Efficacy and tolerability of saxagliptin compared with glimepiride in elderly patients with type 2 diabetes: a randomized, controlled study (GENERATION)
G. Schernthaner1, S. Durán-Garcia2, M. Hanefeld3, G. Langslet4, L. Niskanen5, C. J. Östgren6, E. Malvolti7* & E. Hardy8
1
Department of Medicine I, Rudolfstiftung Hospital, Vienna, Austria
2
Unidad de Gestion de Endocrinología y Nutrición, Hospital Universitario de Valme, Sevilla,
Spain 3
Studycentre Professor Hanefeld, GWT-TUD GmbH, Dresden, Germany
4
The Lipid Clinic, Oslo University Hospital, Oslo, Norway
5
Endocrinology and Metabolism, Abdominal Center, Helsinki University Hospital and
University of Helsinki, Helsinki, Finland 6
Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
7
AstraZeneca, Istanbul, Turkey
8
AstraZeneca LP, Wilmington, DE, USA
*Previously employed by Bristol-Myers Squibb, Paris, France
Correspondence to: Guntram Schernthaner, MD, Department of Medicine I, Rudolfstiftung Hospital-Vienna, Juchgasse 25, A–1030 Vienna, Austria. Phone: (+43) 171 165 2101; Fax: (+43) 171 165 2109 Email: [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.12461
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Abstract Aims: To assess the efficacy and safety of adjunctive saxagliptin vs glimepiride in elderly patients with type 2 diabetes (T2D) and inadequate glycaemic control. Methods: In this multinational, randomized, double-blind, Phase IIIb/IV study (GENERATION; NCT01006603), patients aged ≥ 65 years were randomized (1:1) to receive saxagliptin 5 mg/day or glimepiride ≤6 mg/day, added to metformin, during a 52-week treatment period. The primary endpoint was achievement of HbA1c < 7.0% at Week 52 without confirmed/severe hypoglycaemia. The key secondary endpoint was incidence of confirmed/severe hypoglycaemia. Safety and tolerability were also assessed. Results: Of 720 patients randomized (360 in each treatment group; mean age 72.6 years; mean T2D duration 7.6 years), 574 (79.8%) completed the study (saxagliptin 80.3%; glimepiride 79.2%). Similar proportions of patients achieved the primary endpoint with saxagliptin and glimepiride (37.9% vs 38.2%; odds ratio 0.99; 95% confidence interval 0.73, 1.34; p = 0.9415). However, a significant treatment by age interaction effect was detected (p = 0.0389): saxagliptin was numerically superior to glimepiride for patients aged < 75 years (39.2% vs 33.3%) and numerically inferior for patients aged ≥ 75 years (35.9% vs 45.5%). Incidence of confirmed/severe hypoglycaemia was lower with saxagliptin vs glimepiride (1.1% vs 15.3%; nominal p < 0.0001). Saxagliptin was generally well tolerated, with similar incidences of adverse events, vs glimepiride. Conclusion: As avoiding hypoglycaemia is a key clinical objective in elderly patients, saxagliptin is a suitable alternative to glimepiride in patients with T2D aged ≥ 65 years. Keywords: type 2 diabetes, DPP-4 inhibitor, sulphonylureas, randomized trial
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Introduction In elderly patients with diabetes, the risk of hypoglycaemia is significantly increased compared with younger adults [1,2] and the harm associated with severe hypoglycaemia may counterbalance potential benefits of intensive glucose control [3,4]. While for most patients with type 2 diabetes (T2D), the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend a target HbA1c of < 7.0% [5], glycaemic targets for elderly patients with limited life expectancy, a history of severe hypoglycaemia, long-standing or more complicated T2D are less ambitious than for younger, healthier individuals. A target HbA1c of 7.5–8.0% is considered acceptable, according to recent ADA and EASD guidelines [5]. Saxagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor approved in the EU as additional therapy in adults with T2D with inadequate glycaemic control on monotherapy with metformin, a sulfonylurea or a thiazolidinedione. Saxagliptin is also approved in the EU as a triple oral therapy in combination with metformin plus a sulfonylurea, when this regimen alone provides inadequate glycaemic control, and as combination therapy with insulin (with/without metformin) for adults with T2D [6]. In Phase III studies, saxagliptin improved glycaemic control vs placebo and was similar to active comparators (glipizide or sitagliptin), in combination with metformin [7-9], metformin plus glimepiride [10], other oral antihyperglycaemic drugs [11,12] or insulin [13]. In patients aged ≥65 years, a post hoc analysis of pooled Phase III data showed that saxagliptin (combination therapy or initial monotherapy) provided better glycaemic control than placebo, with low risk of hypoglycaemia [14,15]. Although HbA1c is traditionally used as a primary endpoint for assessing the efficacy of antihyperglycaemic treatments, in elderly patients the risk of hypoglycaemia should also be considered, as both factors contribute to clinical treatment decision-making. This study evaluated whether saxagliptin was superior to glimepiride as add-on to metformin in
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improving glycaemic control without hypoglycaemia in elderly patients (≥ 65 years old) with T2D.
Methods Patients Patients aged ≥ 65 years with T2D, on stable metformin monotherapy at any dose for ≥ 8 weeks prior to enrolment, and with HbA1c of 7.0–9.0%, were eligible. Excluded were: patients with type 1 diabetes mellitus; treatment with any antihyperglycaemic therapy other than metformin monotherapy within 8 weeks prior to enrolment; treatment with systemic glucocorticoids (except for replacement therapy) or cytochrome P450 3A4 inducers; history of ketoacidosis or hyperosmolar non-ketonic coma; history of haemoglobinopathies; renal impairment (creatinine clearance [CrCl] < 60 mL/min); cognitive function problems; alcohol or illegal drug abuse for ≤ 12 months prior to enrolment; history of hypersensitivity or contraindication to study drugs. Additional exclusion criteria were: aspartate aminotransferase levels > 3-fold the upper limit of the normal (ULN) and/or alanine aminotransferase levels > 3-fold ULN and/or total bilirubin > 34 μmol/L; and creatine kinase > 10-fold ULN. All patients abstained from donating blood, plasma or platelets during the study. The study was conducted in compliance with the ethical principles originating from the Declaration of Helsinki and the International Conference on Harmonisation notes for Guidance on Good Clinical Practice. The study protocol was approved by an Independent Ethics Committee or Institutional Review Board. All patients provided written informed consent before enrolment.
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Study Design This 52-week, multinational, randomized, double-blind, active-controlled, parallel-arm, Phase IIIb/IV study (GENERATION; NCT01006603) was conducted between October 2009 and June 2012 at 152 sites in 12 European countries and Mexico. The study consisted of a 2-week screening period, 2-week enrolment period, 2-week single-blinded (to patients only) placebo-lead-in period, and 52-week double-blinded treatment period, comprising a 12-week titration period and a 40-week maintenance period (supplementary figure). After lead-in, patients were randomized (1:1) to receive saxagliptin 5 mg/day and placebo or glimepiride 1 mg/day and placebo, added to metformin. Randomization was done via an interactive web response system and was stratified by age to include ~60% of patients aged < 75 years and ~40% aged ≥ 75 years. During the titration period, glimepiride or placebo was up-titrated every 3 weeks in 1 or 2 mg/day increments to the optimal dose (fasting plasma glucose ≤ 6.1 mmol/L), up to 6 mg/day. During maintenance, no up-titration was performed. Glimepiride or placebo could be down-titrated if recurrent hypoglycaemia occurred.
Assessments The primary efficacy endpoint was the proportion of patients achieving HbA1c < 7.0% at Week 52 without confirmed/severe hypoglycaemia. Confirmed hypoglycaemia was defined as a symptomatic or asymptomatic event with plasma glucose < 3.0 mmol/L, requiring no external assistance. Severe hypoglycaemia was defined as a symptomatic event requiring external assistance due to severe impairment in consciousness or behaviour, with or without plasma glucose < 3.0 mmol/L, but with prompt recovery after glucose/glucagon administration. The key secondary endpoint was the proportion of patients with ≥ 1 confirmed/severe hypoglycaemic event over the treatment period. Other secondary endpoints included the
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proportion of patients achieving HbA1c < 7.0% or ≤ 6.5% at Week 52, and the change from baseline to Week 52 in mean HbA1c. Post hoc analyses were conducted to determine the number of confirmed/severe hypoglycaemic events over time, and the incidence of confirmed/severe hypoglycaemia by HbA1c category at Week 52 (< 7.0% or ≥ 7.0%) stratified by age group, and by HbA1c category at Week 52 (< 6.5%; ≥ 6.5%–< 7.0%; ≥ 7.0%–< 7.5%, and ≥ 7.5%). Safety and tolerability assessments included adverse events (AEs) and body weight.
