with low baseline prevalence of kidney disease, participants were randomly assigned to add-on therapy with sitagliptin, liraglutide, glimepiride, or glargine over a mean follow-up of five years [53,71]. The incidence of moderately or severely increased albuminuria or impaired kidney function was similar among the four groups.

●Patients at high risk for kidney disease – In patients at high risk for kidney disease, DPP-4 inhibitors neither promote kidney disease progression nor provide protective effects. In the linagliptin cardiovascular outcomes trial, 6991 patients with type 2 diabetes and high risk for CV and kidney disease were randomly assigned to linagliptin or placebo, in addition to background glucose-lowering therapy (predominantly metformin, sulfonylurea, insulin) [65]. After a median follow-up of 2.2 years, the secondary kidney outcome (composite of end-stage kidney disease, death due to kidney failure, or a sustained decrease of at least 40 percent in eGFR from baseline) did not differ between groups and occurred in 9.4 and 8.8 percent of patients in the linagliptin and placebo groups, respectively (HR 1.04, 95% CI 0.89-1.22).

●Patients with preexisting chronic kidney disease – In patients with preexisting chronic kidney disease, DPP-4 inhibitor therapy also does not appear detrimental nor beneficial for kidney function. In a trial in patients with type 2 diabetes and eGFR <30 mL/min/1.73 m² (but not requiring dialysis), average eGFR remained overall stable over one year of treatment with either linagliptin or placebo when added to background glucose-lowering therapy (median change in eGFR -0.8 versus -2.2 mL/min/1.73 m², respectively) [56].

The impact of DPP-4 inhibitor therapy on risk and progression of neuropathy and retinopathy is unknown due to insufficient clinical data. In the GRADE comparative effectiveness trial, the incidence of peripheral neuropathy was similar between participants who received DPP-4 inhibitor therapy and those in the other three treatment groups [71].

Hypoglycemia and body weight — DPP-4 inhibitors do not affect body weight or risk of hypoglycemia in the absence of concomitant treatment with insulin or sulfonylureas [5].

●Hypoglycemia – DPP-4 inhibitors confer low risk of hypoglycemia when used as monotherapy or in combination with other glucose-lowering medications. In a comparative effectiveness trial in 5047 participants with type 2 diabetes, treatment with sitagliptin as add-on therapy to metformin led to a low rate of severe hypoglycemia (0.7 percent) over a mean follow-up of five years [53]. Several trials have demonstrated a lower frequency of hypoglycemia with DPP-4 inhibitors than with sulfonylureas when added to metformin monotherapy [31,53,75]. For example, in a two-year trial in 1551 patients with type 2 diabetes on metformin therapy (mean baseline A1C 7.7 percent), linagliptin treatment led to a lower frequency of hypoglycemia than glimepiride (7 versus 36 percent of patients, respectively) [75].

In patients with chronic kidney disease, including those requiring dialysis, this low risk of hypoglycemia with DPP-4 inhibitor therapy is also evident [56]. For example, in patients with end-stage kidney disease requiring dialysis, treatment with sitagliptin led to a lower frequency of severe hypoglycemia than treatment with glipizide (0 versus 7.7 percent, respectively) despite comparable A1C reduction [55].

●Body weight – DPP-4 inhibitors are overall neutral with regard to body weight. In a comparative effectiveness trial in 5047 participants with type 2 diabetes, treatment with sitagliptin as add-on therapy to metformin resulted in a mean body weight loss of 2 kg over a mean follow-up of five years [53]. In trials that compared add-on therapy with a DPP-4 inhibitor or sulfonylurea, DPP-4 inhibitor treatment led to less body weight gain [31,75]. For example, in a trial in 1551 patients with type 2 diabetes on metformin monotherapy, add-on treatment with linagliptin reduced body weight relative to glimepiride over two years (-1.4 versus +1.3 kg body weight change, respectively). In a trial that compared alogliptin monotherapy with a traditional Japanese diet, the diet led to greater body weight loss (change in body mass index [BMI] -0.9 versus -0.1 kg^/m²with diet and alogliptin, respectively) [75,76].

ADVERSE EFFECTS — The dipeptidyl peptidase 4 (DPP-4) inhibitors were well tolerated in short-term studies and in the five-year GRADE trial [53]. Commonly reported side effects include headache, nasopharyngitis, and upper respiratory tract infection [15,25,77-79]. Some [19,39], but not all [18,29,35], studies have reported a slightly increased risk of gastrointestinal side effects with sitagliptin. The long-term safety of DPP-4 inhibitors beyond three to five years of therapy has not been established.

