Drug Safety Evaluation

Linagliptin for the treatment of type 2 diabetes mellitus: a drug safety evaluation 1.

Introduction

2.

Linagliptin mechanism of action, pharmacokinetics and

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pharmacodynamics 3.

Brief review of clinical utility

4.

Safety and tolerability

5.

Conclusion

6.

Expert opinion

Anthony H Barnett Heart of England NHS Foundation Trust and University of Birmingham, Diabetes Centre, Birmingham, UK

Introduction: Established treatments for type 2 diabetes mellitus (T2DM) have side effects that limit their use in specific populations. New therapies with improved safety profiles are needed, especially because of the chronic and progressive nature of T2DM. Areas covered: This review describes the overall safety and tolerability of linagliptin -- a dipeptidyl peptidase-4 inhibitor that improves glycemic control without increasing risk for hypoglycemia and without weight gain. Specifically, the safety of linagliptin is evaluated in difficult-to-treat patients with T2DM, in relation to risk of cardiovascular (CV) events and acute pancreatitis, and in comparison with other antihyperglycemic drugs. Expert opinion: Linagliptin is generally well tolerated in a broad range of patient populations. It can be used in patients with renal impairment without dose titration and may be a rational alternative treatment in this vulnerable population. Ongoing long-term trials are fully evaluating the CV and renal safety profile of linagliptin. Keywords: dipeptidyl peptidase-4 inhibitors, linagliptin, safety, tolerability, type 2 diabetes mellitus Expert Opin. Drug Saf. [Early Online]

1.

Introduction

The worldwide incidence of diabetes is increasing at an alarming rate with the number of people who had diabetes in 2013 (382 million) [1] exceeding the number previously projected for 2030 (366 million) [2]. Age at the onset of type 2 diabetes mellitus (T2DM) is also a growing concern -- a 2005 survey showed that mean age at the diagnosis of T2DM in the US fell from 52 years to 46 years from 1988 to 2000 [3]. In 2011, 63% of adult patients diagnosed within the past year were between 40 and 64 years and 16% were between 18 and 39 years [4]. This trend combined with increased life expectancy in the modern age means that patients are likely to be on antidiabetes treatment for decades. Therefore, along with efficacy, the merits of treatments are determined by their long-term safety profile. Patients with T2DM are at increased risk of complications such as cardiovascular (CV) disease, renal disease, neuropathy and retinopathy. In choosing a treatment regimen to manage hyperglycemia, particular attention must be given to preventing or minimizing the progression of these co-morbidities, while also avoiding hypoglycemia [5]. International guidelines recommend metformin as the first-line therapy when tolerated [5]. To achieve or maintain glycemic targets, the great majority of patients progress over time to needing combination therapy. Traditionally, a sulfonylurea (SU), thiazolidinedione, and/or insulin are added as a second or a third drug [5,6]. These drugs are efficacious but have safety concerns particularly in vulnerable populations including patients with renal dysfunction, CV risk factors or disease, advanced age or obesity. 10.1517/14740338.2014.971008 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

1

A. H. Barnett

Box 1. Drug summary. Drug name (generic) Phase (for indication under discussion) Indication (specific to discussion) Pharmacology description/mechanism of action

Route of administration Chemical structure

Linagliptin Approved in the US and EU Linagliptin is a dipeptidyl peptidase (DPP)-4 inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation Oral O

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N

N

N N

O

N N

N NH2

Pivotal trial(s)

EudraCT EudraCT EudraCT EudraCT

No.: No.: No.: No.:

2007-002456-41 2007-002448-10 2007-002457-24 2007-002450-28

Since 2006, dipeptidyl peptidase (DPP)-4 inhibitors have emerged as a new class of antihyperglycemic drug with an improved safety profile [7]. Linagliptin (Box 1) was approved in 2011 for use as monotherapy or combination therapy at a 5-mg oral daily dose [8]. Linagliptin and metformin fixeddose combination tablets (single pill) have also been available since 2012. The tablets contain 2.5 mg linagliptin and one of three doses of metformin in the US (500, 850 or 1000 mg) or one of two doses of metformin in the EU (850 or 1000 mg). The maximum recommended dose is 2.5 mg linagliptin/1000 mg metformin twice daily [9]. This article reviews safety characteristics of linagliptin with a focus on treatment of challenging populations, special events of interest and comparison versus established oral antidiabetes drugs (OADs).

Linagliptin mechanism of action, pharmacokinetics and pharmacodynamics 2.