Analytical Methods Blood samples for assessing glycaemic parameters were collected at every visit during the treatment period and were analysed centrally (Quintiles Laboratories Ltd., Europe). Patients self-monitored glucose levels using a glucometer (Accu-Chek©, Roche Diagnostics) at least every second day during lead-in and titration and at least once a week during maintenance. Blood glucose levels and hypoglycaemic events were recorded in patients’ diaries.
Statistical Analysis A sample size of 698 patients (349/treatment arm) was calculated for detecting superiority for saxagliptin in the primary endpoint, with a two-sided significance level of 0.05 and 80% power. This assumed a 10% drop-out rate and an odds ratio (OR) of 1.55 for achieving target HbA1c without hypoglycaemia with saxagliptin, compared with glimepiride. The safety population, including all randomized patients who took ≥ 1 dose of the study medication, was used for reporting safety and tolerability results and for primary, key secondary and post hoc efficacy assessments. The full analysis population, defined as safety population patients with non-missing baseline and ≥ 1 post-baseline efficacy data for ≥ 1 variable, was used for reporting other secondary endpoints.
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Patients who did not complete the 52-week treatment period were considered as nonresponders, that is, as having not achieved HbA1c < 7.0% at Week 52 without confirmed/severe hypoglycaemia. Non-continuous endpoints were analysed using a Cochran-Mantel-Haenszel test with continuity correction stratified by age; treatment-by-age interaction and treatment-bybaseline HbA1c interaction was determined using a logistic regression model. To control for multiplicity, primary and key secondary endpoints were tested in a pre-specified hierarchy. Continuous endpoints were analysed using an analysis of covariance (ANCOVA) model, with treatment group and age as fixed effects and baseline value of the endpoint as a covariate. Statistical analyses were performed by AptivSolution GmbH, Germany.
Results Patient Disposition Of 720 patients randomized, 718 received study medication, and 574 (79.8%) completed the 52-week treatment period (saxagliptin 80.3%; glimepiride 79.2%) [Figure 1]. Safety and full analysis populations comprised 718 and 709 patients, respectively.
Demographics and Baseline Characteristics Demographics, baseline characteristics and medical history were balanced across treatment groups and were generally representative of an elderly population with T2D, inadequate glycaemic control, and normal renal function or mild renal impairment (Table 1). The mean dose of glimepiride was 3.3 mg/day.
Efficacy Primary efficacy endpoint Proportions of patients achieving HbA1c < 7.0% at Week 52 without confirmed/severe hypoglycaemia were similar with saxagliptin and glimepiride: 37.9% vs 38.2% (OR 0.99; This article is protected by copyright. All rights reserved
95% confidence interval [CI]: 0.73, 1.34; p = 0.9415) [Table 2]. However, a significant treatment by age interaction was detected (p = 0.0389). The proportion of patients aged < 75 years achieving the primary endpoint was numerically higher with saxagliptin, compared with glimepiride (39.2% vs 33.3%), whereas in patients aged ≥ 75 years, the opposite occurred (35.9% vs 45.5%). A treatment interaction by baseline HbA1c was also identified (p = 0.0822). The proportion of patients with baseline HbA1c levels < 7% and 7% – < 8% achieving the primary endpoint was numerically higher with saxagliptin, compared with glimepiride (< 7%: 56.1% vs 53.5% and 7% – < 8%: 43.5% vs 40.2%). In patients with baseline HbA1c ≥ 8%, fewer patients in both groups reached the primary endpoint; a numerically lower proportion with saxagliptin reached the primary endpoint, compared with glimepiride (12.3% vs 25.3%).
Key secondary endpoint Fewer saxagliptin-treated patients experienced ≥ 1 confirmed/severe hypoglycaemic event over the treatment period, compared with glimepiride: 1.1% vs 15.3% (OR 0.06; 95% CI 0.02, 0.17; nominal p < 0.0001). The difference between saxagliptin vs glimepiride was numerically greater in patients aged < 75 years compared with patients aged ≥ 75 years (ORs 0.04 vs 0.12; nominal p = 0.3018) [Table 2]. With glimepiride, fewer patients aged ≥ 75 years experienced hypoglycaemia, compared with patients aged < 75 years (10.5% vs 18.5%).
Secondary efficacy endpoints Overall, a lower proportion of saxagliptin-treated patients achieved HbA1c < 7.0% at Week 52, vs glimepiride: 44:7% vs 54.7% (nominal p = 0.0077). The difference between treatment groups was numerically, but not significantly greater in patients aged ≥ 75 years vs < 75 years (nominal p = 0.1071). A lower proportion of saxagliptin-treated patients vs glimepiride also achieved HbA1c ≤ 6.5% (18.5% vs 30.9%, nominal p < 0.0001; Table 2).
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Adjusted mean HbA1c change from baseline at Week 52 was smaller with saxagliptin vs glimepiride: 0.44% vs 0.64% (nominal p < 0.0001) [Table 2], with a greater difference between treatment groups in patients aged ≥ 75 years, compared with patients aged < 75 years (Table 2). Mean HbA1c changes from baseline were similar between age groups with saxagliptin, and numerically greater in patients aged ≥ 75 years, compared with patients aged < 75 years, with glimepiride (nominal p = 0.0839, p = 0.0001) (Table 2). Post hoc analyses assessing potential mechanisms, including baseline estimated glomerular filtration rate, did not reveal any conclusive results (see Supplementary Material).
Post hoc analyses With glimepiride, confirmed/severe hypoglycaemia occurred throughout the treatment period; events were more common during Weeks 4–16 (figure 2A). Furthermore, with glimepiride, hypoglycaemia occurred more frequently in patients who achieved HbA1c < 7.0%, compared with HbA1c ≥ 7.0% at Week 52, for the overall population and for patients aged < 75 years (figure 2B). With saxagliptin, confirmed/severe hypoglycaemia incidence was low or absent for all HbA1c intervals; with glimepiride, hypoglycaemia incidence was highest for the lower HbA1c intervals (figure 2C).
Safety and Tolerability Saxagliptin was generally well tolerated in this population. The incidence of AEs (excluding hypoglycaemia) was similar with both treatments, and for each age group. The proportion of patients experiencing any hypoglycaemic event was lower with saxagliptin vs glimepiride (5.8% vs 34.8%). The most common AEs with saxagliptin were nasopharyngitis, arthralgia and diarrhoea (Table 3). More saxagliptin-treated patients experienced serious AEs (SAEs), compared with glimepiride (11.4% vs 8.9%). Four patients experienced SAEs considered to be related to
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treatment (saxagliptin: cholecystitis, malignant hepatic neoplasm and bladder calculus; glimepiride: hypoglycaemia). Discontinuations due to AEs were higher with saxagliptin (4.5%), compared with glimepiride (3.1%), most frequently due to neoplasm (saxagliptin n = 4: bladder transitional cell carcinoma, colon cancer, malignant hepatic neoplasm and lymphoma; glimepiride n = 0) and nervous system disorders (saxagliptin n = 3: headache, lethargy and syncope; glimepiride n = 4: dementia, dizziness, epilepsy and migraine). There were two deaths in the study (saxagliptin: myocardial infarction; glimepiride: unknown cause), considered unrelated to treatment. Neoplasm incidence was imbalanced with saxagliptin vs glimepiride (n=10 vs n=3). With saxagliptin, events were in multiple organ systems and occurred mostly in patients with cancer risk factors and ≤6 months exposure to saxagliptin in 8/10 cases. One event was considered related to saxagliptin treatment: a patient with hepatocellular carcinoma risk factors developed malignant hepatic neoplasm ~4.5 months post-randomization. More saxagliptin-treated patients reported fractures, compared with glimepiride (n = 9 vs n = 4). With saxagliptin, fractures occurred in patients with prior osteoporosis risk factors or preexisting osteoporosis, were associated with ≤9 months’ exposure and were not considered treatment-related. No differences between treatment groups were noted for infection, opportunistic infection, skin lesion or localized oedema. In particular, there were no instances of lymphocytopenia, thrombocytopenia or pancreatitis. More heart failure events were observed with glimepiride compared with saxagliptin (n = 6 [three SAEs] vs n = 1 [SAE]). Patients treated with saxagliptin showed a mean reduction in body weight at Week 52 vs baseline, compared with a mean increase with glimepiride (-0.8 kg; 95% CI -1.2, -0.4 vs +1.0 kg; 95% CI 0.6, 1.3).
