Safety and efficacy of the DPP-4 inhibitor linagliptin in elderly patients with type 2 diabetes: a comprehensive analysis of data from 1331 individuals aged ≥65 years G. Schernthaner1, A. H. Barnett2, S. Patel3, U. Hehnke4, M. von Eynatten5 & H.-J. Woerle4 1
Rudolfstiftung Hospital, Vienna, Austria
2
Diabetes Centre, Heart of England NHS Foundation Trust and University of Birmingham,
Birmingham, UK 3
Boehringer Ingelheim Ltd, Bracknell, UK
4
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
5
Boehringer Ingelheim Inc., Ridgefield, CT, USA
Correspondence to: Prof. Dr. Guntram Schernthaner, Head of the Department of Medicine I, Rudolfstiftung Hospital-Vienna, Juchgasse 25, A - 1030 Vienna, Austria. Phone: +43-1-71165-2101 +43-1-71165-2107 Fax:
+43-1-71165-2109
E-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/dom.12321
This article is protected by copyright. All rights reserved
Abstract Aims: With rising prevalence of type 2 diabetes mellitus (T2DM), clinical evidence regarding the treatment of elderly patients is needed. This study investigated individual patient data from a comprehensive trials programme to evaluate the safety and efficacy of the DPP-4 inhibitor linagliptin across a range of glucose-lowering regimens in a large elderly population with T2DM. Methods: Data were pooled from individuals ≥65 years who participated in seven Phase 3, placebo-controlled clinical trials of linagliptin (24–52 weeks). Safety was assessed by incidence and severity of adverse events (AEs) with a focus on hypoglycaemia. The primary efficacy endpoint was change in HbA1c. Results: In total, 841 subjects received linagliptin 5 mg qd and 490 received placebo. At baseline, the population had mean ± SD age of 71.0 ± 4.6 years and mean HbA1c 8.0 ± 0.8%; 63.5% of subjects received ≥2 antidiabetes drugs. Overall AEs and drug-related AEs were experienced by similar proportions of patients (linagliptin 71.3%, placebo 73.3%; linagliptin 18.1%, placebo 19.8%, respectively). The incidence of investigator-reported hypoglycaemia was 21.4% with linagliptin and 25.7% with placebo. Severe hypoglycaemic events were rare and numerically lower with linagliptin (1.0% vs. 1.8%). At week 24, the placebo-corrected adjusted mean ± SE HbA1c reduction with linagliptin was –0.62 ± 0.06% (95% CI: –0.73, –0.51). Conclusions: Data from this large cohort demonstrate that linagliptin is a well-tolerated and efficacious therapy for elderly patients with T2DM. Treatment with linagliptin may support individualized treatment goals while effectively managing the risk of hypoglycaemia or drugrelated side effects. Introduction Diabetes affects up to one quarter of adults aged ≥65 years with type 2 diabetes mellitus
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(T2DM), according to US data [1]. In developed countries, the majority of patients with diabetes are ≥65 years of age (approximately 50 million) [2]. With rising incidence of T2DM and an aging global population, elderly patients are likely to be an increasingly important atrisk group in the future. Optimization of treatment for the elderly population may be hindered by factors such as the complexity of therapeutic regimens, inadequate dose titration of oral antidiabetes drugs (OAD) or insulin, comorbidities, polypharmacy and both hypoglycaemia and fear of hypoglycaemia [3]. Recent research has confirmed the dangers of hypoglycaemia and associated its incidence with significantly increased risks for cardiovascular events, death from cardiovascular causes and all-cause mortality [4-9]. In patients aged 50 to 80 years who have T2DM and cardiovascular disease, severe hypoglycaemia is associated with an increased risk for severe ventricular arrhythmias [8]. During severe hypoglycaemia, patients exhibit high-risk symptoms such as hypothermia, severe hypertension, hypokalaemia, and prolongation of the QT interval due to activation of the sympathoadrenal system and the release of counterregulatory hormones [9]. Connections between hypoglycaemia and changes in the electrical activity of the heart are particularly worrisome as they may lead to sudden cardiac death [10]. The haemodynamic changes and transient cardiac stresses associated with hypoglycaemia can be especially dangerous in elderly patients [10], and a bidirectional association between hypoglycaemia and dementia has been observed in older patients [11]. Severe hypoglycaemia can lead to neuroglycopenia, with symptoms such as confusion, dizziness, loss of consciousness and potential coma [12]. Concerns about hypoglycaemia have led to publication of less stringent glucose-reduction targets for elderly patients aimed at reducing risk for hypoglycaemia [13,14]. Among elderly patients with T2DM treated with sulphonylureas, observational data have shown increased frequency of hypoglycaemia leading to prolonged hospitalization [15,16]. In