DPP-4 is a proteolytic enzyme with diverse substrates including the incretin hormones, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP) [10]. The incretins are key hormones in glucose homeostasis. After food intake, GLP-1 and GIP are secreted by intestinal enteroendocrine cells and distributed to various organs and tissues via the bloodstream. The incretins regulate plasma glucose mainly by stimulating pancreatic b cells to enhance insulin secretion, and in animal studies have been shown to increase b-cell proliferation and survival and inhibit apoptosis. GLP-1 also suppresses glucagon secretion from pancreatic a cells, delays gastric emptying and increases satiety. GLP-1 and GIP, however, are rapidly degraded by DPP-4 [11]. Inhibition of DPP-4 prevents this degradation, thereby prolonging the half-life of the two incretins. Sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin are currently marketed DPP-4 inhibitors for management of 2

(clinicaltrials.gov: (clinicaltrials.gov: (clinicaltrials.gov: (clinicaltrials.gov:

NCT00641043) NCT00621140) NCT00601250) NCT00602472)

hyperglycemia. Linagliptin is the most potent and selective member of its class (in vitro IC50, 1 nM; > 104-fold selectivity over other DPP isoforms) [12]. In patients with T2DM, linagliptin 5 mg/day attained steady state between 4 and 6 days, with Cmax of 11.1 nmol/l reached in 1.5 h [13]. Similar drug exposure has been observed in other studies [14]. Linagliptin has a unique pharmacokinetic (PK) profile compared with other DPP-4 inhibitors [15]. It displays high plasma protein binding (70 -- 80%, concentration-dependent), a long terminal half-life (mean t½ = 131 h at steady state) [13] and lower bioavailability (~ 30%) [16] than other DPP-4 inhibitors. A major, clinically relevant PK difference between linagliptin and other DPP-4 inhibitors is its non-renal route of elimination [17]. Linagliptin is primarily excreted unchanged; after a 10-mg dose of 14C-labeled drug, 90.1% of recovered radioactivity was associated with the parent compound (84.7% in feces and 5.4% in urine in analyses up to 120 h) [17]. Exposure of linagliptin is minimally affected by renal or hepatic impairment in patients with T2DM [18,19], making it a viable treatment option without dose adjustment in those populations. Preclinical studies showed that linagliptin is extensively distributed in tissues with maximum concentration found in the intestine, liver and kidney where DPP-4 is highly expressed [20]. Co-dosing of linagliptin with other OADs (metformin, pioglitazone, glyburide or empagliflozin), CV drugs (warfarin, digoxin or simvastatin) or oral contraceptives did not affect mutual exposures [21-28]. In a 12-day study in patients with T2DM, linagliptin 5 mg daily achieved mean maximum DPP-4 inhibition of 92.3% at steady state, which was sustained through the study period (84.8% on day 12) [13]. In the same study, GLP-1 levels increased dose dependently and were higher (12.4 -- 14.0 pmol/l) on day 13 than on day -1

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Linagliptin

(1.43 -- 3.83 pmol/l). In a longer 4-week study, maximum DPP-4 inhibition of 91 -- 93% was observed at steady state depending on the linagliptin dose, which was maintained (82 -- 90%) at the end of the 24-h dosing period [29]. In this study, placebo-corrected mean increases in GLP-1 levels ranged from 7.3 to 8.39 pmol/l depending on the dose.

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3.

Brief review of clinical utility

Efficacy of linagliptin as mono- and combination therapy has been evaluated in an extensive Phase III clinical trial program. Linagliptin 5 mg daily alone achieved a placebo-corrected change of -0.69% (p < 0.0001) in glycated hemaglobin (HbA1c) at 24 weeks. Additionally, fasting plasma glucose (FPG) and 2-h postprandial glucose (PPG) were significantly lowered (-1.3 and -3.2 mmol/l) compared with placebo [30]. Since the glucose-lowering mechanism of DPP-4 inhibitors complements the mechanisms of other established drugs (especially insulin sensitizers), they potentially confer an additive effect in achieving glycemic control. In patients with T2DM insufficiently controlled with metformin, the addition of linagliptin achieved a placebo-corrected mean change of -0.64% in HbA1c after 24 weeks [31]. Initial combination of linagliptin 2.5 mg plus metformin 1000 mg showed improved glycemic control compared with metformin 1000 mg alone after 24 weeks (placebo-adjusted mean changes in HbA1c of -1.7, and -1.2%, both p < 0.0001) [32]. Significant reductions in HbA1c were also achieved with linagliptin added on to pioglitazone (with or without metformin, -0.57 and -0.51%, respectively) [33,34], basal insulin (-0.65%) [35] and an SU (with or without metformin, -0.62 and -0.47%, respectively) [36,37] (all p < 0.0001). 4.

