DPP-4 inhibitors: focus on safety.

Review

DPP-4 inhibitors: focus on safety Sri Harsha Tella & Marc S Rendell† †

The Association of Diabetes Investigators, Omaha, NE, USA

1.

Introduction

2.

Chemistry, pharmacokinetics and pharmacodynamics of

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by Monash University on 12/15/14 For personal use only.

DPP-4-i 3.

Drug interaction studies

4.

Safety profile of DPP-4-i

5.

Conclusion

6.

Expert opinion

Introduction: Dipeptidyl peptidase inhibitors (DPP-4-i) are highly selective inhibitors of the enzyme DPP-4. They act by increasing levels of incretin hormones, which have potent effects on insulin and glucagon release, gastric emptying, and satiety. Our goal is to review the safety issues related to DPP-4-i. Areas covered: This review is based upon a PubMed search of the literature using keywords alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin, DPP-4-i, glucagon-like polypeptide-1 agonists, as well as extensive personal clinical trial experience with each of these agents. The current DPP-4-i have very different chemical structures. Saxagliptin has significant cytochrome P450 metabolism and carries a risk of drug interactions. Linagliptin has primarily entero-hepatic excretion, a benefit in renally impaired patients. A concern arose related to congestive heart failure in the SAVOR TIMI trial of saxagliptin. Several major cardiac studies are underway, with two concluded. Despite lingering uncertainty related to pancreatitis and pancreatic cancer, large randomized trials have not shown an increased risk with DPP-4-i treatment. Cutaneous adverse effects occur with a low frequency with some of these agents. Expert opinion: DPP-4-i are an additional choice in the group of anti-hyperglycemics. Their principal advantage is a low incidence of hypoglycemia, making these agents desirable in patients such as the elderly and those with cardiac disease. Several large trials have hinted at less cardiac risk with DPP-4-i than with sulfonylureas. The CAROLINA Trial comparing linagliptin and glimepiride may provide a conclusive answer to this question. Keywords: alogliptin, dipeptidyl peptidase -4 inhibitors, glucagon-like polypeptide-1, linagliptin, saxagliptin, sitagliptin, vildagliptin Expert Opin. Drug Saf. [Early Online]

1.

Introduction

Incretins are hormones secreted by specific intestinal cells in response to oral nutrient intake. After a meal, incretin action results in an augmented insulin secretion over and above the response solely attributable to the rise in plasma glucose concentration [1]. Glucagon-like polypeptide-1(GLP)-1 and glucose-dependent insulinotropic peptide, also known as gastric inhibitory polypeptide (GIP), are the two incretin hormones that have the greatest effect on glucose control. GIP and GLP-1 are both secreted within minutes of food entry into the intestines and act through distinct receptors [2]. Both peptides act on pancreatic b-cells to stimulate insulin secretion in relation to blood glucose concentration; when glucose levels are normal, incretin-stimulated insulin secretion is suppressed. GIP is secreted by the K-cells of the duodenum and jejunum in response to glucose and fat ingestion and promotes glucose-dependent insulin secretion and energy storage by adipocytes [3]. Effects of GIP include stimulation of lipoprotein lipase activity, modulation of fatty acid synthesis, incorporation of fatty acids into triglycerides [4] and promotion of b-cell proliferation and cell survival [5,6]. Plasma concentrations of GIP are reported to be normal or increased in diabetes but the insulinotropic effect is deficient [7,8]. GIP stimulates insulin release during hyperglycemia but does not suppress glucagon release [9]. After hypoglycemia, GIP release 10.1517/14740338.2015.977863 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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SH Tella & M. S. Rendell

Article highlights. .

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The DPP-4 inhibitors (DPP-4-i) act by increasing levels of incretin hormones, which have potent effects on insulin and glucagon release, gastric emptying, and satiety. There are a variety of DPP-4-i with differing chemical structures. The DPP-4-i, with the exception of saxagliptin, have relatively few potential drug interactions. Linagliptin has primarily hepatic excretion, a significant advantage in renally impaired patients. A number of cardiac long-term studies are underway, with fairly reassuring results. Saxagliptin was associated with an increased incidence of congestive heart failure hospitalizations. Despite initial concerns that glucagon-like polypeptide-1 agonists and DPP-4-i might promote pancreatitis and pancreatic cancer, the evidence at this point does not implicate these agents. A low incidence of skin reactions has been observed with some of the DPP-4-i. DPP-4-i treatment is associated with a much lower frequency of hypoglycemia than sulfonylurea therapy. The lower incidence of hypoglycemia with DPP-4-i may translate into less cardiac events than with sulfonylureas, particularly in the elderly population.