Immune function — Although the DPP-4 inhibitors are relatively specific for glucagon-like peptide 1 (GLP-1), the long-term consequences of DPP-4 inhibition, including effects on other DPP-4 substrates, are unknown. Due to the ubiquitous nature of dipeptidyl peptidase substrates and the variable specificity of DPP-4 inhibitors, each agent within this class will need to be scrutinized individually for drug-specific side effects [80]. The risk of side effects may be higher with less selective DPP-4 inhibitors. Residual crossover with other DPP-4 substrates (particularly with respect to immune function) remains a concern, although this has not been reported in short-term clinical trials.

●Nasopharyngitis – A meta-analysis of sitagliptin and vildagliptin studies with available side effect data reported a small increased risk of nasopharyngitis (relative risk [RR] 1.2, 95% CI 1.0-1.4), urinary tract infection (RR 1.5, 95% CI 1.0-2.2), and headache (RR 1.4, 95% CI 1.1-1.7) [77]. A subsequent meta-analysis of trials (18 to 104 weeks duration) comparing a DPP-4 inhibitor (sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin) with placebo (44 trials), a comparator from another class of antidiabetic agents (20 trials), or another DPP-4 inhibitor (3 trials) showed a small increased risk of nasopharyngitis compared with placebo (6 versus 5.3 percent, RR 1.13, 95% CI 0.99-1.29), which was predominantly driven by the sitagliptin subgroup (5.3 versus 4.1 percent; RR 1.35, 95% CI 1.03-1.77) [78]. The risk of upper respiratory and urinary tract infections was not significantly elevated, whereas the risk of dizziness and headache was slightly elevated (8.2 versus 7.5 percent; RR 1.14, 95% CI 1.02-1.26). In the three head-to-head trials, there were no clinically significant differences in adverse effects among DPP-4 inhibitors.

●COVID-19 – DPP-4 has been implicated in the pathogenesis of coronavirus infections, including coronavirus disease 2019 (COVID-19). However, DPP-4 inhibitors should not be initiated solely for protection against COVID-19 complications. Patients already taking DPP-4 inhibitors should continue therapy during COVID-19 infection unless they develop a new contraindication to treatment. In population-based observational studies, the use of DPP-4 inhibitors was not associated with increased risk of COVID-19 infection or complications [81-83].

Some observational studies suggest protective effects of DPP-4 inhibitor use during COVID-19 infection, including reduced mortality [84,85]. No randomized controlled trials have been conducted to compare the use of DPP-4 inhibitors with other diabetes drugs on COVID-19-related outcomes.

Pancreas — DPP-4 inhibitors should not be initiated in patients with a history of pancreatitis. Acute pancreatitis has been reported in association with DPP-4 inhibitors, but data are insufficient to determine a causal relationship [86-91]. Pancreatitis should be considered in patients with persistent, severe abdominal pain (with or without nausea), and DPP-4 inhibitors should be discontinued in such patients. If pancreatitis is confirmed, a DPP-4 inhibitor should not be restarted.

There have been postmarketing case reports of acute pancreatitis in patients using sitagliptin, saxagliptin, and alogliptin [92-94], similar to case reports describing pancreatitis in patients treated with GLP-1 receptor agonists. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Pancreas'.)

Observational studies have reported conflicting results, with some showing no difference in risk of pancreatitis in patients taking GLP-1-based therapies compared with other oral agents [86,90,95] and one showing an increased risk in users versus nonusers [87]. As examples:

●In a retrospective cohort study of a claims database, the incidence of acute pancreatitis in sitagliptin users was 5.6 cases per 1000 patient-years, which was similar to the incidence in the control group with diabetes [86].

●In a population-based, case-control study, compared with nonuse, use of GLP-1-based therapy (sitagliptin or exenatide) was associated with an increased risk of hospitalization for acute pancreatitis (adjusted odds ratio [OR] 2.07, 95% CI 1.36-3.13) [87].

Meta-analyses of randomized trials did not identify an increased risk [88,89]. The overall incidence of pancreatitis was low (35 cases among 68,318 patients, 20 in patients taking DPP-4 inhibitors and 15 in the comparator groups) [89]. More carefully designed observational studies are warranted to definitively establish risk and whether risk may vary among specific DPP-4 inhibitors.