Safety and tolerability

Overall safety SUs, thiazolidinediones, and insulin as drug classes are efficacious but can be associated with serious side effects including hypoglycemia (SUs and insulin), weight gain (SUs, thiazolidinediones and insulin), fluid retention (thiazolidinediones), increased risk of bone fracture (thiazolidinediones) and congestive heart failure (thiazolidinediones). In a representative sampling of Phase III randomized controlled trials in broadly defined T2DM populations (Table 1), linagliptin has been shown to be associated with a favorable safety profile with a low risk of hypoglycemia and no significant weight gain [30-36]. In these studies, the majority of the adverse events (AEs) observed were mild to moderate. The rates of serious adverse events (SAEs) were comparable between linagliptin and placebo groups. With linagliptin monotherapy, the most common AE was hyperglycemia (8.6 vs 22.8% with placebo) [30]. Linagliptin did not show excess risk of infections compared with placebo; the generally high incidence of infections is likely a result of the overall poor health associated with the diabetes state. In extension 4.1

studies, the tolerability as well as the efficacy of linagliptin alone or in addition to other OADs was sustained over 1- or 2-year treatment durations [38,39]. A detailed safety analysis of all available placebo-controlled linagliptin clinical trials (22 trials, 7400 patients, with or without background therapies) has helped clarify further the safety profile of linagliptin [40]. In the linagliptin and placebo groups of this analysis, the rates of overall AEs (57.3 vs 61.8%), SAEs (4.8 vs 6.4%) and drug-related AEs (11.7 vs 13.7%) were similar. Incidences of AEs by system organ class were also comparable for linagliptin and placebo groups (Figure 1). Hypoglycemia Older age and kidney dysfunction contribute independently to increased risk of hypoglycemia. In a recent evidence-based systematic review of adults with T2DM, severe hypoglycemia increased risk of all-cause mortality, neurologic effects and hospitalization, and decreased quality of life [41]. Other possible serious consequences of hypoglycemia include higher risk of acute CV events, falls, fractures and dementia [42]. DPP-4 inhibitors carry low intrinsic risk of hypoglycemia because their insulinotropic effects are glucose-dependent. In Phase III trials, linagliptin did not increase the incidence of hypoglycemia compared with placebo when it was given as monotherapy or in combination with metformin, pioglitazone or insulin, although in the insulin trial use of insulin rescue therapy was greater among placebo-treated patients. When given in combination with an SU, linagliptin showed a higher incidence of hypoglycemia than placebo (Table 1). SUs, which increase insulin secretion by pancreatic b cells, have been shown to augment hypoglycemia [43-45]. The pooled analysis of linagliptin safety and tolerability revealed that among patients taking an SU, hypoglycemia occurred at a higher rate with linagliptin (22.1%) than with placebo (14.5%) [40]. However, when all background therapies were taken into consideration, similar percentages of patients experienced overall investigator-defined hypoglycemia in both the linagliptin (11.5%) and placebo (14.0%) arms. The frequencies of severe hypoglycemia requiring resuscitative assistance were also similar between groups (0.4 and 0.5%). Based on available evidence, product labeling advises that consideration should be given to lowering the doses of insulin or SUs when administered concomitantly with linagliptin to reduce the risk of hypoglycemia [8]. 4.2

4.3

Safety in specific patient populations Elderly

4.3.1

Older (‡ 65 years) patients with T2DM are a particularly challenging population to treat. Co-morbidities, such as CV disease and renal impairment, the potential for drug--drug interactions resulting from complex treatment regimens, and age-related decline in pancreatic islet function combine to increase the risk of hypoglycemia. Thus, when optimizing

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Table 1. Safety findings of interest in Phase III trials of linagliptin as mono- or combination therapy in type 2 diabetes mellitus. Treatment, duration

N*

SAEs, %

Hypoglycemia, n (%)†

Change in mean body weight (SE), (kg)

Infections and infestations, n (%)

Linagliptin monotherapy [30], 24 weeks Linagliptin + metformin [31], 24 weeks Linagliptin + metformin initial combination [32], 24 weeks§ Linagliptin + SU [37], 18 weeks Linagliptin + metformin + SU [36], 24 weeks Linagliptin + metformin + pioglitazone [33], 24 weeks Linagliptin + basal insulin [35], ‡ 52 weeks** Linagliptin + pioglitazone [34], 24 weeks

Lina: 336 Pbo: 167 Lina: 523 Pbo: 177 Lina: 143 Pbo: 72 Lina: 161 Pbo: 84 Lina: 792 Pbo: 263 Lina: 183 Pbo: 89