This box summarizes key points contained in the article.

stimulates glucagon secretion [10]. The magnitude of the reduction in GIP efficacy in patients with type 2 diabetes appears to be comparable to the impairment in glucoseinduced insulin secretion in such patients [3,7,8]. GLP-1 is a 37-amino acid peptide secreted from the L-cells of the ileum and colon into the blood stream. GLP-1 produces a glucose-dependent increase in insulin secretion by the bcell. Other effects of GLP-1 include suppression of glucagon secretion, slowing of gastric emptying time and promotion of satiety [1]. GLP-1 also stimulates differentiation and proliferation of b-cells and inhibition of apoptosis [3]. Although postprandial GLP-1 release appears to be equivalent in patients with type 2 diabetes and controls, the insulinotropic effect of GLP-1 is blunted in diabetes [7,11]. GLP-1 has additional actions beyond those of GIP on glucose sensors, as well as inhibition of gastric emptying, reduction of food intake and suppression of glucagon secretion [1]. GLP-1 appears to be the key hormone mediating the suppression of glucagon secretion after a meal [12,13]. GLP-1 infusions have been more effective than those of GIP in lowering plasma glucose in diabetes [14]. GLP-1 also promotes satiety, and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies [15,16]. Both GIP and GLP-1 are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) [16]. Pharmaceutical development has concentrated on GLP-1 rather than on GIP. Several studies have now shown that GLP-1 can lower glucose levels even in patients with severe b-cell impairment, presumably as a result of lowered glucagon levels and other non-insulin 2

secretory mechanisms [17]. GLP-1 effects can be provided therapeutically either by giving supplemental GLP-1 analogs, or by slowing degradation of endogenous GLP-1 with inhibitors of the DPP-4 enzyme [16]. There are currently three GLP-1 analogs with resistance to DPP-4 degradation in clinical use, exenatide, liraglutide, and albiglutide [18-20]. In addition, dulaglutide has very recently been approved, and several more such agents are in development [21]. Gastrointestinal issues, related to the motility effects of GLP-1, are the most frequent adverse effects of the GLP-1 analogs. The alternative to supplementation of GLP-1 is to inhibit the rapid degradation of this hormone by DPP-4. Several DDP-4 inhibitors (DPP-4-i) with diverse chemical structures have been developed and have come into clinical use as monotherapy, and in combination with metformin and various other hypoglycemic agents, as well as insulin. The first approved DPP-4-i was sitagliptin, a fluorinated b amino acid [22,23]. Sitagliptin is generally well tolerated with an overall incidence of adverse experiences comparable to placebo, a low incidence of gastrointestinal complaints and of hypoglycemia, and a neutral effect on body weight. Vildagliptin, a nitrile-based agent, is in use in most countries, except in the United States because Novartis elected not to pursue further studies requested by the FDA for approval. [24,25]. Saxagliptin, also nitrile based, is a DPP-4-i approved in 2010. It is 10-fold more potent than vildagliptin and sitagliptin with an inhibi tory constant (Ki) of 1.3 nmol/l for DPP-4 at 37 C (Ki for vildagliptin and sitagliptin is 13 and 18 nmol/l, respectively) [26]. Saxagliptin is metabolized by CYP3A4/5 to an active hydroxy metabolite M2 (BMS 510849) that is twofold less potent than the parent molecule with Ki of 2.6 nmol/l. When saxagliptin is co-administered with specific inhibitors (ketoconazole, diltiazem) or inducers (rifampicin) of CYP3A4/5 isoforms, a reduction in dose is recommended (Table 1) [27]. Linagliptin is one of the recently approved DPP-4-i [28]. Linagliptin has a xanthine base and is differentiated from other DPP-4-i in being primarily excreted unchanged via entero-hepatic mechanisms, a clear advantage in renal impairment. Alogliptin, a nitrile-containing pyrimidinedione, is another DPP-4-i, developed by Takeda Pharmaceutical Co. [29]. Alogliptin was approved for use in Japan in April 2010 and subsequently in the United States in 2013. Despite the marked differences in chemical structures, each of these agents very strongly inhibits DPP-4 activity. The purpose of this review is to address safety issues related to the DPP-4-i.

Chemistry, pharmacokinetics and pharmacodynamics of DPP-4-i

2.

Though all DDP-4 inhibitors have a common mechanism of action, the chemical structures are quite diverse, leading to potential differences within this class of agents (Figure 1) [30].

Expert Opin. Drug Saf. (2014) 14(1)

DPP-4 inhibitors: focus on safety

Table 1. Summary of DPP-4-i. Name of drug Sitagliptin (Januvia, Xelevia, Glactiv, Tesavel)


Saxagliptin (OnglyzaTM)

Vildagliptin (Galvus)

Linagliptin (Trajenta, Tradjenta, Trazenta, Trayenta) Alogliptin (Nesina)

Points to consider

Dosing regimen (oral)

Advantages: no drug interactions. First DPP-4-i that was approved Caution: mild increased risk of nasopharyngitis, upper respiratory infection, urinary tract infection, sinusitis Metabolized to active metabolite M2 by CYP3A4/5 Caution: dose adjustments required when co-administered with inducers (Rifampin) or inhibitors (Ketokonazole) of CYP3A4/5 mild increased risk of lymphopenia, hypersensitivity reactions, nasopharyngitis increased hospitalizations due to heart failure in SAVOR trial Inhibits DPP8 and 9 along with DPP-4 Caution: baseline liver enzymes to be determined before initiation of therapy and every 3 months thereafter for an year

