Drugs Aging DOI 10.1007/s40266-015-0271-z
ORIGINAL RESEARCH ARTICLE
Efficacy and Tolerability of Sitagliptin Compared with Glimepiride in Elderly Patients with Type 2 Diabetes Mellitus and Inadequate Glycemic Control: A Randomized, Double-Blind, Non-Inferiority Trial Paul Hartley1 • Yue Shentu2 • Patricia Betz-Schiff2 • Gregory T. Golm2 Christine McCrary Sisk2 • Samuel S. Engel2 • R. Ravi Shankar2
•
Ó Springer International Publishing Switzerland 2015
Abstract Objective The aim of this study was to evaluate the efficacy and tolerability of sitagliptin compared with glimepiride in elderly patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control with diet and exercise alone. Methods This was a randomized, parallel-group, multinational, non-inferiority clinical trial with an activecontrolled, double-blind treatment period in which patients C65 and B85 years of age with T2DM were screened at 85 sites. Patients were randomized to once-daily sitagliptin (100 or 50 mg, depending on renal function) or glimepiride (in titrated doses) for 30 weeks. The main outcome measures were change from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight; and the incidence of symptomatic hypoglycemia. Results The mean baseline HbA1c was 7.8 % in both the sitagliptin group (n = 197) and the glimepiride group (n = 191). After 30 weeks, the least squares (LS) mean change in HbA1c baseline was -0.32 % with sitagliptin and -0.51 % with glimepiride, for a between-group difference (95 % CI) of 0.19 % (0.03–0.34). This result met the pre-specified criterion for declaring non-inferiority, which required that the upper 95 % confidence limit lie below 0.4 %. The LS mean change in FPG from baseline was -14.5 mg/dL with sitagliptin and -21.2 mg/dL with Electronic supplementary material The online version of this article (doi:10.1007/s40266-015-0271-z) contains supplementary material, which is available to authorized users. & R. Ravi Shankar [email protected]
glimepiride, for a between-group difference (95 % CI) of 6.7 mg/dL (0.7–12.7). The percentages of patients with adverse events of symptomatic hypoglycemia were 0.8 % in the sitagliptin group and 4.7 % in the glimepiride group (between-treatment difference = -3.9 %, p = 0.009). The LS mean change in body weight from baseline was 0.4 kg with sitagliptin and 1.1 kg with glimepiride, for a betweengroup difference of -0.7 kg (p = 0.011). Conclusion In elderly patients with T2DM and inadequate glycemic control with diet and exercise alone, sitagliptin provided non-inferior glycemic control after 30 weeks of treatment compared with glimepiride. Compared with glimepiride, sitagliptin had a lower risk of hypoglycemia. Sitagliptin was weight-neutral; while the between-group difference in change from baseline in body weight was statistically significant, the modest difference may not be clinically meaningful. Study Identifier ClinicalTrials.gov NCT01189890. Key Points This randomized, double-blind, non-inferiority study compared the efficacy and tolerability of sitagliptin with glimepiride in elderly patients with type 2 diabetes mellitus and inadequate glycemic control with diet and exercise alone. Sitagliptin provided non-inferior glycemic control after 30 weeks of treatment compared with glimepiride.
1
Preferred Primary Care Physicians, Uniontown, PA, USA
The risk of symptomatic hypoglycemia was significantly lower with sitagliptin than with glimepiride.
2
Merck & Co., Inc., Kenilworth, NJ, USA
Sitagliptin was weight-neutral.