Lina: 4.2 Pbo: 3.0 Lina: 3.4 Pbo: 2.3 Lina: 1.4 Pbo: 1.4 Lina: 3.1 Pbo: 1.2 Lina: 3.2 Pbo: 3.8 Lina: 2.2 Pbo: 3.4

Lina: 1 (0.3) Pbo: 1 (0.6) Lina: 3 (0.6) Pbo: 5 (2.8) Lina: 0 (0) Pbo: 1 (1.4) Lina: 9 (5.6) Pbo: 4 (4.8) Lina: 180 (22.7) Pbo: 39 (14.8) Lina: 10 (5.5) Pbo: 5 (5.6)

No significant change

Lina: 55 (16.4) Pbo: 38 (22.8) Lina: 112 (21.4) Pbo: 38 (21.5) Lina: 33 (23.1) Pbo: 16 (22.2) Lina: 20 (12.4) Pbo: 4 (4.8) Lina: 170 (21.5) Pbo: 76 (28.9) NR

Lina: 631 Pbo: 630 Lina: 259 Pbo: 130

Lina: 13.8 Pbo: 13.2 NR

Lina: 198 (31.4) Pbo: 207 (32.9) Lina: NR (1.2) Pbo: NR (0.0)

Lina: -0.3 (0.19) Pbo: -0.04 (0.18) Lina: 2.3 (NR) Pbo: 1.2 (NR)zz

Lina: -0.4 (NR) Pbo: -0.5 (NR) Lina: -0.8 (0.3) Pbo: -0.7 (0.4) Lina: 0.43 (NR) Pbo: -0.01 (NR){ Lina: 0.27 (0.09) Pbo: -0.06 (0.16)# Lina: 0.5 (0.29) Pbo: 0.67 (0.35)

NR NR

*Number of patients treated. † Investigator-defined. § Data shown for linagliptin 2.5 mg + metformin 1000 mg b.i.d. { p = 0.12. # p = 0.0803. **Maximum duration 110 weeks. zz 95% confidence interval: 0.2, 2.0; p = 0.014. Lina: Linagliptin; NR: Not reported; Pbo: Placebo; SAE: Serious adverse events; SU: Sulfonylurea.

glucose-lowering treatment in this population, safety is of critical importance, and glycemic targets may be less stringent (HbA1c 7.5 -- 8.0%) to offset risk for hypoglycemia [46]. In a dedicated 24-week trial of patients ‡ 70 years, linagliptin added to background glucose-lowering therapy had a safety profile comparable to placebo [47]. AEs occurred at the same rate (75.9%) in both groups; 21.0 and 8.6% of patients receiving linagliptin and 13.9 and 6.3% of patients receiving placebo experienced drug-related and SAEs, respectively. No SAEs were considered to be drug related. No drug-related CV events, neoplasms or clinically relevant changes in body weight or renal function were observed. The frequency of hypoglycemia (24.1 and 16.5% with linagliptin and placebo, respectively) was not significantly different (p = 0.2083). In patients ‡ 65 years, analysis of safety data pooled from seven randomized controlled Phase III trials revealed similar findings. In the linagliptin and placebo groups, drug-related AEs occurred in 18.1 and 19.8% of patients, respectively, hypoglycemia in 21.4 and 25.7% (severe in 1.0 and 1.8%) of patients, and at least one adjudicated CV event in 0.8 and 1.0% of patients [48]. Both linagliptin and placebo were weight neutral (adjusted means [± SE], -0.32 [0.15] kg and -0.40 [0.23] kg, [p = 0.7258]). Of particular interest in the treatment of elderly patients with T2DM, a pooled analysis of data for a subset of patients ‡ 70 years from two Phase III trials has provided 4

hypothesis-generating evidence that linagliptin may reduce the risk of hypoglycemia versus placebo when given on a background of insulin [49]. Patients with renal impairment Treating hyperglycemia in patients with compromised renal function is another challenge for physicians because many drugs in clinical use for T2DM either need dose adjustment or are contraindicated [50,51]. Linagliptin is indicated without dose adjustment in patients at all stages of kidney disease including end-stage renal disease [8], and thus offers a potential advantage. The use of linagliptin without dose adjustment is supported by a study in renally impaired patients with or without T2DM in which linagliptin exposure at steady state after multiple dosing at 5 mg/day did not vary significantly [18]. In a 1-year trial of 133 patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73 m2), similar proportions of patients experienced drug-related AEs in the linagliptin and placebo groups (45.6 vs 44.6%) [52]. No clinically relevant reduction in eGFR values occurred with linagliptin or placebo (median change from baseline -0.8 vs -2.2 ml /min/1.73 m2, respectively). Percentages of patients with renal and urinary disorders were similar (25.0 vs 21.5% for linagliptin vs placebo, respectively). No linagliptin-related renal failure was reported. 4.3.2