Advantages: primarily excreted unchanged through entero-hepatic circulation, making it drug of choice DPP-4-i in renal impairment No drug interactions with agents that are inducers and inhibitors of CYP450 mild increased risk of lymphopenia, hypersensitivity reactions, nasopharyngitis

Normal kidney function: 100 mg daily CLCR 30 -- 50 ml/min: 50 mg daily CLCR < 30 ml/min: 25 mg daily 2.5 mg or 5 mg daily CLCR < 50 ml/min: 2.5 mg daily

Not approved in USA, approved in Japan and European Union Available in 50 mg and 100 mg daily No dosage adjustment required for mild renal impairment; dosage reductions are recommended for moderate or severe impairment, including ESRD, with caution advised in ESRD requiring hemodialysis, as experience is limited 5 mg daily no dosage adjustments required in renal disease The recommended dosage of alogliptin is 25 mg daily, with the dosage reduced to 12.5 mg daily in patients with moderate renal impairment (i.e., CLCR 30 -- 50 ml/min [1.8 -- 3 l/h]) and to 6.25 mg once daily in those with severe renal impairment (i.e., CLCR < 30 ml/min [< 1.8 l/h]) or ESRD

CLCR: Creatinine clearance; DPP-4-i: Dipeptidyl peptidase inhibitors.

Alogliptin is a benzonitrile that forms non-covalent bonds with the catalytic site of DPP 4. In animal studies, the half maximal inhibitory concentration (IC50) of alogliptin was 7 nmol/l for DPP-4, compared with IC50 values of > 100,000 nmol/l for DPP-2, DPP-8 and DPP-9 (i.e., > 10,000-fold greater selectivity for DPP-4) [29]. Saxagliptin is metabolized by CYP3A4/5 to an active metabolite, which is about half as potent as the parent compound, with terminal half-lives of 2.5 and 3.1 h, respectively [26]. However, the mean half-life for plasma DPP-4 inhibition was 26.9 h [26]. Sitagliptin is a b amino acid derivative with terminal halflife between 10 and 12 h [22,31], although for sitagliptin as for saxagliptin and vildagliptin, the biological activity lasts far longer. Linagliptin has a unique xanthine-based structure and has a long terminal half-life (up to 184 h) [32,33]. Linagliptin is cleared primarily through non-renal pathways and undergoes entero-hepatic circulation. Unlike the other DPP-4 agents, the dose of linagliptin does not have to be adjusted in patients with renal impairment. Vildagliptin is excreted by the kidney but is rapidly converted to an inactive metabolite, which constitutes ~ 85% of

the excreted drug [34,35]. Vildagliptin has a much shorter plasma half-life than the other DPP-4-i with a recommended twice daily administration [35,36], although the biological activity is much longer due to covalent bonding to DPP-4 [37]. In actual use the effect of vildagliptin at 100 mg daily is no different than that of 50 mg taken twice daily [38]. Due to the quick inactivation, vildagliptin dosage does not have to be modified in patients with mild renal impairment, although the dose must be reduced in patients with more advanced kidney failure [39]. All of these DPP-4 agents are highly selective for DPP-4, > 10,000-fold for linagliptin and alogliptin, > 2500-fold for sitagliptin, > 500-fold for vildagliptin and > 100-fold for saxagliptin [40]. Administration of DPP-4-i with a high-fat meal has not shown any significant change in total and peak plasma levels. DPP-4-i may therefore be administered with or without food [41-43]. 3.

Drug interaction studies

The DPP-4-i as a group have few relevant drug interactions [27]. The only exception concerns saxagliptin, which is metabolized to an active metabolite by CYP3A4/5. Therefore,


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A.

B.


C.

D.

E.

Figure 1. Chemical structures of the five DPP-4 inhibitors: (A) sitagliptin, (B) vildagliptin, (C) saxagliptin, (D) alogliptin, (E) linagliptin. Structures taken from Pharmaprojects -- copyright to Citeline Drug Intelligence (an informa business). Readers are referred to Informa-Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).

exposure to saxagliptin and its primary metabolite may be significantly modified when saxagliptin is coadministered with specific inhibitors (ketoconazole, diltiazem) or inducers (rifampicin) of CYP3A4/5 isoforms [27]. The DPP-4-i are largely free of significant interactions with agents often co-administered to type 2 diabetes patients. There are no interactive pharmacokinetic effects between DPP-4-i and other oral hypoglycemics including sulfonylureas, metformin or thiazolidinediones [27,44-53]. There are no significant interactions with lipid lowering agents [54-60]. DPP-4-i have no effect on hormonal contraception [61-63]. Anticoagulation with warfarin is not affected [64-67]. No dose adjustment of digoxin is recommended for co-administration of DPP-4-i [68-70]. It has been suggested that DPP-4-i may decrease the degradation of inflammatory peptides such as substance P and bradykinin. As a result, DPP-4-i use may be associated with a higher incidence of angiotensin converting enzyme inhibitor4

related angioedema [71]. There have been no reported interactions with amlodipine or angiotensin receptor blockers [72]. As the metabolism of saxagliptin is mediated by CYP3A4 and CYP3A5 isoenzymes, strong inhibitors and inducers of these isoenzymes will alter the pharmacokinetics of saxagliptin. Co-administration of a single dose of saxagliptin 100 mg with ketoconazole significantly increased the Cmax and AUC of saxagliptin by 62% and 2.5-fold, and decreased the Cmax and AUC of M2 by 95 and 91% [27]. Similar significant increases in plasma concentrations of saxagliptin are expected with other substrates CYP 3A4, 3A5 system such as diltiazem, atazanavir, ritonavir and clarithromycin. 4.