This article is protected by copyright. All rights reserved
a population-based study of patients aged ≥65 years, serious hypoglycaemia leading to hospitalization or death occurred at rates of 1.23 events per 100 patient-years for those treated with sulphonylureas and 2.76 events per 100 patient-years for those treated with insulin [16]. For elderly patients, however, the long-acting properties of sulphonylureas often make extended hospitalization (>72 h) for hypoglycaemia unavoidable, while insulin-induced hypoglycaemia may in some instances be treated relatively quickly without admission [15]. Additionally, insulins and glucose-lowering drugs are two of the most commonly implicated medications in hospitalizations for drug-related adverse events (AEs) among the elderly [17]. Along with these risks, elderly patients with T2DM suffer higher rates of mortality than nondiabetic elderly individuals. A population-based study of US patients with diabetes found excess mortality at all age groups, and a standardized mortality ratio of 1.41 [95% confidence interval (CI): 1.39, 1.43] compared with the overall elderly population [18]. In addition, elderly patients with T2DM experience a higher incidence of renal impairment (itself a risk factor for hypoglycaemia) and increased susceptibility to drug–drug interactions, as well as other heightened safety and tolerability concerns [14,19]. Glycaemic control may also be important to maintenance of cognitive function in the elderly [20]. Dipeptidyl peptidase (DPP)-4 inhibitors have features such as oral dosing, good tolerability and low hypoglycaemic risk that may be attractive for elderly patients. However, evidence for the use of DPP-4 inhibitors in elderly patients is limited, in part, by the dearth of dedicated clinical trials in this population [19]. Some recent studies have evaluated DPP-4 inhibitors in elderly populations [21-24], but the patients enrolled were not necessarily representative of real-world practice. Greater evidence weighing the efficacy and safety of these drugs against their impact on long-term clinical outcomes is needed. Linagliptin, a DPP-4 inhibitor with a primarily non-renal route of excretion, may be administered as an oral 5-mg once-daily dose regardless of renal or hepatic impairment and has a low propensity for drug–drug interactions [25]. The efficacy and safety of linagliptin in elderly patients with T2DM has been demonstrated in a randomized, placebo-controlled clinical trial that included 241 patients
This article is protected by copyright. All rights reserved
aged ≥70 years with inadequate glycaemic control on stable backgrounds of metformin and/or sulphonylurea and/or basal insulin [26]. This analysis of data from 1331 elderly patients with T2DM was undertaken to further evaluate the efficacy and safety of linagliptin in a broader elderly population across a wider range of therapeutic regimens, and to screen for potential rare safety events that may not be detected in individual studies.
Methods Patient population For efficacy and safety endpoints, data were pooled from individuals with T2DM aged ≥65 years who participated in any of seven randomized, double-blind, placebo-controlled Phase 3 trials of linagliptin given once daily as monotherapy or in addition to other glucose-lowering therapies for up to 24 and 52 weeks duration (Table 1) [26-32]. In one study, patients could continue to receive treatment until all randomized patients had received 52 weeks of treatment for a maximum permissible duration of 78 weeks [30]. Safety analyses were performed on the full treatment period, and efficacy assessments were limited to 24 weeks to provide a comparative perspective across the population. The studies were carried out according to the Declaration of Helsinki and Good Clinical Practice (GCP) principles (October 1996) and national GCP regulations where applicable. The protocols and informed consent and patient information forms were reviewed and approved by the local institutional review boards.