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Discussion Treatment of elderly patients with T2D is a unique challenge, where the risk of hypoglycaemia and associated complications must be balanced against potential benefits of glucose control [16]. Although the risk of microvascular and macrovascular events has been shown to increase significantly with HbA1c above thresholds of 6.5% and 7.0%, respectively [17], intensive glycaemic control may have either no influence or potentially a detrimental effect on cardiovascular (CV) outcomes in patients with a relatively long duration of diabetes and risk factors for CV disease [18]. Severe hypoglycaemia has been shown to be associated with an increased risk of CV disease and severe ventricular arrhythmias [19,20]. As a consequence, recent guidelines emphasize the need for individualizing HbA1c targets in elderly patients, rather than achieving strict glycaemic control [5] and recommend that hypoglycaemia, ability to self-manage, cognitive status, comorbidities and life expectancy are considered when treating this population [21]. On the other hand, the evidence base for using individualized glycaemic targets is limited. A recent study in elderly patients with T2D showed vildagliptin to be superior to placebo in achieving individualized glycaemic targets [22]. Mean HbA1c targets set by investigators were ~7.0%, the lowest target recommended in this population [21]. In the GENERATION study, the superiority of saxagliptin vs glimepiride was not demonstrated for the primary endpoint. Saxagliptin was numerically superior to glimepiride for the primary endpoint in patients aged < 75 years and numerically inferior in patients aged ≥ 75 years, with a statistically significant interaction of treatment with age. Whereas the incidence of confirmed/severe hypoglycaemia was substantially higher with glimepiride vs saxagliptin, more glimepiride-treated patients achieved the HbA1c target, compared with saxagliptin. The incidence of hypoglycaemia with saxagliptin was low, even for patients achieving the lowest HbA1c values. Furthermore, with glimepiride, hypoglycaemia occurred throughout the treatment period and across all levels of glycaemic control.
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An important factor contributing to the study not achieving its primary endpoint was the unexpected difference in the efficacy of glimepiride between age groups. With glimepiride, glycaemic control was greater and hypoglycaemia incidence lower in patients aged ≥ 75 years, compared with < 75 years, whereas with saxagliptin the same parameters were consistent across the age groups. Though better glycaemic control was observed in patients aged ≥ 75 years on glimepiride, this may not constitute a benefit if it is accompanied by a higher rate of hypoglycaemia. There is a tendency for glimepiride clearance to increase with decreasing renal function [23], which may affect glycaemic efficacy; furthermore, hypoglycaemia incidence with glimepiride is higher in patients with mild renal impairment vs normal renal function [24]. However, in this study, the increased glimepiride efficacy in patients aged ≥ 75 years could not be attributed to differences in baseline renal function between populations, and patients with CrCl < 60 mL/min had been excluded from the study. Lack of awareness of hypoglycaemic symptoms may explain the unexpected lower incidence of hypoglycaemia in patients aged ≥ 75 years [25]. In elderly patients, fewer individual hypoglycaemic symptoms of lower intensity are generally reported, compared with younger adults [26], and symptoms are often non-specific in nature, including weakness, unsteadiness, sleepiness, faintness and poor concentration [26]. Therefore, in this study, hypoglycaemia could have been under-reported, which may account for the reduced hypoglycaemia incidence observed in the older age group of glimepiride-treated patients. With saxagliptin, the number of patients reporting hypoglycaemia may have been too low for this effect to become apparent. As we are not aware of other studies testing saxagliptin versus glimepiride in elderly patients with T2D, the results of this study should ideally be interpreted in the context of other head-to-head studies between DPP-4 inhibitors and sulphonylureas in elderly patients with T2D. A recent meta-analysis [27] identified 12 randomized studies between DPP-4 inhibitors and sulphonylureas; however only one study enrolled elderly patients only and none used an endpoint combining glucose lowering and hypoglycaemia as in the This article is protected by copyright. All rights reserved
GENERATION study. The meta-analysis confirmed that patients on DPP-4 inhibitors were less likely to achieve HbA1c < 7% compared with those on sulphonylureas (OR 0.91; 95% CI 0.84, 0.99), but had a lower risk of hypoglycaemia on DPP-4 inhibitors compared with sulphonylureas (OR 0.13; 95% CI 0.11, 0.16) [27]. In the randomized study which enrolled elderly patients with T2D, glycaemic control with alogliptin was found to be non-inferior to glipizide and alogliptin had a lower risk of hypoglycaemia compared with glipizide (5.4% vs 26.0%) [28]. However, results from the alogliptin-glipizide head-to-head study were not analysed by age group, so it is difficult to relate them to those obtained in the current study. Also recently reported were two placebo-controlled studies in elderly patients (≥ 70 years) with T2D treated with other DPP-4 inhibitors (vildagliptin [22] and linagliptin [29]). The definition of hypoglycaemia used was in line with GENERATION for the vildagliptin study (< 3.1 mmol/L) [22] and a less stringent definition was used for the linagliptin study (< 3.9 mmol/L) [29]. While it is not appropriate to compare results with GENERATION directly, HbA1c reductions from baseline and low rates of hypoglycaemia were demonstrated in all both studies and GENERATION, in elderly patients [22,29], though it should be noted that the percentage of patients with hypoglycaemia was not reported by age subgroups in the two placebo-controlled studies. Saxagliptin add-on to metformin was generally well tolerated in patients aged ≥ 65 years, with an overall incidence of AEs similar to glimepiride. The safety profile of saxagliptin was consistent with that reported in previous studies in older patients [14,15]. No pancreatitis was observed. An imbalance in AEs of neoplasm and fracture was observed with saxagliptin vs glimepiride; however, events occurred in patients with prior risk factors, and the exposure to saxagliptin was short. Furthermore, the size and duration of the present study was insufficient for evaluating rare events. Safety findings should be considered in the context of the overall saxagliptin clinical programme, where no imbalances in AEs of neoplasm and fracture have been observed with saxagliptin in this age group [14,15]. The overall CV safety with saxagliptin was previously assessed in the SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) This article is protected by copyright. All rights reserved
study of ~16,500 patients with T2D with a history of, or at risk for, CV events [30]. Saxagliptin was non-inferior to placebo for CV safety in the overall population and in patients aged > 75 years [30]. Furthermore, in the overall population, there were no imbalances in malignancies, fractures and events of pancreatitis between saxagliptin and placebo groups. In the GENERATION study, CV events were balanced across the two groups, though their incidence was too low for a meaningful comparison. Several limitations should be considered when interpreting the results of this study. The primary endpoint included only patient-reported confirmed/severe hypoglycaemia; this was deemed the most rigorous method, though the rate of hypoglycaemia may have been underestimated; as noted above, elderly patients may under-report hypoglycaemic symptoms. Furthermore, a more stringent definition of hypoglycaemia was used (blood glucose < 3.0 mmol/L) than the < 3.9 mmol/L value recommended by some professional diabetes societies [31]. Patients with chronic kidney disease were excluded from this study, since at the time of planning, guidelines recommended that renal dysfunction was a contraindication for metformin. Finally, glycaemic targets were based on guidelines valid when the study protocol was developed [32] and were not individualized. A target HbA1c of < 7.0% may no longer be considered appropriate for certain elderly patients [5,21]. Overall, the GENERATION study showed that saxagliptin provided glycaemic control with low risk of hypoglycaemia and was well tolerated in patients aged ≥ 65 years, inadequately controlled on metformin. As avoidance of hypoglycaemia is a key clinical objective in elderly patients, saxagliptin is a suitable alternative to glimepiride in this population. Given the paucity of data in this age group, this study adds significant value to the evidence available for treating elderly patients with T2D.