Safety profile of DPP-4-i

Tissues that strongly express DPP-4 include the heart and blood vessels, exocrine pancreas, kidney, and the lymph nodes.




4.1

DPP-4-i effects on the immune system

DPP-8 and DPP-9 enzymes (located in leukocytes) are involved in T-cell activation and the process of cell adhesion, migration and apoptosis [73]. Inhibition of DPP-8 and DPP-9 suppresses mitogen-stimulated T-cell responses [74,75]. In preclinical studies, there is some evidence that DPP-4-i may reduce inflammation [76]. There is a slight decrease in the lymphocyte number induced by saxagliptin, but mice treated with saxagliptin and vildagliptin had no abnormality of innate immune response induced by Toll-like receptor ligands; cytokine production, immune cell activation and lymphocyte trafficking were normal [77]. Linagliptin treatment reduced inflammation and accelerated epithelialization of wounds of diabetic mice [78]. Sitagliptin treatment in healthy volunteers did not affect the percentage of leukocyte subsets within peripheral blood mononuclear cells (PBMCs), plasma chemokine/cytokine levels or cytokines released by stimulation of PBMCs with either lipopolysaccharide or anti-CD3 [79]. A study of the WHOAdverse Drug Reactions database suggested an increased incidence of nasopharyngitis in patients receiving DPP-4-i compared to those receiving biguanides, but these results are questionable as there is a greater tendency to report issues associated with more recently introduced agents [80]. There is no suggestion to date that DPP-4-i may reduce the response to infection. In human studies, there is evidence that sitagliptin exerts anti-inflammatory effects [81]. Cardiac effects of DPP-4-i In the heart, DPP-4 cleaves multiple peptides, including Btype (brain) natriuretic peptide 1 -- 32 (BNP 1 -- 32), a peptide secreted by the heart that plays a key factor in regulating body fluid homeostasis and vascular tone [82,83]. Moreover, BNP reduces cardiac remodeling after acute myocardial infarction [84,85]. DPP-4 cleaves BNP (1 -- 32) into BNP (3 -- 32), which has reduced physiological activity compared to that of BNP (1-32) [86]. DPP-4 also truncates Stromal cell-derived factor-1a protein, a chemokine that promotes neoangiogenesis by promoting the homing of endothelial progenitor cells to the sites of injury or trauma [87]. The cardio-protective effect of DPP-4 was demonstrated in a porcine model of heart failure [88]. In a rodent model of myocardial infarction, it was demonstrated that DPP-4-i were associated with decrease in infarct size, enhanced neovascularization and left ventricular (LV) ejection fraction with an improvement in overall survival [89], and additional animal studies have also supported a cardio protective effect of DPP-4-i [90,91]. In human studies, increased circulating levels of endothelial progenitor cells were noted in a study of the effects of sitagliptin in type 2 diabetes subjects [92]. Reduction in blood pressure by DPP-4 treatment has been recorded in both diabetic and non-diabetic hypertensive subjects [93-95]. Sitagliptin attenuated the stunning of myocardium after an ischemic insult and also improved the overall cardiac 4.2