Assessments In these studies, safety was assessed by the incidence and severity of investigator-reported adverse events (AEs) categorized using the Medical Dictionary for Regulatory Activities
This article is protected by copyright. All rights reserved
(MedDRA) as preferred terms (PTs) grouped into system organ classes (SOC), and by incidence and severity of asymptomatic or symptomatic hypoglycaemia for up to the maximal period of exposure. AEs of interest, based on prior experience with the DPP-4 inhibitor class, included hypersensitivity reactions, renal AEs, pancreatitis and increased liver enzymes. In addition, cardiovascular events [adjudicated by independent external clinical event committees (CEC)] were assessed. Severe hypoglycaemia was characterized as an event requiring the assistance of another person to administer carbohydrate, glucagon or other resuscitative actions. Serious AEs were events that resulted in death, were immediately life-threatening, resulted in persistent or significant disability/incapacity, required or prolonged patient hospitalization, or led to a congenital anomaly/birth defect. The primary and secondary efficacy endpoints of these studies were change from baseline to 24 weeks in glycated haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), respectively. Categorical HbA1c responses were assessed secondarily.
Data analysis Safety analyses were performed on all patients treated with ≥1 dose of study medication. Efficacy analyses were performed on all randomized patients treated with ≥1 dose of study drug, who had a baseline and ≥1 on-treatment HbA1c measurement. Missing data were imputed using a last observation carried forward (LOCF) approach. The change in mean HbA1c from baseline to week 24 was compared between the linagliptin and placebo groups using an analysis of covariance model that included continuous baseline HbA1c, treatment, study, washout and study × treatment interaction.
Results In total, 841 individuals with T2DM received linagliptin 5 mg once daily, and 490 received matching placebo (figure 1). Median exposure to linagliptin and placebo was 173.0 and
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176.5 days, respectively; and maximal exposure was 531 and 527 days (~76 weeks). Study drug was discontinued by 7.8% of linagliptin patients and 11.6% of placebo subjects. The overall population was 53.6% male (Table 2). Mean ± SD age was 71.0 ± 4.6 years (range, 65−91 years). Patients were primarily Caucasian (81.7%) or Asian (15.7%). Baseline clinical characteristics were similar in both groups. Mean ± SD HbA1c was 8.0 ± 0.8% and 8.1 ± 0.8%, in the linagliptin and placebo groups, respectively. FPG was 157.5 ± 41.8 mg/dl and 154.4 ± 45.8 mg/dl (8.7 ± 2.3 mmol/l and 8.6 ± 2.5 mmol/l), respectively. Most patients in the analysis set had been diagnosed with T2DM ≥5 years prior to study entry, and most were receiving a regimen that consisted of ≥2 antidiabetes drugs (Table 2). Use of insulin and sulphonylureas were numerically imbalanced, with 34.2% and 56.8% of linagliptin and placebo patients, respectively, including insulin in their regimens, and 46.7% and 31.4%, respectively, using sulphonylureas. In total, 78.2% and 86.8% of linagliptin and placebo patients had background treatments associated with increased risk of hypoglycaemia. Approximately three quarters of patients had some degree of renal impairment, and most were receiving concomitant antihypertensive treatment. Cardiac disorders were prevalent in nearly one third of patients at study entry, and 15.3% of patients had a history of coronary artery disease, myocardial infarction or angina pectoris.
Safety As shown in Table 3, overall AEs and drug-related AEs were experienced by comparable proportions of patients in the linagliptin and placebo groups (linagliptin 71.3% and placebo 73.3%; linagliptin 18.1% and placebo 19.8%, respectively). Serious AEs were experienced by 7.5% and 12.9% of linagliptin and placebo patients, respectively. In both groups, 3.7% of patients discontinued treatment due to AEs.