Increased risks of subclinical pancreatic inflammation, pancreatic cancer, and neuroendocrine tumors also have been reported in sitagliptin users [92,96-98]. A causal relationship has not been established. After a review of currently available data, the US Food and Drug Administration (FDA) and the European Medicines Agency agreed that there was insufficient evidence to confirm an increased risk of pancreatic cancer with use of GLP-1-based therapies [99-101]. However, concerns remain [102], and pancreatic adverse effects will continue to be monitored and reported [99,101,103].

Liver — Although uncommon, cases of hepatic dysfunction (liver enzyme elevations, hepatitis) have been reported in patients taking vildagliptin and alogliptin [17,79]. As a result, liver biochemical tests should be evaluated prior to initiation of vildagliptin and alogliptin and at three-month intervals during the first year of therapy [17]. If an increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) of three times the upper limit of normal or greater persists, the drugs should be discontinued.

Inflammatory bowel disease — In a population-based study using data from the United Kingdom Clinical Practice Research Datalink, use of DPP-4 inhibitors was associated with an increased risk of inflammatory bowel disease compared with other diabetes drugs (53.4 versus 34.5 per 100,000 person-years, hazard ratio [HR] 1.75, 95% CI 1.22-2.49) [104]. The median duration of follow-up was 3.6 years. The risk peaked after three to four years of use and decreased after more than four years of use. These findings require confirmation and further investigation into possible mechanisms.

Skin — DPP-4 inhibitors are contraindicated in patients with a history of a serious hypersensitivity reaction after previous exposure [105]. In postmarketing reports, sitagliptin, saxagliptin, linagliptin, and alogliptin have been associated with hypersensitivity reactions, including anaphylaxis and angioedema, blistering skin conditions (eg, bullous pemphigoid), and Stevens-Johnson syndrome [106-109]. Skin lesions also occurred in normal volunteers given four to six times the proposed therapeutic dose of vildagliptin [110]. Reports of angioedema in association with DPP-4 inhibitors are reviewed separately. (See "ACE inhibitor-induced angioedema", section on 'Dipeptidyl peptidase-4 inhibitors'.)

Musculoskeletal — Some DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin) have been associated with severe joint pain [111,112]. Other reported musculoskeletal side effects include myalgias, muscle weakness, and muscle spasms. Symptoms have been reported from two days to five months after initiating DPP-4 inhibitors. In most patients, symptoms resolved within a month after discontinuing the drug [113]. Some patients developed recurrent, severe joint pain after restarting the same or a different DPP-4 inhibitor [112,113]. If a patient develops severe and persistent joint pain while taking a DPP-4 inhibitor, the drug should be discontinued and the patient assessed for resolution of symptoms. If symptoms resolve, a different class of diabetes medication should be prescribed. If symptoms do not resolve after one month of drug discontinuation, they are unlikely the result of DPP-4 inhibitor use, and alternative causes for the symptoms should be sought.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults".)

SUMMARY AND RECOMMENDATIONS

●Mechanism of action – Dipeptidyl peptidase 4 (DPP-4) inhibitors are a class of oral diabetes drugs that inhibit the enzyme DPP-4. DPP-4 is a ubiquitous enzyme expressed on the surface of most cell types that deactivates a variety of other bioactive peptides, including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). DPP-4 inhibitors could potentially affect glucose regulation through multiple effects (table 1). (See 'Mechanism of action' above and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Gastrointestinal peptides'.)

●Patient selection

•Intolerance or contraindications to metformin – DPP-4 inhibitors are not considered as initial therapy for most patients with type 2 diabetes. DPP-4 inhibitors can be considered as monotherapy in patients with type 2 diabetes who are intolerant of or have contraindications to metformin and to other glucose-lowering agents if indicated for cardiovascular or kidney benefit. They may be a good option for glucose-lowering therapy particularly in patients at high risk of hypoglycemia, including older patients and those with chronic kidney disease. (See 'Patient selection' above and 'Hypoglycemia and body weight' above and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Initial pharmacologic therapy'.)

•Inadequate glucose lowering on initial therapy – DPP-4 inhibitors can be considered as add-on drug therapy for patients who need additional glucose lowering while on any of the following:

-Metformin

-A thiazolidinedione

-Basal insulin

-A sulfonylurea

-A sodium-glucose cotransporter 2 (SGLT2) inhibitor

Very limited data support the efficacy of DPP-4 inhibitors in combination with prandial insulin. DPP-4 inhibitors and GLP-1 receptor agonists should not be used in combination. (See 'Patient selection' above.)