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1 Introduction Type 2 diabetes mellitus (T2DM) among the elderly (C65 years) is an important public health concern. Alterations in carbohydrate metabolism with advancing age increase the risk of developing T2DM. Data from the 2009–2012 National Health and Nutrition Examination Survey indicate that 25.9 % of US individuals C65 years of age have diagnosed or undiagnosed diabetes [1]. As life expectancy has increased, the global burden of T2DM among the elderly is projected to more than double from the year 2000 to 2030 [2]. Management of elderly patients with T2DM is a challenge due to the presence of co-morbidities and other factors [3]. In addition to a greater likelihood of impaired renal, cardiovascular, and cognitive function, elderly patients are particularly susceptible to hypoglycemia and its associated untoward effects (e.g., unsteadiness may result in falls and fractures) [4, 5]. Risk factors associated with hypoglycemia in elderly patients with T2DM include disability, poor nutrition, and polypharmacy [6]. In addition, elderly patients often lack the typical symptoms of hypoglycemia, and this reduced awareness places them at risk for under-treatment and resultant neuroglycopenic manifestations [7]. Hypoglycemia may exacerbate cognitive decline in the elderly [8, 9], which, in turn, may result in medication errors, improper glucose monitoring, and irregular/insufficient food intake, further confounding successful disease management. These factors highlight the importance of avoiding hypoglycemia to improve health outcomes, quality of life, and anti-diabetic medication adherence in elderly patients with T2DM. Sulfonylurea treatment is associated with an increased risk for hypoglycemia among elderly patients [4, 10]. A recent study demonstrated that elderly patients were at increased risk for sulfonylurea-related hypoglycemia during hospitalization compared with younger patients [11]. This finding may be related to the compromised counterregulatory hormone responses to hypoglycemia [12] and the decreased awareness of symptoms of hypoglycemia often seen in elderly patients [7]. In addition, some drugs may potentiate sulfonylurea activity and increase the risk of hypoglycemia by displacing sulfonylureas from plasma proteins, reducing hepatic metabolism of sulfonylureas, decreasing urinary excretion of sulfonylureas, or producing hypoglycemic action in addition to the effects of sulfonylureas [13]. Antihyperglycemic agents (AHAs) that provide similar efficacy as sulfonylureas with less hypoglycemia would be an important clinical advance for the management of elderly patients with T2DM. Sitagliptin is an oral AHA with characteristics that may provide particular benefits for the treatment of T2DM
among elderly patients [14]. Sitagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor that inhibits the enzymatic degradation and inactivation of the incretins, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) [15]. Through this mechanism of action, sitagliptin improves glycemic control, with a low risk of hypoglycemia [16]. Sitagliptin has been found to be effective and well-tolerated in patients with moderate/severe renal insufficiency, including end-stage renal disease [17, 18], which is of particular importance to the elderly in view of the decline in renal function with age. In a phase III, randomized, double-blind, placebocontrolled study, treatment with sitagliptin monotherapy produced rapid and sustained glucose lowering in elderly patients with T2DM, without associated hypoglycemia or increased body weight [19]. In a retrospective pooled analysis of data from three randomized, double-blind studies, sitagliptin provided similar glycemic improvement with less hypoglycemia compared with sulfonylurea in the subgroup of T2DM patients aged 65 years or older [20]. The present study prospectively assessed the efficacy and tolerability of sitagliptin compared with glimepiride in elderly patients with T2DM and inadequate glycemic control with diet and exercise alone.