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Hospitalizations due to serious AEs were observed in 7.4% and 11.4% of linagliptin and placebo patients, respectively. Of the linagliptin patients with serious AEs, 17 experienced infections and infestations (including bronchitis and pneumonia) and 15 experienced cardiac disorders (including angina, atrial fibrillation and congestive heart failure). Similar incidences of these events were observed in the placebo group. Hypersensitivity reactions, hepatobiliary AEs and changes in liver enzymes were rare, with all occurring in
Rudolfstiftung Hospital, Vienna, Austria
2
Diabetes Centre, Heart of England NHS Foundation Trust and University of Birmingham,
Birmingham, UK 3
Boehringer Ingelheim Ltd, Bracknell, UK
4
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
5
Boehringer Ingelheim Inc., Ridgefield, CT, USA
Correspondence to: Prof. Dr. Guntram Schernthaner, Head of the Department of Medicine I, Rudolfstiftung Hospital-Vienna, Juchgasse 25, A - 1030 Vienna, Austria. Phone: +43-1-71165-2101 +43-1-71165-2107 Fax:
+43-1-71165-2109
E-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/dom.12321
This article is protected by copyright. All rights reserved
Abstract Aims: With rising prevalence of type 2 diabetes mellitus (T2DM), clinical evidence regarding the treatment of elderly patients is needed. This study investigated individual patient data from a comprehensive trials programme to evaluate the safety and efficacy of the DPP-4 inhibitor linagliptin across a range of glucose-lowering regimens in a large elderly population with T2DM. Methods: Data were pooled from individuals ≥65 years who participated in seven Phase 3, placebo-controlled clinical trials of linagliptin (24–52 weeks). Safety was assessed by incidence and severity of adverse events (AEs) with a focus on hypoglycaemia. The primary efficacy endpoint was change in HbA1c. Results: In total, 841 subjects received linagliptin 5 mg qd and 490 received placebo. At baseline, the population had mean ± SD age of 71.0 ± 4.6 years and mean HbA1c 8.0 ± 0.8%; 63.5% of subjects received ≥2 antidiabetes drugs. Overall AEs and drug-related AEs were experienced by similar proportions of patients (linagliptin 71.3%, placebo 73.3%; linagliptin 18.1%, placebo 19.8%, respectively). The incidence of investigator-reported hypoglycaemia was 21.4% with linagliptin and 25.7% with placebo. Severe hypoglycaemic events were rare and numerically lower with linagliptin (1.0% vs. 1.8%). At week 24, the placebo-corrected adjusted mean ± SE HbA1c reduction with linagliptin was –0.62 ± 0.06% (95% CI: –0.73, –0.51). Conclusions: Data from this large cohort demonstrate that linagliptin is a well-tolerated and efficacious therapy for elderly patients with T2DM. Treatment with linagliptin may support individualized treatment goals while effectively managing the risk of hypoglycaemia or drugrelated side effects. Introduction Diabetes affects up to one quarter of adults aged ≥65 years with type 2 diabetes mellitus
This article is protected by copyright. All rights reserved
(T2DM), according to US data [1]. In developed countries, the majority of patients with diabetes are ≥65 years of age (approximately 50 million) [2]. With rising incidence of T2DM and an aging global population, elderly patients are likely to be an increasingly important atrisk group in the future. Optimization of treatment for the elderly population may be hindered by factors such as the complexity of therapeutic regimens, inadequate dose titration of oral antidiabetes drugs (OAD) or insulin, comorbidities, polypharmacy and both hypoglycaemia and fear of hypoglycaemia [3]. Recent research has confirmed the dangers of hypoglycaemia and associated its incidence with significantly increased risks for cardiovascular events, death from cardiovascular causes and all-cause mortality [4-9]. In patients aged 50 to 80 years who have T2DM and cardiovascular disease, severe hypoglycaemia is associated with an increased risk for severe ventricular arrhythmias [8]. During severe hypoglycaemia, patients exhibit high-risk symptoms such as hypothermia, severe hypertension, hypokalaemia, and prolongation of the QT interval due to activation of the sympathoadrenal system and the release of counterregulatory hormones [9]. Connections between hypoglycaemia and changes in the electrical activity of the heart are particularly worrisome as they may lead to sudden cardiac death [10]. The haemodynamic changes and transient cardiac stresses associated with hypoglycaemia can be especially dangerous in elderly patients [10], and a bidirectional association between hypoglycaemia and dementia has been observed in older patients [11]. Severe hypoglycaemia can lead to neuroglycopenia, with symptoms such as confusion, dizziness, loss of consciousness and potential coma [12]. Concerns about hypoglycaemia have led to publication of less stringent glucose-reduction targets for elderly patients aimed at reducing risk for hypoglycaemia [13,14]. Among elderly patients with T2DM treated with sulphonylureas, observational data have shown increased frequency of hypoglycaemia leading to prolonged hospitalization [15,16]. In