performance in patients with coronary artery disease during dobutamine stress echocardiography [96]. A randomized controlled trial is currently under way to assess the effects of sitagliptin on the progression of atherosclerosis [97]. In a cardiovascular safety evaluation trial (VIVIDD) [98] in diabetic subjects with ventricular dysfunction, subjects were randomized to receive either vildagliptin (n = 128) or placebo (n = 126) for 52 weeks. There were no differences in LV function after 1 year. At the end of the study significant increases in LV end-diastolic volume (p = 0.007), end-systolic volume (p = 0.06), and stroke volume (p = 0.002) were recorded in the vildagliptin group [98]. The trial was not powered to assess mortality, but mortality was 8.6% in the vildagliptin cohort compared to 3.2% in the placebo group [98]. All-cause mortality and cardiovascular efficacy of sitagliptin in comparison to Metformin were evaluated in a retrospective cohort study involving 84,756 subjects, out of which 1228 (1.4%) were sitagliptin treated [99]. There was no statistical difference between the two cohorts in terms of all-cause mortality (hazard ratio [HR], 1.25; 95% confidence interval (CI), 0.92 -- 1.71; p = 0.153) or the composite endpoint of stroke, acute myocardial infarction (HR, 1.22; 95% CI, 0.92 -- 1.61; p = 0.164). A pooled analysis of 25 randomized trials suggested no increase in cardiovascular risk in sitagliptin-treated patients [100]. Similarly a meta-analysis of 25 Phase III studies of vildagliptin showed no increased risk of cardiovascular events relative to comparators [101]. A pooled analysis of 20 clinical trials suggested no increased risk of major adverse cardiovascular events or of heart failure in saxagliptin-treated patients [102]. A meta-analysis of eight Phase III studies of linagliptin showed a significantly lower risk of cardiovascular events than for comparators [103]. The clinical evaluation of cardiovascular safety of DPP-4-i has included several large randomized controlled trials. The EXAMINE trial of alogliptin focused on type 2 diabetes patients who had experienced a recent acute coronary syndrome (ACS) [104]. At the end of 18 months, no significant differences were found in cardiovascular mortality (3.3 vs 4.1 %) (HR 0.79; 95 % CI 0.60 -- 1.04), nonfatal MI (6.9 vs 6.5%) (HR 1.08; 95% CI 0.88 -- 1.33) or nonfatal stroke (1.1 vs 1.2%) (HR 0.91; 95% CI 0.55 -- 1.50), unstable angina within 1 day of hospitalization (12.7 vs 13.4%) (HR 0.95), all-cause mortality (5.7 vs 6.5%) (HR 0.88; 95% CI 0.71 -- 1.09), incidence of hypoglycemia, malignancies (pancreatic cancer) or renal function, in comparison with placebo. Moreover, in post-hoc analysis, no significant difference in heart failure hospitalizations was noted between the alogliptin and placebo groups (HR 0.98; 95% CI 0.82 -1.21) [105]. In the SAVOR TMI 53 trial, a total of 16,492 diabetic subjects were randomized to receive either saxagliptin (n = 8822) or placebo (n = 8212) for a period of 2.1 years [106]. No significant difference in cardiovascular mortality was found between the saxagliptin cohort (7.3%) and the placebo group


5



(7.2%) (HR 1.00, p < 0.001 for non-inferiority). Nor were differences observed in nonfatal MI, nonfatal stroke, unstable angina within 1 day of hospitalization, or chronic pancreatitis, in comparison with placebo. No difference in heart failure event rates was noted: 1059 subjects in the saxagliptin group and 1034 subjects in the placebo group (12.8 and 12.4%, respectively, HR, 1.02; 95% CI, 0.94 -- 1.11; p = 0.66). The study was not powered to analyze heart failure outcomes. However, there was a slight increase in heart failure hospitalizations in the saxagliptin cohort (289 subjects, 3.5%) when compared to that of placebo (228 subjects, 2.8%) (HR, 1.27; 95% CI, 1.07 -- 1.51; p = 0.007). In an insurance data claims study, type 2 diabetes patients with diagnosed heart failure who were sitagliptin treated were more likely to be hospitalized for heart failure [107]. In a meta-analysis of 50 DPP-4 clinical trials [108], there was no difference in cardiovascular mortality (relative risk [RR] 0.97, 95% CI 0.85 -- 1.11, p = 0.70), all-cause mortality (RR 1.01, 95% CI 0.91 -- 1.13, p = 0.83), ACS (RR 0.97, 95% CI 0.87 -- 1.08, p = 0.59) or stroke (RR 0.98, 95% CI 0.81 -- 1.18, p = 0.80) [95]. However, there was a statistically significant increase in heart failure outcomes (RR 1.16, 95% CI 1.01 -- 1.33, p = 0.04), perhaps dominated by inclusion of data from the SAVOR TMI trial of saxagliptin. Vildagliptin has been associated with leg edema, but there has been no suggestion of an increased incidence of heart failure [109]. Two other major cardiovascular trials involving Linagliptin (CAROLINA [110] and CARMELINA [111]) and one study using sitagliptin (The Trial Evaluating Cardiovascular Outcomes with Sitagliptin) [112] are ongoing. The primary composite cardiovascular endpoints of these studies are time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. The CAROLINA Trial is of particular interest because it will compare cardiovascular events in patients treated with DPP-4-i to those treated with glimperide, a sulfonylurea.

Concern for pancreatitis and pancreatic cancer with DPP-4 treatment

4.3

Initially one of the great hopes for incretin-based therapies was that GLP-1 appeared to stimulate b-cell regeneration. In pre-clinical studies, animal models exhibit b-cell hypertrophy, b-cell proliferation, a reduction in b-cell apoptosis, and an increase in neogenesis from islet elements with overall b-cell regeneration and increased mass [113,114]. However, this enthusiasm was tempered by a review of the FDA Adverse Event Reporting System database, which recorded many reports of pancreatitis in exenatide and sitagliptin-treated patients [115,116]. A pancreatic autopsy study reported that there was a fourfold increase in both a- and b-cell mass in people who had diabetes and were receiving incretin-based therapies when compared to diabetes patients who had been receiving other therapies [117]. In a viewpoint, Butler et al. [118] stated that incretin-based therapies are 6