2 Patients and Methods 2.1 Patient Selection Criteria Eligible patients were community-dwelling, C65 and B85 years of age, and had T2DM that was inadequately controlled with diet and exercise alone [glycated hemoglobin (HbA1c) C7.0 % and B9.0 %]. Patients who had been previously treated with a DPP-4 inhibitor, or had been treated with insulin or GLP-1 mimetics (e.g., liraglutide, exenatide) within 8 weeks prior to screening, or peroxisome proliferator-activated receptor (PPAR)-c agonists within 16 weeks prior to screening, were excluded. Patients with type 1 diabetes, active liver disease, recent history of cardiovascular disease (acute coronary syndrome, coronary artery intervention, New York Heart Association Class III/ IV heart failure, stroke, transient ischemic neurologic event, or new/worsening symptoms of coronary heart disease), inadequately controlled hypertension, severe peripheral vascular disease, triglycerides [600 mg/dL, history of infection with HIV, history of malignancy or clinically important hematologic disorder, or an estimated glomerular filtration rate (eGFR; calculated using the Modification of Diet in Renal Disease formula) \35 mL/ min/1.73 m2 were also excluded. All patients provided written informed consent to participate, and the study protocol was reviewed and approved
Sitagliptin vs. Glimepiride in Elderly Patients
by the appropriate committees and authorities for each study site. The study was performed in accordance with the Declaration of Helsinki. 2.2 Study Design This was a multinational (patients screened at 85 sites), randomized, parallel-group, non-inferiority study with an active-controlled, double-blind treatment period (Sitagliptin Protocol 251; ClinicalTrials.gov NCT01189890 [21]; Fig. 1, Supplementary Material). Patients who were not receiving an AHA (for C12 weeks prior to Visit 1) with HbA1c C7.0 and B9.0 % directly entered a 2-week placebo run-in period. Patients who were receiving treatment with oral AHAs as either monotherapy or low-dose dualcombination therapy (i.e., B50 % of maximum dose of each agent) with HbA1c C6.5 and B8.5 % were to discontinue their AHA and enter a 2-week placebo run-in period after completing a 6-week AHA wash-off period. Patients with HbA1c C7.0 and B9.0 % at the beginning of the 2-week single-blind placebo run-in period were eligible to be randomized to treatment for 30 weeks with either sitagliptin or glimepiride if they satisfied all other entry criteria. Randomization of allocation numbers was performed using a computer-generated allocation schedule and implemented at the study sites using an Interactive Voice Response System (IVRS). The dose of sitagliptin was based upon the eGFR (patients with an eGFR
C50 mL/min/1.73 m2 received sitagliptin 100 mg once daily or matching placebo, and patients with an eGFR C35 and \50 mL/min/1.73 m2 received sitagliptin 50 mg once daily or matching placebo). Patients who initially received sitagliptin 100 mg once daily were to down-titrate their dose to 50 mg once daily if their eGFR was consistently \50 mL/min/1.73 m2 (and C30 mL/min/1.73 m2). Patients who initially received sitagliptin 50 mg once daily (as well as those for whom the dose was down-titrated from 100 to 50 mg once daily) were to be discontinued from the study if their eGFR was consistently\30 mL/min/1.73 m2. Glimepiride or matching placebo was started at a dose of 1 mg once daily and could be up-titrated to a maximum dose of 6 mg/day over the first 18 weeks, after which the dose was not to be increased for the remainder of the trial. The dose of glimepiride could be down-titrated throughout the trial to avoid or control hypoglycemia. Patients receiving C4 mg/day of glimepiride for at least 2 weeks who met protocol-specified hyperglycemic criteria were to be discontinued. 2.3 Study Endpoints The primary efficacy endpoint was the change from baseline in HbA1c after 30 weeks of treatment. After an overnight fast, blood was collected for the assessment of HbA1c at baseline and at various timepoints during the study. HbA1c was determined by high-performance liquid
Glycemic Discontinuation Criteria (Patients on at least 4 mg of glimepiride or glimepiride placebo for 2 weeks) After Week 3 through Week 6: FPG >270 mg/dL (14.99 mmol/L) After Week 6 through Week 12: FPG >240 mg/dL (13.33 mmol/L) After Week 12 through Week 30: FPG >200 mg/dL (11.11 mmol/L) Sitagliptin 100 mg q.d. or 50 mg q.d. • Patients not on oral AHAs at screening (for ≥12 weeks): A1C 7.0%-9.0% • Patients on oral AHA at screening: A1C 6.5%-8.5%
Screening/Wash-off
Visit 1 Screening
Visit 2 Week -8
R Glimepiride: starting dose 1 mg, up-titrate as needed up to maximum dose of 6 mg q.d. through Week 18
Single-blind Placebo run-in
Visit 3 Week -2
Visit 4 Day 1
Double-blind Treatment Period
Visit 5 Week 6
Visit 6 Week 12
Visit 7 Week 18
Visit 8 Week 24
Visit 9 Week 30
Phone F/U Week 32
Fig. 1 Study design. A1C glycated hemoglobin, AHA antihyperglycemic agent, FPG fasting plasma glucose, F/U follow-up, q.d. once daily, R randomization