This article is protected by copyright. All rights reserved
a population-based study of patients aged ≥65 years, serious hypoglycaemia leading to hospitalization or death occurred at rates of 1.23 events per 100 patient-years for those treated with sulphonylureas and 2.76 events per 100 patient-years for those treated with insulin [16]. For elderly patients, however, the long-acting properties of sulphonylureas often make extended hospitalization (>72 h) for hypoglycaemia unavoidable, while insulin-induced hypoglycaemia may in some instances be treated relatively quickly without admission [15]. Additionally, insulins and glucose-lowering drugs are two of the most commonly implicated medications in hospitalizations for drug-related adverse events (AEs) among the elderly [17]. Along with these risks, elderly patients with T2DM suffer higher rates of mortality than nondiabetic elderly individuals. A population-based study of US patients with diabetes found excess mortality at all age groups, and a standardized mortality ratio of 1.41 [95% confidence interval (CI): 1.39, 1.43] compared with the overall elderly population [18]. In addition, elderly patients with T2DM experience a higher incidence of renal impairment (itself a risk factor for hypoglycaemia) and increased susceptibility to drug–drug interactions, as well as other heightened safety and tolerability concerns [14,19]. Glycaemic control may also be important to maintenance of cognitive function in the elderly [20]. Dipeptidyl peptidase (DPP)-4 inhibitors have features such as oral dosing, good tolerability and low hypoglycaemic risk that may be attractive for elderly patients. However, evidence for the use of DPP-4 inhibitors in elderly patients is limited, in part, by the dearth of dedicated clinical trials in this population [19]. Some recent studies have evaluated DPP-4 inhibitors in elderly populations [21-24], but the patients enrolled were not necessarily representative of real-world practice. Greater evidence weighing the efficacy and safety of these drugs against their impact on long-term clinical outcomes is needed. Linagliptin, a DPP-4 inhibitor with a primarily non-renal route of excretion, may be administered as an oral 5-mg once-daily dose regardless of renal or hepatic impairment and has a low propensity for drug–drug interactions [25]. The efficacy and safety of linagliptin in elderly patients with T2DM has been demonstrated in a randomized, placebo-controlled clinical trial that included 241 patients
This article is protected by copyright. All rights reserved
aged ≥70 years with inadequate glycaemic control on stable backgrounds of metformin and/or sulphonylurea and/or basal insulin [26]. This analysis of data from 1331 elderly patients with T2DM was undertaken to further evaluate the efficacy and safety of linagliptin in a broader elderly population across a wider range of therapeutic regimens, and to screen for potential rare safety events that may not be detected in individual studies.
Methods Patient population For efficacy and safety endpoints, data were pooled from individuals with T2DM aged ≥65 years who participated in any of seven randomized, double-blind, placebo-controlled Phase 3 trials of linagliptin given once daily as monotherapy or in addition to other glucose-lowering therapies for up to 24 and 52 weeks duration (Table 1) [26-32]. In one study, patients could continue to receive treatment until all randomized patients had received 52 weeks of treatment for a maximum permissible duration of 78 weeks [30]. Safety analyses were performed on the full treatment period, and efficacy assessments were limited to 24 weeks to provide a comparative perspective across the population. The studies were carried out according to the Declaration of Helsinki and Good Clinical Practice (GCP) principles (October 1996) and national GCP regulations where applicable. The protocols and informed consent and patient information forms were reviewed and approved by the local institutional review boards.