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Acknowledgements Medical writing services were provided by Ioana Dumitrescu, PhD, of QXV Communications, Macclesfield, UK and were funded by AstraZeneca and Bristol-Myers Squibb. This study was funded by AstraZeneca and Bristol-Myers Squibb.
Conflict of Interest Guntram Schernthaner reports personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceuticals, Novo Nordisk, Sanofi, Servier Laboratories, and Takeda, outside the submitted work. Markolf Hanefeld reports personal fees from Bayer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Roche, Sanofi-Aventis, and Takeda, outside the submitted work. Carl Johan Östgren reports personal fees from AstraZeneca during the conduct of the study and personal fees from AstraZeneca and Bristol-Myers Squibb, outside the submitted work. Leo Niskanen reports research grant from AstraZeneca during the conduct of the study and personal fees from Novo Nordisk, GlaxoSmithKline, and Janssen-Cilag, a research grant from Sanofi, and personal fees and research grants from AstraZeneca, Boehringer Ingelheim, and Eli Lilly, outside the submitted work. Gisle Langslet reports personal fees from Bristol-Myers Squibb and Janssen Pharmaceuticals, outside the submitted work. Santiago Durán-Garcia reports personal fees from AstraZeneca during the conduct of the study and personal fees from AstraZeneca and Bristol-Myers Squibb, outside the submitted work. Elise Hardy is an employee of AstraZeneca. Elmas Malvolti is currently an employee of AstraZeneca and was employed by BristolMyers Squib at the time the study took place.
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Contributor Statements Guntram Schernthaner was involved in planning and designing the study, and was responsible for data interpretation and manuscript review. Markolf Hanefeld was responsible for the study conduct, data interpretation and manuscript review. Carl Johan Östgren was responsible for data collection and interpretation, and manuscript review. Leo Niskanen was responsible for data acquisition and interpretation, and manuscript review. Gisle Langslet was responsible for the study conduct, data acquisition, analysis and interpretation, and manuscript review. Santiago Durán-Garcia contributed to the conduct of the study, the acquisition, analysis and interpretation of the data, and reviewed the manuscript. Elise Hardy was responsible for data analysis, data interpretation, and manuscript development. Elmas Malvolti was responsible for data analysis, data interpretation, and manuscript development.
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18. Skyler JS, Bergenstal R, Bonow RO et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care 2009; 32: 187-192. 19. Goto A, Arah OA, Goto M, Terauchi Y, Noda M. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ 2013; 347: f4533. 20. Stahn A, Pistrosch F, Ganz X et al. Relationship between hypoglycemic episodes and ventricular arrhythmias in patients with type 2 diabetes and cardiovascular diseases. Diabetes Care 2013; 37: 516-520. 21. Sinclair A, Morley JE, Rodriguez-Manas L et al. Diabetes mellitus in older people: position statement on behalf of the International Association of Gerontology and Geriatrics (IAGG), the European Diabetes Working Party for Older People (EDWPOP), and the International Task Force of Experts in Diabetes. J Am Med Dir Assoc 2012; 13: 497-502. 22. Strain WD, Lukashevich V, Kothny W, Hoellinger MJ, Paldanius PM. Individualised treatment targets for elderly patients with type 2 diabetes using vildagliptin add-on or lone therapy (INTERVAL): a 24 week, randomised, double-blind, placebo-controlled study. Lancet 2013; 382: 409-416. 23. Accord Healthcare. Glimepiride 4 mg tablets: summary of product characteristics. http://www.medicines.org.uk/EMC/history/25845/SPC/Glimepiride+4+mg+Tablets. Accessed 12 June 2013. 24. Schernthaner G, Grimaldi A, Di MU et al. GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Invest 2004; 34: 535-542.
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25. Bremer JP, Jauch-Chara K, Hallschmid M, Schmid S, Schultes B. Hypoglycemia unawareness in older compared with middle-aged patients with type 2 diabetes. Diabetes Care 2009; 32: 1513-1517. 26. McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabet Med 2001; 18: 690-705. 27. Zhang Y, Hong J, Chi J, Gu W, Ning G, Wang W. Head-to-head comparison of dipeptidyl peptidase-IV inhibitors and sulfonylureas - a meta-analysis from randomized clinical trials. Diabetes Metab Res Rev 2014; 30: 241-256. 28. Rosenstock J, Wilson C, Fleck P. Alogliptin versus glipizide monotherapy in elderly type 2 diabetes mellitus patients with mild hyperglycaemia: a prospective, double-blind, randomized, 1-year study. Diabetes Obes Metab 2013; 15: 906-914. 29. Barnett AH, Huisman H, Jones R, von EM, Patel S, Woerle HJ. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet 2013; 382: 1413-1423. 30. Scirica BM, Bhatt DL, Braunwald E et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1317-1326. 31. American Diabetes Association Workgroup on Hypoglycemia Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 2005; 28: 1245-1249. 32. Nathan DM, Buse JB, Davidson MB et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009; 32: 193-203.
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Table 1. Demographic and baseline clinical characteristics.
All patients
Saxagliptin + metformin
Glimepiride + metformin
(n = 360)
(n = 360)
Men, n (%)
217 (60.3)
228 (63.3)
445 (61.8)
Age, years, mean (SD)
72.5 (5.7)
72.7 (5.4)
72.6 (5.6)
Age ≥ 75 years, n (%)
143 (39.7)
144 (40.0)
287 (39.9)
White
352 (97.8)
355 (98.6)
707 (98.2)
Other
8 (2.2)
5 (1.4)
13 (1.8)
29.9 (5.0)
29.3 (4.7)
29.6 (4.9)
< 25
51 (14.2)
66 (18.3)
117 (16.3)
≥ 25 and < 30
147 (40.8)
137 (38.1)
284 (39.4)
≥ 30
161 (44.7)
156 (43.3)
317 (44.0)
Central Europe
133 (36.9)
141 (39.2)
274 (38.1)
Latin countries
74 (20.6)
62 (17.2)
136 (18.9)
Nordic countries
153 (42.5)
157 (43.6)
310 (43.1)
Duration of T2D, years, mean (SD)
7.6 (6.4)
7.6 (6.0)
7.6 (6.2)
HbA1c , %, mean (SD) [mmol/mol]a
7.58 (0.67) [59]
7.62 (0.65) [60]
7.60 (0.66) [60]
Metformin dose, mg, mean (SD)b
1,647 (705)
1,572 (671)
1,609 (689)
Abnormal medical history, n (%)c
278 (77.2)
290 (80.6)
568 (78.9)
Musculoskeletal & connective tissue disorders
120 (33.3)
121 (33.6)
241 (33.5)
Gastrointestinal disorders
85 (23.6)
82 (22.8)
167 (23.2)
Reproductive system & breast disorders
52 (14.4)
60 (16.7)
112 (15.6)
Neoplasms
53 (14.7)
49 (13.6)
102 (14.2)
(n = 720)
Race, n (%)
2
BMI, kg/m , mean (SD)
a
BMI categorization, n (%)a
Geographic region, n (%)
Medical history, most commonly affected body systems, n (%)c
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History of vascular diseases, n (%)c Hypertension
276 (76.7)
279 (77.5)
555 (77.1)
Coronary artery disease
31 (8.6)
36 (10.0)
67 (9.3)
Previous myocardial infarction
34 (9.4)
20 (5.6)
54 (7.5)
Cardiovascular accident
19 (5.3)
21 (5.8)
40 (5.6)
Stable angina
17 (4.7)
21 (5.8)
38 (5.3)
History of lipid disorder, n (%)c
220 (61.1)
213 (59.2)
433 (60.1)
a
n = 718 (n = 359 saxagliptin; n = 359 glimepiride); b n = 715 (n = 357 saxagliptin; n = 358 glimepiride); cn = 720 (n = 360 saxagliptin; n = 360 glimepiride).