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Linagliptin

A. Linagliptin 5 mg Placebo

30

25.0

Patients, %

21.3 20 12.7

11.4 10 5.9 3.2

3.3

3.3

7.0

3.4

0 Eye disorders

General disorders, administration site conditions

Gastrointestinal disorders

B. 30

Infections, infestations

Linagliptin 5 mg Placebo

27.8

Patients, %

20.5 20 12.2

11.2 10 5.2

5.7

5.4

8.1

6.4

9.6

0 Injuries, poisoning, and procedural complications

Investigations

Metabolism and nutrition disorders

Musculoskeletal, connective tissue disorders

Nervous system disorders

C. 30

Patients, %

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Cardiac disorders

Linagliptin 5 mg Placebo

20

10 1.8

2.9

3.5

4.4

4.5

5.1

3.8

4.4

0 Psychiatric disorders

Renal and urinary disorders

Skin and subcutaneous tissue disorders

Vascular disorders

Figure 1. Summary of adverse events by system organ class in a pooled population of patients participating in the linagliptin clinical trials program. Data taken from [40].

Frequency of symptomatic hypoglycemia was comparable between groups (33.5 and 33.8% for linagliptin and placebo, respectively) with low rates of severe hypoglycemia (4.4 and 4.6%, respectively). In another long-term (1 year) randomized controlled trial, patients with T2DM and moderate-to-severe renal

impairment (eGFR < 60 ml /min/1.73 m2) were treated with linagliptin 5 mg/day or placebo for 12 weeks; patients in the placebo group were then switched to glimepiride 1 -- 4 mg, and the treatments were continued up to 52 weeks [53]. During the 40-week extension phase, drugrelated AEs occurred at a lower rate with linagliptin than

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A. H. Barnett

with glimepiride (38.3 and 46.5%, respectively), and hypoglycemia was less frequent with linagliptin than with glimepiride (57.9 and 69.3%, respectively). Patients treated with linagliptin had a small decrease in body weight compared with patients in the glimepiride group. Based on the aforementioned clinical trial data, linagliptin would appear to be well tolerated in patients with T2DM and renal dysfunction without worsening the risk of hypoglycemia or renal disease. Of interest, in a pooled analysis of four trials in patients with T2DM and renal dysfunction, linagliptin given on top of renin-angiotensin-aldosterone system inhibitors was associated with significantly reduced urine albumin-to-creatinine ratio (UACR) by 32% compared with a 6% reduction with placebo -- a between-group reduction of 28% (95% confidence interval [CI]: -47 -- -2; p = 0.0357) after 24-weeks treatment [54]. This led to the hypothesis that linagliptin might confer beneficial renal effects independent of its glucose-lowering efficacy. A prospective clinical study, MARLINA-T2D (NCT01792518) is underway to assess this hypothesis. MARLINA-T2D will evaluate the efficacy and safety of linagliptin in patients with T2DM and renal disease (UACR 30 -- 3000 mg/g within 1 year of randomization). Renal efficacy measures, including change in albuminuria (UACR), will be assessed after 24 weeks of treatment [55]. Patients with hepatic impairment In an open-label, parallel group, Phase I trial, exposure of linagliptin (steady state) was observed to be lower in patients with mild-to-moderate hepatic impairment and similar in patients with severe hepatic impairment (single dose) as compared with healthy subjects. However, the extent of DPP-4 inhibition remained unaffected (84 -- 90%) [19]. Thus, although linagliptin is primarily excreted via the gut and bile, no dose adjustment is required in patients with hepatic impairment [8]. 4.3.3

Non-White patients Prevalence of diabetes, obesity and complications of diabetes is higher in African Americans than in White patients [56,57]. In a 24-week study of linagliptin in Black/African American patients with T2DM, the safety and tolerability of linagliptin were comparable to placebo [58]. Overall AEs occurred at similar rates with linagliptin and placebo (58.5 and 61.7%, respectively). Drug-related AEs were observed in 3.8 and 9.2% of linagliptin and placebo patients, respectively. Hypoglycemia was infrequent (three patients in the linagliptin group and one in the placebo group), and no severe cases occurred. No significant between-group differences in body weight or waist circumference were observed. In a pooled analysis of 12 randomized controlled trials in Asian patients (from centers in China, India, Israel, Japan, Korea, the Philippines, Malaysia, Taiwan, Thailand and Turkey), 12.1 and 8.4% of patients in the linagliptin and placebo groups experienced drug-related AEs. Rates of overall 4.3.4