Assessments In these studies, safety was assessed by the incidence and severity of investigator-reported adverse events (AEs) categorized using the Medical Dictionary for Regulatory Activities
This article is protected by copyright. All rights reserved
(MedDRA) as preferred terms (PTs) grouped into system organ classes (SOC), and by incidence and severity of asymptomatic or symptomatic hypoglycaemia for up to the maximal period of exposure. AEs of interest, based on prior experience with the DPP-4 inhibitor class, included hypersensitivity reactions, renal AEs, pancreatitis and increased liver enzymes. In addition, cardiovascular events [adjudicated by independent external clinical event committees (CEC)] were assessed. Severe hypoglycaemia was characterized as an event requiring the assistance of another person to administer carbohydrate, glucagon or other resuscitative actions. Serious AEs were events that resulted in death, were immediately life-threatening, resulted in persistent or significant disability/incapacity, required or prolonged patient hospitalization, or led to a congenital anomaly/birth defect. The primary and secondary efficacy endpoints of these studies were change from baseline to 24 weeks in glycated haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), respectively. Categorical HbA1c responses were assessed secondarily.
Data analysis Safety analyses were performed on all patients treated with ≥1 dose of study medication. Efficacy analyses were performed on all randomized patients treated with ≥1 dose of study drug, who had a baseline and ≥1 on-treatment HbA1c measurement. Missing data were imputed using a last observation carried forward (LOCF) approach. The change in mean HbA1c from baseline to week 24 was compared between the linagliptin and placebo groups using an analysis of covariance model that included continuous baseline HbA1c, treatment, study, washout and study × treatment interaction.
Results In total, 841 individuals with T2DM received linagliptin 5 mg once daily, and 490 received matching placebo (figure 1). Median exposure to linagliptin and placebo was 173.0 and
This article is protected by copyright. All rights reserved
176.5 days, respectively; and maximal exposure was 531 and 527 days (~76 weeks). Study drug was discontinued by 7.8% of linagliptin patients and 11.6% of placebo subjects. The overall population was 53.6% male (Table 2). Mean ± SD age was 71.0 ± 4.6 years (range, 65−91 years). Patients were primarily Caucasian (81.7%) or Asian (15.7%). Baseline clinical characteristics were similar in both groups. Mean ± SD HbA1c was 8.0 ± 0.8% and 8.1 ± 0.8%, in the linagliptin and placebo groups, respectively. FPG was 157.5 ± 41.8 mg/dl and 154.4 ± 45.8 mg/dl (8.7 ± 2.3 mmol/l and 8.6 ± 2.5 mmol/l), respectively. Most patients in the analysis set had been diagnosed with T2DM ≥5 years prior to study entry, and most were receiving a regimen that consisted of ≥2 antidiabetes drugs (Table 2). Use of insulin and sulphonylureas were numerically imbalanced, with 34.2% and 56.8% of linagliptin and placebo patients, respectively, including insulin in their regimens, and 46.7% and 31.4%, respectively, using sulphonylureas. In total, 78.2% and 86.8% of linagliptin and placebo patients had background treatments associated with increased risk of hypoglycaemia. Approximately three quarters of patients had some degree of renal impairment, and most were receiving concomitant antihypertensive treatment. Cardiac disorders were prevalent in nearly one third of patients at study entry, and 15.3% of patients had a history of coronary artery disease, myocardial infarction or angina pectoris.
Safety As shown in Table 3, overall AEs and drug-related AEs were experienced by comparable proportions of patients in the linagliptin and placebo groups (linagliptin 71.3% and placebo 73.3%; linagliptin 18.1% and placebo 19.8%, respectively). Serious AEs were experienced by 7.5% and 12.9% of linagliptin and placebo patients, respectively. In both groups, 3.7% of patients discontinued treatment due to AEs.
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Hospitalizations due to serious AEs were observed in 7.4% and 11.4% of linagliptin and placebo patients, respectively. Of the linagliptin patients with serious AEs, 17 experienced infections and infestations (including bronchitis and pneumonia) and 15 experienced cardiac disorders (including angina, atrial fibrillation and congestive heart failure). Similar incidences of these events were observed in the placebo group. Hypersensitivity reactions, hepatobiliary AEs and changes in liver enzymes were rare, with all occurring in