BMI, body mass index; SD, standard deviation; T2D, type 2 diabetes.
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Table 2. Efficacy results at Week 52. Saxagliptin + metformin
Glimepiride + metformin
359
359
136 (37.9)
137 (38.2)
85 (39.2)
72 (33.3)
< 75 years,a n (%)
51 (35.9)
65 (45.5)
≥ 75 years,b n (%)
23 (56.1)
23 (53.5)
< 7% baseline HbA1c, n (%)c
103 (43.5)
92 (40.2)
10 (12.3)
22 (25.3)
HbA1c < 7.0% without confirmed/severe hypoglycaemic events, n All patients, n (%)
7% – < 8% baseline HbA1c, n (%)d
OR* or difference† (95% CI)
0.99 (0.73, 1.34); p = 0.9415* 1.29 (0.87, 1.91)* 0.67 (0.42, 1.08)* 1.15 (0.48, 2.75)* 1.14 (0.79, 1.65)* 0.41 (0.18, 0.94)*
≥ 8% baseline HbA1c, n (%)e ≥ 1 confirmed/severe hypoglycaemic events, n All patients, n (%) a
< 75 years, n (%) b
359
359
4 (1.1)
55 (15.3)
2 (0.9)
40 (18.5)
2 (1.4)
15 (10.5)
0.06 (0.02, 0.17); p < 0.0001* 0.04 (
G. Schernthaner1, S. Durán-Garcia2, M. Hanefeld3, G. Langslet4, L. Niskanen5, C. J. Östgren6, E. Malvolti7* & E. Hardy8
1
Department of Medicine I, Rudolfstiftung Hospital, Vienna, Austria
2
Unidad de Gestion de Endocrinología y Nutrición, Hospital Universitario de Valme, Sevilla,
Spain 3
Studycentre Professor Hanefeld, GWT-TUD GmbH, Dresden, Germany
4
The Lipid Clinic, Oslo University Hospital, Oslo, Norway
5
Endocrinology and Metabolism, Abdominal Center, Helsinki University Hospital and
University of Helsinki, Helsinki, Finland 6
Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
7
AstraZeneca, Istanbul, Turkey
8
AstraZeneca LP, Wilmington, DE, USA
*Previously employed by Bristol-Myers Squibb, Paris, France
Correspondence to: Guntram Schernthaner, MD, Department of Medicine I, Rudolfstiftung Hospital-Vienna, Juchgasse 25, A–1030 Vienna, Austria. Phone: (+43) 171 165 2101; Fax: (+43) 171 165 2109 Email: [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.12461
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Abstract Aims: To assess the efficacy and safety of adjunctive saxagliptin vs glimepiride in elderly patients with type 2 diabetes (T2D) and inadequate glycaemic control. Methods: In this multinational, randomized, double-blind, Phase IIIb/IV study (GENERATION; NCT01006603), patients aged ≥ 65 years were randomized (1:1) to receive saxagliptin 5 mg/day or glimepiride ≤6 mg/day, added to metformin, during a 52-week treatment period. The primary endpoint was achievement of HbA1c < 7.0% at Week 52 without confirmed/severe hypoglycaemia. The key secondary endpoint was incidence of confirmed/severe hypoglycaemia. Safety and tolerability were also assessed. Results: Of 720 patients randomized (360 in each treatment group; mean age 72.6 years; mean T2D duration 7.6 years), 574 (79.8%) completed the study (saxagliptin 80.3%; glimepiride 79.2%). Similar proportions of patients achieved the primary endpoint with saxagliptin and glimepiride (37.9% vs 38.2%; odds ratio 0.99; 95% confidence interval 0.73, 1.34; p = 0.9415). However, a significant treatment by age interaction effect was detected (p = 0.0389): saxagliptin was numerically superior to glimepiride for patients aged < 75 years (39.2% vs 33.3%) and numerically inferior for patients aged ≥ 75 years (35.9% vs 45.5%). Incidence of confirmed/severe hypoglycaemia was lower with saxagliptin vs glimepiride (1.1% vs 15.3%; nominal p < 0.0001). Saxagliptin was generally well tolerated, with similar incidences of adverse events, vs glimepiride. Conclusion: As avoiding hypoglycaemia is a key clinical objective in elderly patients, saxagliptin is a suitable alternative to glimepiride in patients with T2D aged ≥ 65 years. Keywords: type 2 diabetes, DPP-4 inhibitor, sulphonylureas, randomized trial
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Introduction In elderly patients with diabetes, the risk of hypoglycaemia is significantly increased compared with younger adults [1,2] and the harm associated with severe hypoglycaemia may counterbalance potential benefits of intensive glucose control [3,4]. While for most patients with type 2 diabetes (T2D), the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend a target HbA1c of < 7.0% [5], glycaemic targets for elderly patients with limited life expectancy, a history of severe hypoglycaemia, long-standing or more complicated T2D are less ambitious than for younger, healthier individuals. A target HbA1c of 7.5–8.0% is considered acceptable, according to recent ADA and EASD guidelines [5]. Saxagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor approved in the EU as additional therapy in adults with T2D with inadequate glycaemic control on monotherapy with metformin, a sulfonylurea or a thiazolidinedione. Saxagliptin is also approved in the EU as a triple oral therapy in combination with metformin plus a sulfonylurea, when this regimen alone provides inadequate glycaemic control, and as combination therapy with insulin (with/without metformin) for adults with T2D [6]. In Phase III studies, saxagliptin improved glycaemic control vs placebo and was similar to active comparators (glipizide or sitagliptin), in combination with metformin [7-9], metformin plus glimepiride [10], other oral antihyperglycaemic drugs [11,12] or insulin [13]. In patients aged ≥65 years, a post hoc analysis of pooled Phase III data showed that saxagliptin (combination therapy or initial monotherapy) provided better glycaemic control than placebo, with low risk of hypoglycaemia [14,15]. Although HbA1c is traditionally used as a primary endpoint for assessing the efficacy of antihyperglycaemic treatments, in elderly patients the risk of hypoglycaemia should also be considered, as both factors contribute to clinical treatment decision-making. This study evaluated whether saxagliptin was superior to glimepiride as add-on to metformin in
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improving glycaemic control without hypoglycaemia in elderly patients (≥ 65 years old) with T2D.
Methods Patients Patients aged ≥ 65 years with T2D, on stable metformin monotherapy at any dose for ≥ 8 weeks prior to enrolment, and with HbA1c of 7.0–9.0%, were eligible. Excluded were: patients with type 1 diabetes mellitus; treatment with any antihyperglycaemic therapy other than metformin monotherapy within 8 weeks prior to enrolment; treatment with systemic glucocorticoids (except for replacement therapy) or cytochrome P450 3A4 inducers; history of ketoacidosis or hyperosmolar non-ketonic coma; history of haemoglobinopathies; renal impairment (creatinine clearance [CrCl] < 60 mL/min); cognitive function problems; alcohol or illegal drug abuse for ≤ 12 months prior to enrolment; history of hypersensitivity or contraindication to study drugs. Additional exclusion criteria were: aspartate aminotransferase levels > 3-fold the upper limit of the normal (ULN) and/or alanine aminotransferase levels > 3-fold ULN and/or total bilirubin > 34 μmol/L; and creatine kinase > 10-fold ULN. All patients abstained from donating blood, plasma or platelets during the study. The study was conducted in compliance with the ethical principles originating from the Declaration of Helsinki and the International Conference on Harmonisation notes for Guidance on Good Clinical Practice. The study protocol was approved by an Independent Ethics Committee or Institutional Review Board. All patients provided written informed consent before enrolment.