associated with increased acute pancreatitis, chronic pancreatitis, pancreatic and medullary carcinoma of thyroid. In a counterpoint, Nauck argued that the benefits of incretin therapy far outweigh these risks [119]. He added that there exists a bias in that serum lipase is elevated in patients who are taking incretin-based therapies, which does not necessarily indicate pancreatitis. A recent meta-analysis conducted by Monami et al. did not find an increased risk of pancreatitis associated with DPP-4-i [120]. The two recent large multi-center randomized placebo-controlled trials EXAMINE [104] and SAVORTIMI [106] showed no significant difference between the active and placebo groups in acute or chronic pancreatitis. In the SAVOR TIMI trial, 0.3% of the saxagliptin subjects developed acute pancreatitis compared to 0.2% in the placebo group. The U.S. FDA and the European Medicines Agency jointly published their review of the totality of evidence for an association between use of GLP-1 agonists and DPP-4-i and possible pancreatitis and pancreatic cancer [121]. They carefully reviewed data from animal exposure studies as well as clinical studies with > 28,000 patients who received some form of incretin-based therapy. They did not find evidence supporting a causal association of the incretin agents with either pancreatitis or pancreatic cancer. Skin toxicity of DPP-4-i Preclinical studies done with vildagliptin and saxagliptin have raised concerns regarding necrotic skin lesions that were observed in monkeys [109,122,123]. However, these lesions were not observed in preclinical or clinical studies with the other DPP-4-i [124], nor have they surfaced in clinical use of the various agents. Yet, skin conditions of a different type have been documented with several agents. Post approval of sitagliptin, serious allergic and hypersensitivity reactions such as anaphylaxis, angioedema, and exfoliative skin conditions including the Stevens--Johnson syndrome were reported [125]. There has been a slight increase in cutaneous adverse events such as pruritus in alogliptin-treated patients when compared to placebo [126]. 4.4

DPP-4-i and liver disease There is increased DPP-4 mRNA expression in the livers of individuals suffering from non-alcoholic fatty liver disease (NAFLD) [127]. Moreover, serum DPP-4 activity and hepatic expression of DPP-4 are correlated with extent of disease and NAFLD grading [128]. With the possible exception of vildagliptin, none of the DPP-4-i has shown hepatotoxicity in clinical trials. Vildagliptin has exhibited a low incidence of increased liver enzymes [109]. Yet hepatic impairment has not affected vildagliptin pharmacokinetics [129]. Measurement of liver enzymes is recommended within 3 months of beginning vildagliptin treatment, and its use is contraindicated in patients with significant liver disease. No dosage adjustment of linagliptin, alogliptin, saxagliptin, or sitagliptin is recommended in 4.5



patients with liver disease, although linagliptin is primarily excreted by entero-hepatic mechanisms. DPP-4-i in renal disease All the DPP-4-i except linagliptin are eliminated renally and are reported to accumulate in patients with renal insufficiency. Dosage adjustment is recommended in patients with moderate-to-severe renal impairment when administering sitagliptin (50 mg in moderate renal impairment, 25 mg in severe impairment) [130], saxagliptin (2.5 mg in both moderate and severe renal impairment) [131], alogliptin (6.25 mg in severe renal disease including dialysis patients) [132] and vildagliptin [133] (50 mg in both moderate and severe renal impairment). Linagliptin, however, has primarily a non-renal route of excretion and can be used without dose adjustment in patients at all stages of renal disease [134].


4.6

DPP-4-i and hypoglycemia Hypoglycemia is a major concern for clinicians and their patients in management of type 2 diabetes. In the ACCORD study, a benchmark long-term outpatient trial, intensive treatment was associated with a 2.5-fold increase in hypoglycemic events [135]. The ACCORD trial was terminated due to increased mortality, including cardiovascular mortality, in the intensively treated groups, possibly related to the unfavorable effect of hypoglycemia in susceptible patients such as those with underlying coronary disease [136]. In a metaanalysis by Griesdale et al. of 26 trials that reported mortality, the pooled RR of death with intensive insulin therapy compared with conventional therapy was 0.93 (95% CI 0.83 -1.04), but, among the 14 trials that reported hypoglycemia, the pooled RR with intensive insulin therapy was 6.0 (95% CI 4.5 -- 8.0) [137]. Because of the glucose-dependent mechanism of action of DPP-4-i (i.e., they stimulate insulin secretion only during hyperglycemia), incretin-based therapies when used alone or with metformin have a low risk of hypoglycemia. Furthermore, DPP-4-i do not suppress glucagon release in response to hypoglycemia [138,139]. In a trial of ~ 2700 patients not well controlled with metformin, vildagliptin and glimepiride produced equivalent reduction in HbA1c but there were 10-fold fewer hypoglycemic reactions recorded with the DPP-4-i [140]. A comparison of sitagliptin with glimepiride in > 1000 patients showed no difference in lowering of HbA1c but three times more episodes of hypoglycemia in the sulfonylurea-treated group [141]. Similarly hypoglycemia occurred in 3% of metformin-treated patients receiving saxagliptin add-on therapy versus 36% of patients receiving glipizide in addition to metformin [142]. In a similar 2-year study comparing linagliptin with glimepiride in metformin-treated patients, fewer participants had hypoglycemia (58 [7%] of 776 vs 280 [36%] of 775 patients, p < 0.0001) or severe hypoglycemia (1 [< 1%] vs 12 [2%]) with linagliptin compared with glimepiride [143], and linagliptin was associated with significantly fewer cardiovascular events (12 vs 26 patients; relative risk 0.46, 95% CI 4.7

0.23 -- 0.91, p = 0.0213). The addition of alogliptin to glyburide therapy resulted in a reduction of HbA1c of ~0.5% with no higher incidence of hypoglycemia than the placebo addition [144]. 5.