DPP-4 inhibitors are not the preferred agents for patients with cardiovascular or kidney disease because they do not impart protective effects on cardiovascular and kidney outcomes. The modest glucose-lowering effectiveness and cost of DPP-4 inhibitors temper our enthusiasm for these drugs. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'.)

●Choice of DPP-4 inhibitor – If the decision is made to use DPP-4 inhibitor therapy for glucose lowering, we typically suggest either sitagliptin or linagliptin (Grade 2C). Our choice is based on data showing the neutral effects of these agents on cardiovascular outcomes including hospitalization for heart failure. The DPP-4 inhibitors appear to have similar glycemic efficacy and result in modest improvement in glycated hemoglobin (A1C). Patient preference and payer coverage are often considerations for selecting a specific DPP-4 inhibitor. (See 'Choice of DPP-4 inhibitor' above and 'Heart failure' above and 'Glycemic efficacy' above.)

For patients with severe chronic kidney disease (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²) in whom a decision has been made to use a DPP-4 inhibitor, we suggest linagliptin (Grade 2C). Linagliptin is primarily eliminated via the enterohepatic system and is the only DPP-4 inhibitor that does not require dose adjustment in individuals with impaired kidney function (table 2). (See 'Efficacy in chronic kidney disease' above.)

●Dosing – DPP-4 inhibitors are available in both single-agent and combined formulations (table 2).

●Cardiovascular and kidney outcomes – DPP-4 inhibitors have generally neither reduced nor increased cardiovascular events or the development or progression of kidney disease. Although short-term use of DPP-4 inhibitors in combination with another glucose-lowering agent does not appear to increase risk of adverse atherosclerotic cardiovascular disease (CVD) outcomes, saxagliptin and alogliptin may increase risk of hospitalization for heart failure in patients with preexisting CVD or high cardiovascular risk. (See 'Cardiovascular effects' above and 'Kidney outcomes' above.)

●Adverse effects – Overall, DPP-4 inhibitors are well tolerated. The use of DPP-4 inhibitors has been associated with a slightly increased risk of upper respiratory tract infections. Data are insufficient to determine whether DPP-4 inhibitors increase risk of acute pancreatitis. (See 'Adverse effects' above.)

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Topic 96015 Version 34.0

References

1 : Incretin-based therapy: a powerful and promising weapon in the treatment of type 2 diabetes mellitus.

2 : Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells.

3 : Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans.

4 : Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients.

5 : Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis.

6 : Type 2 diabetes--therapy with dipeptidyl peptidase IV inhibitors.

7 : Endogenous Glucose-Dependent Insulinotropic Polypeptide Contributes to Sitagliptin-Mediated Improvement inβ-Cell Function in Patients With Type 2 Diabetes.

8 : Comparative effectiveness of dipeptidylpeptidase-4 inhibitors in type 2 diabetes: a systematic review and mixed treatment comparison.

9 : SGLT2 inhibitor plus DPP-4 inhibitor as combination therapy for type 2 diabetes: A systematic review and meta-analysis.

10 : Alogliptin (nesina) for type 2 diabetes.

11 : Sitagliptin/metformin (Janumet) for type 2 diabetes.

12 : Linagliptin/metformin (Jentadueto) for type 2 diabetes mellitus

13 : Saxagliptin/metformin (kombiglyze XR) for type 2 diabetes.

14 : Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes.

15 : Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes.

16 : The dipeptidyl peptidase-4 inhibitor alogliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis.

17 : The dipeptidyl peptidase-4 inhibitor alogliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis.

18 : Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus.

19 : Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes.

20 : Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes.

21 : Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes.

22 : Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response.

23 : Twelve-week monotherapy with the DPP-4 inhibitor vildagliptin improves glycemic control in subjects with type 2 diabetes.

24 : Efficacy and tolerability of vildagliptin monotherapy in drug-naïve patients with type 2 diabetes.

25 : Effect of linagliptin monotherapy on glycaemic control and markers ofβ-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial.

26 : Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study.

27 : Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial.

28 : Comparison between vildagliptin and metformin to sustain reductions in HbA(1c) over 1 year in drug-naïve patients with Type 2 diabetes.