6

AEs (58.0 and 58.2%, respectively) and SAEs (2.4 and 2.7%, respectively) were comparable between groups [59]. Hypoglycemia occurred in 9.7 and 5.3% of patients receiving linagliptin and placebo, respectively. Linagliptin administered alone or as combination therapy for 18 or 24 weeks has been shown to be well tolerated in Hispanic/Latino patients. In a pooled analysis in this population, the rates of overall AEs, SAEs and drug-related AEs were similar with linagliptin and placebo [60]. Hypoglycemia occurred in 17.4 and 21.0% patients in the linagliptin and placebo groups, respectively. Linagliptin was weight neutral and did not worsen kidney function. These features of linagliptin are particularly important to Hispanic/Latino populations, in which obesity and diabetes-related complications are more prevalent than in the general population. Together, the findings of these analyses in ethnic subpopulations provide evidence that linagliptin is generally well tolerated in patients regardless of ethnicity or race. 4.4

Safety with regard to special events of interest Acute pancreatitis/pancreatic cancer

4.4.1

Recent retrospective observational studies of claims databases have raised concerns about a potential link between incretinbased therapies and increased rates of acute pancreatitis and pancreatic cancer [61,62]. However, to date, no preclinical or clinical studies, including long-term clinical studies of DPP-4 inhibitors [63,64] have shown an increased risk. In a joint assessment of pancreatic safety of incretin-based drugs, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) stated that, “assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer as expressed recently in the scientific literature and in the media, are inconsistent with the current data” [65]. In support of this assessment, the comprehensive pooled safety analysis of linagliptin already described found no evidence of increased risk for pancreatic cancer and showed a very low incidence of acute pancreatitis that was comparable to placebo (both groups < 0.1%) [40]. Pancreatitis is, nevertheless, considered a potential risk associated with all incretinbased therapies [65], and prescribing information state to discontinue treatment if pancreatitis is suspected. CV events CV disease is the leading cause of mortality among patients with T2DM [66]. In light of CV safety concerns associated with rosiglitazone [67], the FDA and EMA now require assessment of CV safety for all new antidiabetes treatments before and after approval [68]. A pooled, prospective analysis of adjudicated CV events assessed CV safety of linagliptin versus a comparator group (patients receiving placebo, glimepiride or voglibose) [69]. Of 9459 patients from 19 randomized controlled trials, 5847 received linagliptin and 3612 received a comparator drug. The primary composite end point of CV death, non-fatal stroke, non-fatal myocardial infarction and hospitalization due to unstable angina pectoris occurred at a 4.4.2

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Linagliptin

lower rate in the linagliptin group (13.4/1000 patient years) than in the comparator group (18.9/1000 patient years; hazard ratio = 0.78 [95% CI: 0.55 -- 1.12]). Incidence rates for secondary and tertiary end points were also lower with linagliptin than with a comparator except for the individual end points of CV death, which was the same in both groups, and hospitalization for unstable angina pectoris, which was higher with linagliptin. Incidence of unstable angina was 4.9 and 4.8/1000 patient years in the linagliptin and comparator groups, respectively. This pooled analysis indicated that linagliptin did not increase the risk of CV events. The results from dedicated long-term CV outcomes trials of DPP-4 inhibitors are now emerging. Data published recently for saxagliptin (the SAVOR-TIMI 53 trial) and alogliptin (The EXAMINE trial) [63,64] show no worsening of CV risk in general with these therapies, although data from SAVOR-TIMI 53 did suggest a possible signal for increased heart failure with saxagliptin, which is the subject of further investigation. In the linagliptin comprehensive pooled safety analysis, cardiac failure rates (non-adjudicated, investigator-defined events) were low and comparable between the linagliptin (0.4%) and placebo (0.3%) groups [40]. Although these cardiac failure rates with linagliptin are within the expected range of background incidence in the study population, the number of events are too low to entirely rule out the possibility of an adverse effect. The ongoing CAROLINA trial (NCT01243424) will be the first large head-to-head CV outcomes trial (n = ~ 6100) to compare a DPP-4 inhibitor (linagliptin) with an active treatment (glimepiride) when added to standard care in patients with T2DM at high risk of CV events [70]. CAROLINA will evaluate the impact of longer duration of DPP-4 inhibitor therapy (6 -- 7 years) and earlier introduction of intervention (median duration of diabetes ~ 6 years) on outcomes than SAVOR-TIMI 53 and EXAMINE. Another ongoing linagliptin trial, CARMELINA (NCT01897532), is evaluating CV and renal outcomes with linagliptin in comparison with placebo (estimated n = 8300). It will assess renal disease progression over time. Results of these longterm outcomes trials are anticipated in 2018.