Conclusion

The DPP-4-i prevent degradation of GLP-1, resulting in increased levels of this hormone, which stimulates a glucosedependent increase in insulin secretion by the b-cell, suppresses glucagon secretion, slows gastric emptying time and promotes satiety. There are now five DPP-4-i in international use, alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin, with others in development. These agents have very different chemical structures, yet are all highly potent. Of this group, only saxagliptin has significant CYP metabolism with resultant drug interactions. Overall the DPP-4-i have relatively few interactions with drugs commonly used in the type 2 diabetes population. Despite potential effects on white cells, there is little evidence of effects on the immune system. The EXAMINE and SAVOR-TIMI studies have not suggested increased ischemic events, but the SAVOR-TIMI study found increased hospitalizations for congestive heart failure in the saxagliptin arm. The risk of pancreatitis and pancreatic cancer has generated concern, but several studies and meta-analyses have not supported this concern with either GLP-1 agonists or DPP-4-i. There have been animal study findings of skin lesions with vildagliptin and saxagliptin, but these have not been seen in man. Skin reactions including Stevens--Johnson exfoliative dermatitis have been noted in sitagliptin-treated patients. There is a low incidence of skin complaints, mainly pruritus, in alogliptin-treated subjects. Vildagliptin-treated subjects have had liver enzyme elevations, prompting a recommendation to test liver enzymes in the first several months of use. Alogliptin, sitagliptin, saxagliptin, and vildagliptin undergo renal excretion and must be administered in reduced dosage to patients with renal impairment. Linagliptin has primarily entero-hepatic excretion and may be administered to renal patients without dose reduction. Although DPP-4-i can cause hypoglycemia, the incidence is much lower than for the sulfonylureas. 6.

Expert opinion

The pharmaceutical treatment of type 2 diabetes begins with metformin. When metformin induced suppression of hyperglycemia is insufficient or if intolerance to metformin or renal disease forces discontinuation, there are a variety of other agents available to treat hyperglycemia (Table 2). At present, the current second choice of therapy goes to the sulfonylureas. The disadvantages of sulfonylurea treatment include hypoglycemia, which can be protracted, and weight gain. The DPP4-i are attractive alternatives, with much less hypoglycemia


7


Table 2. Key differential features of antihyperglycemia agents used in the treatment of type 2 diabetes mellitus.


Name of drug

Mechanism of action

Biguanides (e.g., metformin)

Decrease hepatic glucose output, increased insulin sensitivity in periphery

DPP-4-i (linagliptin, vildagliptin, sitagliptin, saxagliptin, alogliptin)

The mechanism of DPP-4-i is to increase incretin levels (GLP-1 and gastric inhibitory polypeptide), which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels. GLP-1 also suppresses glucagon release and promotes a feeling of satiety Increased secretion of insulin from pancreatic b-cells. Sulfonylureas bind to an ATP-dependent K+ channel and inhibit a tonic, hyperpolarizing efflux of potassium, thus causing the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca2+ channels leading to increased secretion of insulin Act by activating PPARs (peroxisome proliferatoractivated receptors),that modulate the expression of the gene-regulated proteins, which control glucose and lipid metabolism Inhibit intestinal carbohydrate digestion

Sulfonylureas (e.g., glibenclamide [glyburide], glipizide)

Thiazolidinediones (e.g., pioglitazone, rosiglitazone) a-Glucosidase inhibitors (e.g., voglibose, acarbose, miglitol) Glinides (e.g., nateglinide, repaglinide)

Increase secretion of insulin from pancreatic b-cells

SGLT-2 inhibitors (Canagliflozin, Dapagliflozin)

Block the re-uptake of glucose in the renal tubules, promoting loss of glucose in the urine

Bromocriptine (Cycloset)

Sympatholytic dopamine D2 agonist. Timed bromocriptine administration within 2 h of awakening is believed to augment low hypothalamic dopamine levels and inhibit excessive sympathetic tone within the CNS, resulting in a reduction in post-meal plasma glucose levels due to enhanced suppression of hepatic glucose production The exact mechanism regulating the glycemic effect of a BAS remains unexplained. Potential mechanisms include effects on the farnesoid X receptor (the bile acid receptor) and TGR5 (a G protein--coupled receptor) within the intestine as well as effects on farnesoid X receptor within the liver, which may ultimately reduce endogenous glucose production. May also increase GLP-1 levels The mechanism of GLP-1 receptor agonists is to inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels, central effect of satiety

BAS (Colesevelam)

GLP-1 receptor agonists (e.g., exenatide, liraglutide)

Points to consider Advantages: weight neutral; low risk of hypoglycemia; low cost; first line agent Disadvantages: gastrointestinal intolerance; potential lactic acidosis; contraindicated if renal function decreased Advantages: weight neutral; low risk of hypoglycemia Disadvantages: high cost, skin reactions with several agents