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Study Design This 52-week, multinational, randomized, double-blind, active-controlled, parallel-arm, Phase IIIb/IV study (GENERATION; NCT01006603) was conducted between October 2009 and June 2012 at 152 sites in 12 European countries and Mexico. The study consisted of a 2-week screening period, 2-week enrolment period, 2-week single-blinded (to patients only) placebo-lead-in period, and 52-week double-blinded treatment period, comprising a 12-week titration period and a 40-week maintenance period (supplementary figure). After lead-in, patients were randomized (1:1) to receive saxagliptin 5 mg/day and placebo or glimepiride 1 mg/day and placebo, added to metformin. Randomization was done via an interactive web response system and was stratified by age to include ~60% of patients aged < 75 years and ~40% aged ≥ 75 years. During the titration period, glimepiride or placebo was up-titrated every 3 weeks in 1 or 2 mg/day increments to the optimal dose (fasting plasma glucose ≤ 6.1 mmol/L), up to 6 mg/day. During maintenance, no up-titration was performed. Glimepiride or placebo could be down-titrated if recurrent hypoglycaemia occurred.
Assessments The primary efficacy endpoint was the proportion of patients achieving HbA1c < 7.0% at Week 52 without confirmed/severe hypoglycaemia. Confirmed hypoglycaemia was defined as a symptomatic or asymptomatic event with plasma glucose < 3.0 mmol/L, requiring no external assistance. Severe hypoglycaemia was defined as a symptomatic event requiring external assistance due to severe impairment in consciousness or behaviour, with or without plasma glucose < 3.0 mmol/L, but with prompt recovery after glucose/glucagon administration. The key secondary endpoint was the proportion of patients with ≥ 1 confirmed/severe hypoglycaemic event over the treatment period. Other secondary endpoints included the
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proportion of patients achieving HbA1c < 7.0% or ≤ 6.5% at Week 52, and the change from baseline to Week 52 in mean HbA1c. Post hoc analyses were conducted to determine the number of confirmed/severe hypoglycaemic events over time, and the incidence of confirmed/severe hypoglycaemia by HbA1c category at Week 52 (< 7.0% or ≥ 7.0%) stratified by age group, and by HbA1c category at Week 52 (< 6.5%; ≥ 6.5%–< 7.0%; ≥ 7.0%–< 7.5%, and ≥ 7.5%). Safety and tolerability assessments included adverse events (AEs) and body weight.
Analytical Methods Blood samples for assessing glycaemic parameters were collected at every visit during the treatment period and were analysed centrally (Quintiles Laboratories Ltd., Europe). Patients self-monitored glucose levels using a glucometer (Accu-Chek©, Roche Diagnostics) at least every second day during lead-in and titration and at least once a week during maintenance. Blood glucose levels and hypoglycaemic events were recorded in patients’ diaries.
Statistical Analysis A sample size of 698 patients (349/treatment arm) was calculated for detecting superiority for saxagliptin in the primary endpoint, with a two-sided significance level of 0.05 and 80% power. This assumed a 10% drop-out rate and an odds ratio (OR) of 1.55 for achieving target HbA1c without hypoglycaemia with saxagliptin, compared with glimepiride. The safety population, including all randomized patients who took ≥ 1 dose of the study medication, was used for reporting safety and tolerability results and for primary, key secondary and post hoc efficacy assessments. The full analysis population, defined as safety population patients with non-missing baseline and ≥ 1 post-baseline efficacy data for ≥ 1 variable, was used for reporting other secondary endpoints.
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Patients who did not complete the 52-week treatment period were considered as nonresponders, that is, as having not achieved HbA1c < 7.0% at Week 52 without confirmed/severe hypoglycaemia. Non-continuous endpoints were analysed using a Cochran-Mantel-Haenszel test with continuity correction stratified by age; treatment-by-age interaction and treatment-bybaseline HbA1c interaction was determined using a logistic regression model. To control for multiplicity, primary and key secondary endpoints were tested in a pre-specified hierarchy. Continuous endpoints were analysed using an analysis of covariance (ANCOVA) model, with treatment group and age as fixed effects and baseline value of the endpoint as a covariate. Statistical analyses were performed by AptivSolution GmbH, Germany.
Results Patient Disposition Of 720 patients randomized, 718 received study medication, and 574 (79.8%) completed the 52-week treatment period (saxagliptin 80.3%; glimepiride 79.2%) [Figure 1]. Safety and full analysis populations comprised 718 and 709 patients, respectively.
Demographics and Baseline Characteristics Demographics, baseline characteristics and medical history were balanced across treatment groups and were generally representative of an elderly population with T2D, inadequate glycaemic control, and normal renal function or mild renal impairment (Table 1). The mean dose of glimepiride was 3.3 mg/day.
Efficacy Primary efficacy endpoint Proportions of patients achieving HbA1c < 7.0% at Week 52 without confirmed/severe hypoglycaemia were similar with saxagliptin and glimepiride: 37.9% vs 38.2% (OR 0.99; This article is protected by copyright. All rights reserved
95% confidence interval [CI]: 0.73, 1.34; p = 0.9415) [Table 2]. However, a significant treatment by age interaction was detected (p = 0.0389). The proportion of patients aged < 75 years achieving the primary endpoint was numerically higher with saxagliptin, compared with glimepiride (39.2% vs 33.3%), whereas in patients aged ≥ 75 years, the opposite occurred (35.9% vs 45.5%). A treatment interaction by baseline HbA1c was also identified (p = 0.0822). The proportion of patients with baseline HbA1c levels < 7% and 7% – < 8% achieving the primary endpoint was numerically higher with saxagliptin, compared with glimepiride (< 7%: 56.1% vs 53.5% and 7% – < 8%: 43.5% vs 40.2%). In patients with baseline HbA1c ≥ 8%, fewer patients in both groups reached the primary endpoint; a numerically lower proportion with saxagliptin reached the primary endpoint, compared with glimepiride (12.3% vs 25.3%).
Key secondary endpoint Fewer saxagliptin-treated patients experienced ≥ 1 confirmed/severe hypoglycaemic event over the treatment period, compared with glimepiride: 1.1% vs 15.3% (OR 0.06; 95% CI 0.02, 0.17; nominal p < 0.0001). The difference between saxagliptin vs glimepiride was numerically greater in patients aged < 75 years compared with patients aged ≥ 75 years (ORs 0.04 vs 0.12; nominal p = 0.3018) [Table 2]. With glimepiride, fewer patients aged ≥ 75 years experienced hypoglycaemia, compared with patients aged < 75 years (10.5% vs 18.5%).
Secondary efficacy endpoints Overall, a lower proportion of saxagliptin-treated patients achieved HbA1c < 7.0% at Week 52, vs glimepiride: 44:7% vs 54.7% (nominal p = 0.0077). The difference between treatment groups was numerically, but not significantly greater in patients aged ≥ 75 years vs < 75 years (nominal p = 0.1071). A lower proportion of saxagliptin-treated patients vs glimepiride also achieved HbA1c ≤ 6.5% (18.5% vs 30.9%, nominal p < 0.0001; Table 2).
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Adjusted mean HbA1c change from baseline at Week 52 was smaller with saxagliptin vs glimepiride: 0.44% vs 0.64% (nominal p < 0.0001) [Table 2], with a greater difference between treatment groups in patients aged ≥ 75 years, compared with patients aged < 75 years (Table 2). Mean HbA1c changes from baseline were similar between age groups with saxagliptin, and numerically greater in patients aged ≥ 75 years, compared with patients aged < 75 years, with glimepiride (nominal p = 0.0839, p = 0.0001) (Table 2). Post hoc analyses assessing potential mechanisms, including baseline estimated glomerular filtration rate, did not reveal any conclusive results (see Supplementary Material).
Post hoc analyses With glimepiride, confirmed/severe hypoglycaemia occurred throughout the treatment period; events were more common during Weeks 4–16 (figure 2A). Furthermore, with glimepiride, hypoglycaemia occurred more frequently in patients who achieved HbA1c < 7.0%, compared with HbA1c ≥ 7.0% at Week 52, for the overall population and for patients aged < 75 years (figure 2B). With saxagliptin, confirmed/severe hypoglycaemia incidence was low or absent for all HbA1c intervals; with glimepiride, hypoglycaemia incidence was highest for the lower HbA1c intervals (figure 2C).