Safety relative to other commonly prescribed OADs 4.5.1 Metformin 4.5

Metformin is widely used as first-line therapy for the treatment of T2DM. Adverse effects of metformin include gastrointestinal reactions and lactic acidosis -- the latter, a rare but life-threatening event that is more likely when common co-morbidities of T2DM are present [71]. Metformin is contraindicated in patients with kidney disorders, although its risk/benefit profile in patients with kidney disease and CV disease has recently been the subject of a comprehensive re-evaluation [72]. Unlike metformin, linagliptin is not associated with gastrointestinal AEs and is not contraindicated in

patients with renal impairment. Linagliptin has been shown to be effective and well tolerated in patients for whom metformin was not tolerated. Over 18 weeks of treatment, linagliptin lowered HbA1c by 0.39%, whereas placebo increased HbA1c by 0.21%; AEs occurred at comparable rates [73]. In the 34-week extension phase of the study, placebo patients were switched to glimepiride. At 52 weeks, the rate of overall AEs was lower but the rate of drug-related AEs was slightly higher with linagliptin (66.2 and 8.6%) versus placebo/ glimepiride (71.1 and 7.9%). During the extension period, hypoglycemia was lower in patients receiving linagliptin (2.2%) versus patients receiving glimepiride (7.8%), with no weight gain. SUs Hypoglycemia and weight gain are persistent side effects of SUs [5]. In a 2-year head-to-head study, linagliptin was shown to be non-inferior to glimepiride in reducing HbA1c with significantly lower rates of hypoglycemia (7 vs 36%, respectively, p < 0.0001), severe hypoglycemia (< 1 vs 2%, respectively) and no body weight gain [74]. These results are consistent with other trials comparing DPP-4 inhibitors and SUs [75,76]. 4.5.2

5.

Conclusion

In a large Phase III clinical trial program and in subsequent pooled data analyses, the DPP-4 inhibitor linagliptin has been shown to be well tolerated in a broad range of patients with T2DM of multiple races/ethnicities, while providing significant improvements in glycemic control. In particular, linagliptin has a low intrinsic risk of hypoglycemia, including severe hypoglycemia. Hypoglycemia is more likely to occur when linagliptin is used in combination with SUs and/or insulin -- drugs which themselves may cause hypoglycemia. Unlike many other agents used to treat hyperglycemia, linagliptin does not promote weight gain. Safety analyses, to date, have indicated that linagliptin does not increase the risk of cardiac disorders, and more specifically the risk of heart failure; however, these were based on short-term studies and so potential risks cannot be excluded until the completion of longer-term CV outcomes trials. Linagliptin can be given without dose adjustment in patients with moderate-to-severe renal impairment and may have the potential for renal benefits in addition to its glucose-lowering effects -- the subject of an ongoing long-term outcome trial. 6.

Expert opinion

The safety profile of the DPP-4 inhibitor class is generally considered to be more favorable than other commonly used antidiabetes therapies largely due to the low risk of hypoglycemia, weight gain and gastrointestinal reactions. Although head-to-head studies comparing OADs are lacking, the results from individual trials suggest that the efficacy of different