29 : Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone.

30 : Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes.

31 : Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial.

32 : The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone.

33 : Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial.

34 : Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes.

35 : Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin.

36 : Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes.

37 : Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study.

38 : Efficacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study.

39 : Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

40 : Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study.

41 : Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study.

42 : Initial combination therapy with alogliptin and pioglitazone in drug-naïve patients with type 2 diabetes.

43 : Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes.

44 : Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial.

45 : Randomized, Double-Blind Trial of Triple Therapy With Saxagliptin Add-on to Dapagliflozin Plus Metformin in Patients With Type 2 Diabetes.

46 : Linagliptin as add-on to empagliflozin and metformin in patients with type 2 diabetes: Two 24-week randomized, double-blind, double-dummy, parallel-group trials.

47 : Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin.

48 : Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial.

49 : Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study.

50 : Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy.

51 : Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes.

52 : Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia.

53 : Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes.

54 : Effects on Clinical Outcomes of Adding Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas to Metformin Therapy in Patients With Type 2 Diabetes Mellitus.

55 : Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis: a 54-week randomized trial.

56 : Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study.

57 : Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study.

58 : One-year safety, tolerability and efficacy of vildagliptin in patients with type 2 diabetes and moderate or severe renal impairment.

59 : Linagliptin added to sulphonylurea in uncontrolled type 2 diabetes patients with moderate-to-severe renal impairment.

60 : Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.

61 : Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial.

62 : Alogliptin after acute coronary syndrome in patients with type 2 diabetes.

63 : Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial.

64 : Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes.

65 : Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial.

66 : Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial.

67 : Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial.

68 : Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial.

69 : Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial.

70 : Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial.

71 : Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes.

72 : Linagliptin Effects on Heart Failure and Related Outcomes in Individuals With Type 2 Diabetes Mellitus at High Cardiovascular and Renal Risk in CARMELINA.

73 : Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies.

74 : Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis.

75 : 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial.

76 : Alogliptin as an initial therapy in patients with newly diagnosed, drug naïve type 2 diabetes: a randomized, control trial.

77 : Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis.

78 : Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta-analysis.

79 : Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta-analysis.

80 : The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.

81 : Use of dipeptidyl peptidase-4 inhibitors and prognosis of COVID-19 in hospitalized patients with type 2 diabetes: A propensity score analysis from the CORONADO study.

82 : No significant association between dipeptidyl peptidase-4 inhibitors and adverse outcomes of COVID-19.

83 : Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study.

84 : Impact of Comorbidities and Glycemia at Admission and Dipeptidyl Peptidase 4 Inhibitors in Patients With Type 2 Diabetes With COVID-19: A Case Series From an Academic Hospital in Lombardy, Italy.

85 : Sitagliptin Treatment at the Time of Hospitalization Was Associated With Reduced Mortality in Patients With Type 2 Diabetes and COVID-19: A Multicenter, Case-Control, Retrospective, Observational Study.

86 : Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective observational pharmacy claims analysis.

87 : Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study.

88 : Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies.

89 : Dipeptidyl peptidase-4 inhibitors and pancreatitis risk: a meta-analysis of randomized clinical trials.

90 : Incretin based drugs and risk of acute pancreatitis in patients with type 2 diabetes: cohort study.

91 : Incretin-based therapy and risk of acute pancreatitis: a nationwide population-based case-control study.

92 : Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies.

93 : Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies.

94 : Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies.

95 : Association Between Incretin-Based Drugs and the Risk of Acute Pancreatitis.

96 : Incretins and risk of neoplasia.

97 : Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed?

98 : Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors.

99 : Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors.

100 : Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors.

101 : Pancreatic safety of incretin-based drugs--FDA and EMA assessment.

102 : European drugs agency clashes with scientists over safety of GLP-1 drugs.

103 : European drugs agency clashes with scientists over safety of GLP-1 drugs.

104 : Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study.

105 : Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study.

106 : Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study.

107 : Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study.

108 : Dipeptidyl peptidase-4 inhibitors and bullous pemphigoid: A systematic review and adjusted meta-analysis.

109 : Association Between Medication Use and Bullous Pemphigoid: A Systematic Review and Meta-analysis.

110 : Association Between Medication Use and Bullous Pemphigoid: A Systematic Review and Meta-analysis.

111 : Association of musculoskeletal complaints and gliptin use: review of spontaneous reports.

112 : DPP-IV inhibitor-associated arthralgias.

خرید پکیج

Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus

References