Safety and Tolerability Saxagliptin was generally well tolerated in this population. The incidence of AEs (excluding hypoglycaemia) was similar with both treatments, and for each age group. The proportion of patients experiencing any hypoglycaemic event was lower with saxagliptin vs glimepiride (5.8% vs 34.8%). The most common AEs with saxagliptin were nasopharyngitis, arthralgia and diarrhoea (Table 3). More saxagliptin-treated patients experienced serious AEs (SAEs), compared with glimepiride (11.4% vs 8.9%). Four patients experienced SAEs considered to be related to
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treatment (saxagliptin: cholecystitis, malignant hepatic neoplasm and bladder calculus; glimepiride: hypoglycaemia). Discontinuations due to AEs were higher with saxagliptin (4.5%), compared with glimepiride (3.1%), most frequently due to neoplasm (saxagliptin n = 4: bladder transitional cell carcinoma, colon cancer, malignant hepatic neoplasm and lymphoma; glimepiride n = 0) and nervous system disorders (saxagliptin n = 3: headache, lethargy and syncope; glimepiride n = 4: dementia, dizziness, epilepsy and migraine). There were two deaths in the study (saxagliptin: myocardial infarction; glimepiride: unknown cause), considered unrelated to treatment. Neoplasm incidence was imbalanced with saxagliptin vs glimepiride (n=10 vs n=3). With saxagliptin, events were in multiple organ systems and occurred mostly in patients with cancer risk factors and ≤6 months exposure to saxagliptin in 8/10 cases. One event was considered related to saxagliptin treatment: a patient with hepatocellular carcinoma risk factors developed malignant hepatic neoplasm ~4.5 months post-randomization. More saxagliptin-treated patients reported fractures, compared with glimepiride (n = 9 vs n = 4). With saxagliptin, fractures occurred in patients with prior osteoporosis risk factors or preexisting osteoporosis, were associated with ≤9 months’ exposure and were not considered treatment-related. No differences between treatment groups were noted for infection, opportunistic infection, skin lesion or localized oedema. In particular, there were no instances of lymphocytopenia, thrombocytopenia or pancreatitis. More heart failure events were observed with glimepiride compared with saxagliptin (n = 6 [three SAEs] vs n = 1 [SAE]). Patients treated with saxagliptin showed a mean reduction in body weight at Week 52 vs baseline, compared with a mean increase with glimepiride (-0.8 kg; 95% CI -1.2, -0.4 vs +1.0 kg; 95% CI 0.6, 1.3).
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Discussion Treatment of elderly patients with T2D is a unique challenge, where the risk of hypoglycaemia and associated complications must be balanced against potential benefits of glucose control [16]. Although the risk of microvascular and macrovascular events has been shown to increase significantly with HbA1c above thresholds of 6.5% and 7.0%, respectively [17], intensive glycaemic control may have either no influence or potentially a detrimental effect on cardiovascular (CV) outcomes in patients with a relatively long duration of diabetes and risk factors for CV disease [18]. Severe hypoglycaemia has been shown to be associated with an increased risk of CV disease and severe ventricular arrhythmias [19,20]. As a consequence, recent guidelines emphasize the need for individualizing HbA1c targets in elderly patients, rather than achieving strict glycaemic control [5] and recommend that hypoglycaemia, ability to self-manage, cognitive status, comorbidities and life expectancy are considered when treating this population [21]. On the other hand, the evidence base for using individualized glycaemic targets is limited. A recent study in elderly patients with T2D showed vildagliptin to be superior to placebo in achieving individualized glycaemic targets [22]. Mean HbA1c targets set by investigators were ~7.0%, the lowest target recommended in this population [21]. In the GENERATION study, the superiority of saxagliptin vs glimepiride was not demonstrated for the primary endpoint. Saxagliptin was numerically superior to glimepiride for the primary endpoint in patients aged < 75 years and numerically inferior in patients aged ≥ 75 years, with a statistically significant interaction of treatment with age. Whereas the incidence of confirmed/severe hypoglycaemia was substantially higher with glimepiride vs saxagliptin, more glimepiride-treated patients achieved the HbA1c target, compared with saxagliptin. The incidence of hypoglycaemia with saxagliptin was low, even for patients achieving the lowest HbA1c values. Furthermore, with glimepiride, hypoglycaemia occurred throughout the treatment period and across all levels of glycaemic control.
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An important factor contributing to the study not achieving its primary endpoint was the unexpected difference in the efficacy of glimepiride between age groups. With glimepiride, glycaemic control was greater and hypoglycaemia incidence lower in patients aged ≥ 75 years, compared with < 75 years, whereas with saxagliptin the same parameters were consistent across the age groups. Though better glycaemic control was observed in patients aged ≥ 75 years on glimepiride, this may not constitute a benefit if it is accompanied by a higher rate of hypoglycaemia. There is a tendency for glimepiride clearance to increase with decreasing renal function [23], which may affect glycaemic efficacy; furthermore, hypoglycaemia incidence with glimepiride is higher in patients with mild renal impairment vs normal renal function [24]. However, in this study, the increased glimepiride efficacy in patients aged ≥ 75 years could not be attributed to differences in baseline renal function between populations, and patients with CrCl < 60 mL/min had been excluded from the study. Lack of awareness of hypoglycaemic symptoms may explain the unexpected lower incidence of hypoglycaemia in patients aged ≥ 75 years [25]. In elderly patients, fewer individual hypoglycaemic symptoms of lower intensity are generally reported, compared with younger adults [26], and symptoms are often non-specific in nature, including weakness, unsteadiness, sleepiness, faintness and poor concentration [26]. Therefore, in this study, hypoglycaemia could have been under-reported, which may account for the reduced hypoglycaemia incidence observed in the older age group of glimepiride-treated patients. With saxagliptin, the number of patients reporting hypoglycaemia may have been too low for this effect to become apparent. As we are not aware of other studies testing saxagliptin versus glimepiride in elderly patients with T2D, the results of this study should ideally be interpreted in the context of other head-to-head studies between DPP-4 inhibitors and sulphonylureas in elderly patients with T2D. A recent meta-analysis [27] identified 12 randomized studies between DPP-4 inhibitors and sulphonylureas; however only one study enrolled elderly patients only and none used an endpoint combining glucose lowering and hypoglycaemia as in the This article is protected by copyright. All rights reserved
GENERATION study. The meta-analysis confirmed that patients on DPP-4 inhibitors were less likely to achieve HbA1c < 7% compared with those on sulphonylureas (OR 0.91; 95% CI 0.84, 0.99), but had a lower risk of hypoglycaemia on DPP-4 inhibitors compared with sulphonylureas (OR 0.13; 95% CI 0.11, 0.16) [27]. In the randomized study which enrolled elderly patients with T2D, glycaemic control with alogliptin was found to be non-inferior to glipizide and alogliptin had a lower risk of hypoglycaemia compared with glipizide (5.4% vs 26.0%) [28]. However, results from the alogliptin-glipizide head-to-head study were not analysed by age group, so it is difficult to relate them to those obtained in the current study. Also recently reported were two placebo-controlled studies in elderly patients (≥ 70 years) with T2D treated with other DPP-4 inhibitors (vildagliptin [22] and linagliptin [29]). The definition of hypoglycaemia used was in line with GENERATION for the vildagliptin study (< 3.1 mmol/L) [22] and a less stringent definition was used for the linagliptin study (< 3.9 mmol/L) [29]. While it is not appropriate to compare results with GENERATION directly, HbA1c reductions from baseline and low rates of hypoglycaemia were demonstrated in all both studies and GENERATION, in elderly patients [22,29], though it should be noted that the percentage of patients with hypoglycaemia was not reported by age subgroups in the two placebo-controlled studies. Saxagliptin add-on to metformin was generally well tolerated in patients aged ≥ 65 years, with an overall incidence of AEs similar to glimepiride. The safety profile of saxagliptin was consistent with that reported in previous studies in older patients [14,15]. No pancreatitis was observed. An imbalance in AEs of neoplasm and fracture was observed with saxagliptin vs glimepiride; however, events occurred in patients with prior risk factors, and the exposure to saxagliptin was short. Furthermore, the size and duration of the present study was insufficient for evaluating rare events. Safety findings should be considered in the context of the overall saxagliptin clinical programme, where no imbalances in AEs of neoplasm and fracture have been observed with saxagliptin in this age group [14,15]. The overall CV safety with saxagliptin was previously assessed in the SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) This article is protected by copyright. All rights reserved
study of ~16,500 patients with T2D with a history of, or at risk for, CV events [30]. Saxagliptin was non-inferior to placebo for CV safety in the overall population and in patients aged > 75 years [30]. Furthermore, in the overall population, there were no imbalances in malignancies, fractures and events of pancreatitis between saxagliptin and placebo groups. In the GENERATION study, CV events were balanced across the two groups, though their incidence was too low for a meaningful comparison. Several limitations should be considered when interpreting the results of this study. The primary endpoint included only patient-reported confirmed/severe hypoglycaemia; this was deemed the most rigorous method, though the rate of hypoglycaemia may have been underestimated; as noted above, elderly patients may under-report hypoglycaemic symptoms. Furthermore, a more stringent definition of hypoglycaemia was used (blood glucose < 3.0 mmol/L) than the < 3.9 mmol/L value recommended by some professional diabetes societies [31]. Patients with chronic kidney disease were excluded from this study, since at the time of planning, guidelines recommended that renal dysfunction was a contraindication for metformin. Finally, glycaemic targets were based on guidelines valid when the study protocol was developed [32] and were not individualized. A target HbA1c of < 7.0% may no longer be considered appropriate for certain elderly patients [5,21]. Overall, the GENERATION study showed that saxagliptin provided glycaemic control with low risk of hypoglycaemia and was well tolerated in patients aged ≥ 65 years, inadequately controlled on metformin. As avoidance of hypoglycaemia is a key clinical objective in elderly patients, saxagliptin is a suitable alternative to glimepiride in this population. Given the paucity of data in this age group, this study adds significant value to the evidence available for treating elderly patients with T2D.