Advantages: low cost Disadvantages: weight gain; hypoglycemia; low durability of effect

Advantages: low hypoglycaemia risk; lipid improvements (pioglitazone) Disadvantages: weight gain; edema; heart failure; bone fractures Advantages: weight neutral; low cost Disadvantages: flatulence; administration up to three times daily Advantages: rapid and short acting Disadvantages: weight gain; hypoglycemia; Ned to administer with each meal Advantages: weight loss, reduction in blood sugar levels with little risk of hypoglycemia Disadvantages: urinary tract and genital infections Advantages: bromocriptine also reduces fasting and post-meal plasma free fatty acid and triglyceride levels. The absence of hypoglycemia as insulin secretion is not stimulated, weight neutrality, no need for dose adjustment in patients with moderate renal insufficiency Disadvantages: high incidence of nausea Advantages: low incidence of hypoglycemia, weight neutral drugs, decrease low density lipoprotein cholesterol Disadvantages: gastorintestinal intolerance, hypertriglyceridemia

Advantages: weight loss; low hypoglycemia risk Disadvantages: gastrointestinal intolerance; pancreatitis (UA), risk of medullary carcinoma thyroid

BAS: Bile acid sequestrants; DPP-4-i: Dipeptidyl peptidase inhibitors; GLP-1: Glucagon-like polypeptide-1.

8



Table 2. Key differential features of antihyperglycemia agents used in the treatment of type 2 diabetes mellitus (continued). Name of drug

Mechanism of action

Amylin agonists (e.g., pramlintide)

Suppresses postprandial glucose secretion; delay gastric emptying

Insulin/insulin analogs (e.g., insulin lispro, insulin glargine)

Replace endogenous insulin

Points to consider Advantages: weight loss Disadvantages: increase in insulin-induced hypoglycemia risk Advantages: provide sustained improvements in glycemia Disadvantages: weight gain; hypoglycemia; fluid retention


BAS: Bile acid sequestrants; DPP-4-i: Dipeptidyl peptidase inhibitors; GLP-1: Glucagon-like polypeptide-1.

and no increase in weight with treatment. At this point, DPP-4-i appear to be poised to take over the role currently served by sulfonylureas. Certainly, higher cost is a deterrent as there are currently no generic DPP-4 choices. In addition, lingering concerns exist about possible safety issues. The increased incidence of pancreatitis and pancreatic cancer in diabetes patients makes it difficult to assess a possible effect of GLP-1 agonists and DPP-4-i. To add to the uncertainty, the class of DPP-4-i includes several agents with markedly different chemical structures, so that safety issues may be specific to certain agents rather than the class as a whole. There have been very few head-to-head studies comparing the different DPP-4-i, but there are known differences in the safety profiles of the five agents. Notably, vildagliptin has been associated with leg edema and liver enzyme changes. As a result it is the only DPP-4-i with recommended measurement of liver enzymes at the outset of treatment. Saxagliptin is metabolized by the CYP3A4/5 system, leading to caution in the event of co-administration of inhibitors or inducers of that system. Adverse skin reactions remain a concern with all the agents, although the incidence appears to be low. All new agents used to treat diabetes receive special scrutiny for possible adverse cardiovascular effects. Here the SAVOR TIMI trial has heightened concern about congestive heart failure hospitalizations with saxagliptin. The EXAMINE trial showing no increase in congestive heart failure episodes with alogliptin was reassuring. Nonetheless, it should be emphasized that no controlled trial focusing specifically on the possible

worsening of congestive heart failure by DPP-4-i has been performed. The dominant safety issue remains ischemic cardiovascular events. There is no evidence from the outcome studies to date that DPP-4-i increase ischemic events. To the contrary, in comparison with sulfonylureas, there appear to be far fewer such events. The ACCORD Trial and many other studies have raised the concern that hypoglycemia may trigger cardiac events. It is plausible that the DPP-4 agents, with far less hypoglycemic episodes than sulfonylureas, would exhibit a more favorable cardiac profile. The CAROLINA Trial is a head-to-head comparison of linagliptin and glimepiride on cardiac outcomes in patients with increased risk. An outcome favoring linagliptin would be a persuasive argument to have DPP-4 agents replace sulfonylureas as the preferred second agent when metformin treatment is insufficient to control diabetes.

Declaration of interest MS Rendell has received grant funding from Bristol-Myers Squibb, Takeda, Merck, Boehringer Ingelheim and Novartis to pursue studies of each of the DPP-4 inhibitors. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.


9


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Affiliation Sri Harsha Tella1,3 MD & Marc S Rendell†2,4 MD † Author for correspondence 1 Creighton Diabetes Center, 601 North 30th Street, Omaha, NE 68131, USA 2 Executive Director, The Association of Diabetes Investigators, 660 South 85th Street, Omaha, NE 68114, USA Fax: +1 402 280 5245; E-mail: [email protected] 3 Resident Physician (PGY 3), Creighton University, Department of Internal Medicine, Omaha, NE 68114, USA [email protected]. 4 Professor of Medicine and Director, Creighton Diabetes Center, 601 North 30th Street, Omaha, NE 68131, USA

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