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A. H. Barnett

DPP-4 inhibitors is similar, providing significant reductions in glucose levels either as monotherapy or in combination with other commonly used OADs. However, each DPP-4 inhibitor has distinct properties relating to their pharmacology (e.g., metabolism, excretion), which can impact their recommended dosage and administration. In this respect, linagliptin offers a unique advantage over most other antidiabetes treatments. Linagliptin is excreted mainly by a non-renal route and its PKs and efficacy are minimally affected in patients with renal impairment. Therefore, it does not require dosage adjustment in patients with any degree of renal dysfunction, a complication which commonly occurs in T2DM. In addition, monitoring of kidney function specifically for linagliptin administration purposes may not be necessary prior to or during treatment. Like several other antidiabetes therapies, DPP-4 inhibitors are taken orally, an administration route that may be considered more convenient than injectable alternatives such as insulin or GLP-1 receptor agonists. When implementing drug therapy for T2DM, metformin and SUs are well established as the recommended first- and second-line therapies, in general. However, both drugs are associated with tolerability and safety concerns. If metformin is contraindicated or if treatment causes gastrointestinal side effects, a DPP-4 inhibitor may be considered for use as firstline therapy [5]. When advancing to combination therapy, deciding which drug to combine with metformin is complicated by the lack of evidence base from long-term comparative trials. Importantly, when adding a second drug to the therapeutic regimen, the potential risk for increased side effects should be given strong consideration. For example, SUs are associated with an increased risk for hypoglycemia and weight gain. Ultimately, as treatment strategies shift towards a more individualized approach [5], the choice of antidiabetes therapy -- especially second-line therapy -- should be based on specific patient preferences, characteristics, drug tolerability and the potential for hypoglycemia and weight gain. In this regard, an extensive clinical trial programme has shown that linagliptin is a suitable alternative to SUs as add-on to metformin, offering specific advantages (low risk of hypoglycemia and weight gain) in a wide range of patients. Linagliptin is suitable for use across a wide range of baseline HbA1c levels. In the trials reviewed in this article (Table 1), inclusion criteria for baseline HbA1c levels typically ranged from 7 to 11%. In any individual trial, linagliptin achieved a greater reduction in HbA1c in patients with baseline HbA1c ‡ 9% than in patients with baseline HbA1c < 9%. Additionally, initial treatment with linagliptin and metformin in patients with severe hyperglycemia (HbA1c > 11.0%) lowered HbA1c by 3.7%, indicating that this combination might be a useful option in severely hyperglycemic patients unwilling to take insulin. In nearly all clinical trials, the weight change observed with linagliptin was clinically non-significant and comparable with placebo. Initial combination treatment with linagliptin plus pioglitazone was associated with a 8

statistically significant weight gain of 1.1 kg relative to placebo plus pioglitazone [34]. Other DPP-4 inhibitors have also shown similar weight gains when combined with pioglitazone, and physicians should be mindful of the potential weight gain when considering this therapeutic combination. As second- or third-line therapy, DPP-4 inhibitors are an attractive choice to use in combination with a variety of other drugs owing to their good safety profile and complementary mechanism of action. Metformin is the widely accepted firstline drug of choice for the treatment of T2DM; however, when treatment with metformin is not suitable, physicians may consider monotherapy with a DPP-4 inhibitor. In addition, many physicians advocate a more aggressive approach to early treatment -- initial combination therapy with metformin plus a DPP-4 inhibitor is one suitable strategy. The choice of DPP-4 inhibitor will very much depend on a multitude of patient- and disease-related factors. From this perspective, linagliptin has a good efficacy and safety profile with the convenience of a single-strength once-daily dose that does not require titration in patients with any degree of renal impairment. Future research needs will focus on supporting more effective management strategies for T2DM patients. Determining the comparative efficacy and safety of linagliptin versus SUs, the common second-line therapy, and other DPP-4 inhibitors will be important, as will the durability of long-term efficacy and safety especially in vulnerable patients such as the elderly. Long-term CV outcomes data and potential renal benefits of linagliptin are not yet established. The ongoing trials CAROLINA [70] and CARMELINA are designed to assess CV safety of linagliptin versus glimepiride (an SU) and versus placebo, respectively. Impact of linagliptin on renal outcomes and renal function parameters will be evaluated in CARMELINA and MARLINA-T2D trials, respectively. Over the next 5 years, the use of DPP-4 inhibitors in clinical practice will become more widespread. With their favorable safety profile, these drugs are an attractive choice as first-line therapy when metformin is contraindicated or not well tolerated, and as second-line therapy when metformin monotherapy fails to maintain glucose control. Recent and ongoing outcomes trials will establish further the CV safety of this class, supporting the use of DPP-4 inhibitors in preference to SUs. Research into the effects of these drugs that extend beyond their glucose-lowering properties may serve to differentiate the members of this class; indeed, several trials of linagliptin are investigating its potential beneficial effects on the CV and renal systems.

Declaration of interest AH Barnett was fully responsible for all content and editorial decisions, was involved at all stages of manuscript development and has approved the final version of the review, which reflects his interpretation and conclusions. Medical writing assistance, supported financially by Boehringer Ingelheim,

Expert Opin. Drug Saf. (2014) 13(12)

Linagliptin

was provided by Radha Narayan, PhD, of Envision Scientific Solutions, during the preparation of this Review. Boehringer Ingelheim was given the opportunity to check the data used in the manuscript for factual accuracy only. AH Barnett has received honoraria for lectures and advisory work from Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Bristol Myers Squibb/AstraZeneca, Takeda, Eli Lilly, Novo Nordisk, Bibliography

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Affiliation Anthony H Barnett Heart of England NHS Foundation Trust and University of Birmingham, Diabetes Centre, Birmingham, UK E-mail: [email protected]

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