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Acknowledgements Medical writing services were provided by Ioana Dumitrescu, PhD, of QXV Communications, Macclesfield, UK and were funded by AstraZeneca and Bristol-Myers Squibb. This study was funded by AstraZeneca and Bristol-Myers Squibb.
Conflict of Interest Guntram Schernthaner reports personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceuticals, Novo Nordisk, Sanofi, Servier Laboratories, and Takeda, outside the submitted work. Markolf Hanefeld reports personal fees from Bayer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Roche, Sanofi-Aventis, and Takeda, outside the submitted work. Carl Johan Östgren reports personal fees from AstraZeneca during the conduct of the study and personal fees from AstraZeneca and Bristol-Myers Squibb, outside the submitted work. Leo Niskanen reports research grant from AstraZeneca during the conduct of the study and personal fees from Novo Nordisk, GlaxoSmithKline, and Janssen-Cilag, a research grant from Sanofi, and personal fees and research grants from AstraZeneca, Boehringer Ingelheim, and Eli Lilly, outside the submitted work. Gisle Langslet reports personal fees from Bristol-Myers Squibb and Janssen Pharmaceuticals, outside the submitted work. Santiago Durán-Garcia reports personal fees from AstraZeneca during the conduct of the study and personal fees from AstraZeneca and Bristol-Myers Squibb, outside the submitted work. Elise Hardy is an employee of AstraZeneca. Elmas Malvolti is currently an employee of AstraZeneca and was employed by BristolMyers Squib at the time the study took place.
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Contributor Statements Guntram Schernthaner was involved in planning and designing the study, and was responsible for data interpretation and manuscript review. Markolf Hanefeld was responsible for the study conduct, data interpretation and manuscript review. Carl Johan Östgren was responsible for data collection and interpretation, and manuscript review. Leo Niskanen was responsible for data acquisition and interpretation, and manuscript review. Gisle Langslet was responsible for the study conduct, data acquisition, analysis and interpretation, and manuscript review. Santiago Durán-Garcia contributed to the conduct of the study, the acquisition, analysis and interpretation of the data, and reviewed the manuscript. Elise Hardy was responsible for data analysis, data interpretation, and manuscript development. Elmas Malvolti was responsible for data analysis, data interpretation, and manuscript development.
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Table 1. Demographic and baseline clinical characteristics.
All patients
Saxagliptin + metformin
Glimepiride + metformin
(n = 360)
(n = 360)
Men, n (%)
217 (60.3)
228 (63.3)
445 (61.8)
Age, years, mean (SD)
72.5 (5.7)
72.7 (5.4)
72.6 (5.6)
Age ≥ 75 years, n (%)
143 (39.7)
144 (40.0)
287 (39.9)
White
352 (97.8)
355 (98.6)
707 (98.2)
Other
8 (2.2)
5 (1.4)
13 (1.8)
29.9 (5.0)
29.3 (4.7)
29.6 (4.9)
< 25
51 (14.2)
66 (18.3)
117 (16.3)
≥ 25 and < 30
147 (40.8)
137 (38.1)
284 (39.4)
≥ 30
161 (44.7)
156 (43.3)
317 (44.0)
Central Europe
133 (36.9)
141 (39.2)
274 (38.1)
Latin countries
74 (20.6)
62 (17.2)
136 (18.9)
Nordic countries
153 (42.5)
157 (43.6)
310 (43.1)
Duration of T2D, years, mean (SD)
7.6 (6.4)
7.6 (6.0)
7.6 (6.2)
HbA1c , %, mean (SD) [mmol/mol]a
7.58 (0.67) [59]
7.62 (0.65) [60]
7.60 (0.66) [60]
Metformin dose, mg, mean (SD)b
1,647 (705)
1,572 (671)
1,609 (689)
Abnormal medical history, n (%)c
278 (77.2)
290 (80.6)
568 (78.9)
Musculoskeletal & connective tissue disorders
120 (33.3)
121 (33.6)
241 (33.5)
Gastrointestinal disorders
85 (23.6)
82 (22.8)
167 (23.2)
Reproductive system & breast disorders
52 (14.4)
60 (16.7)
112 (15.6)
Neoplasms
53 (14.7)
49 (13.6)
102 (14.2)
(n = 720)
Race, n (%)
2
BMI, kg/m , mean (SD)
a
BMI categorization, n (%)a
Geographic region, n (%)
Medical history, most commonly affected body systems, n (%)c
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History of vascular diseases, n (%)c Hypertension
276 (76.7)
279 (77.5)
555 (77.1)
Coronary artery disease
31 (8.6)
36 (10.0)
67 (9.3)
Previous myocardial infarction
34 (9.4)
20 (5.6)
54 (7.5)
Cardiovascular accident
19 (5.3)
21 (5.8)
40 (5.6)
Stable angina
17 (4.7)
21 (5.8)
38 (5.3)
History of lipid disorder, n (%)c
220 (61.1)
213 (59.2)
433 (60.1)
a
n = 718 (n = 359 saxagliptin; n = 359 glimepiride); b n = 715 (n = 357 saxagliptin; n = 358 glimepiride); cn = 720 (n = 360 saxagliptin; n = 360 glimepiride).
BMI, body mass index; SD, standard deviation; T2D, type 2 diabetes.
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Table 2. Efficacy results at Week 52. Saxagliptin + metformin
Glimepiride + metformin
359
359
136 (37.9)
137 (38.2)
85 (39.2)
72 (33.3)
< 75 years,a n (%)
51 (35.9)
65 (45.5)
≥ 75 years,b n (%)
23 (56.1)
23 (53.5)
< 7% baseline HbA1c, n (%)c
103 (43.5)
92 (40.2)
10 (12.3)
22 (25.3)
HbA1c < 7.0% without confirmed/severe hypoglycaemic events, n All patients, n (%)
7% – < 8% baseline HbA1c, n (%)d
OR* or difference† (95% CI)
0.99 (0.73, 1.34); p = 0.9415* 1.29 (0.87, 1.91)* 0.67 (0.42, 1.08)* 1.15 (0.48, 2.75)* 1.14 (0.79, 1.65)* 0.41 (0.18, 0.94)*
≥ 8% baseline HbA1c, n (%)e ≥ 1 confirmed/severe hypoglycaemic events, n All patients, n (%) a
< 75 years, n (%) b
359
359
4 (1.1)
55 (15.3)
2 (0.9)
40 (18.5)
2 (1.4)
15 (10.5)
0.06 (0.02, 0.17); p < 0.0001* 0.04 (