P. Hartley et al.
chromatography (Tosoh A1c 2.2; Tosoh Medics, Foster City, CA, USA). A secondary efficacy endpoint was the change from baseline in fasting plasma glucose (FPG) after 30 weeks of treatment. Safety and tolerability of sitagliptin compared with glimepiride were evaluated throughout the study by a review of safety parameters, including adverse experiences (AEs), laboratory safety parameters, body weight, and vital signs. The primary safety endpoint was the incidence of AEs of symptomatic hypoglycemia, defined as an episode with clinical symptoms attributed to hypoglycemia, without regard to glucose level. Asymptomatic hypoglycemia, defined as episodes without symptoms of hypoglycemia, but with a glucose level B70 mg/dL, was also reported; these events could be reported as AEs of asymptomatic hypoglycemia at the discretion of the investigator. Two weeks after the final study visit, patients were contacted by telephone to assess for post-study serious AEs. All laboratory efficacy and safety measurements were performed at central laboratories (PPD, Highland Heights, KY, USA, and Brussels, Belgium; Covance, Princeton, NJ, USA). 2.4 Statistical Analyses Analysis of covariance (ANCOVA) was used to compare the treatment groups in terms of the mean change from baseline at week 30 for HbA1c and FPG. The model adjusted for the baseline value (HbA1c or FPG), eGFR (35 B eGFR C50 mL/min/1.73 m2), and age (\75, C75 years). The primary population was the Per-Protocol (PP) population, defined as all randomized patients who had a baseline measurement, a measurement at week 30, and no major protocol violations. A secondary population was the full analysis set (FAS), which included all randomized subjects who took at least one dose of study medication and had outcome measurements both at baseline and at least one post-baseline timepoint. The last-observation-carriedforward method was used for subjects with missing data at week 30. Non-inferiority of sitagliptin to glimepiride was to be declared if the upper boundary of the two-sided confidence interval for the difference in means (sitagliptin minus glimepiride) for HbA1c was less than the non-inferiority margin, d = 0.4 for the analysis in the PP population. The study was designed to have 93 % power to declare non-inferiority based on the expectation that the PP population would have 176 patients per group, and the assumption that the true, underlying difference (sitagliptin minus glimepiride) in HbA1c is 0.1 % and the standard deviation (SD) of the change from baseline in HbA1c is 0.8 %. Safety analyses included all randomized patients who received at least one dose of study medication. For the pre-
specified clinical AE of symptomatic hypoglycemia and for the mean change from baseline in body weight at week 30, inferential testing to compare sitagliptin to glimepiride was pre-specified. The between-treatment difference in the percentages of patients with AEs of symptomatic hypoglycemia was compared using the Miettinen and Nurminen method [22], stratified by eGFR and age. The change from baseline in body weight was analyzed using the same ANCOVA model described above based on all treated subjects with data at baseline and week 30.
3 Results 3.1 Patient Disposition and Characteristics Of the 480 randomized patients, 404 (84.2 %) completed the study and 76 (15.8 %) discontinued from the study (Fig. 2). The percentages of patients who completed and discontinued from the study were similar in both treatment groups. The reasons for discontinuation were generally similar between treatment groups, with a slightly higher percentage of patients in the sitagliptin treatment group who discontinued because of lack of efficacy, and slightly higher percentages of patients in the glimepiride treatment group who discontinued because of lost to follow-up or protocol violations. The treatment groups were wellbalanced for baseline demographics and efficacy variables (Table 1). In the overall population at baseline, the mean (±SD) age was 70.7 (4.9) years and body mass index was 29.7 (4.6) kg/m2; mean HbA1c (±SD) at baseline was 7.78 (0.69) %, reflective of mild-to-moderate hyperglycemia. 3.2 Efficacy In the PP population, the least squares (LS) mean HbA1c change from baseline at week 30 was -0.32 % in the sitagliptin treatment group and -0.51 % in the glimepiride treatment group, for a between-group difference (95 % CI) of 0.19 % (0.03–0.34). The upper limit of the two-sided 95 % CI for the between-group LS mean difference (0.34 %) was less than the pre-specified non-inferiority margin of 0.4 %, which met the criterion for declaring noninferiority of sitagliptin to glimepiride in lowering HbA1c. This result was supported by results in the secondary FAS population, for which the upper limit of the two-sided 95 % CI was 0.396 %. At week 30 in the PP population, the percentages of patients in the sitagliptin and glimepiride groups [between-group differences (95 % CI)], respectively, with HbA1c \7.5 % were 61.9 and 64.9 % [-3.0 (-12.6 to 6.6)], with HbA1c \7.0 % were 33.5 and 46.6 % [-12.8 (-22.3 to -3.1)], and with HbA1c \6.5 % were 9.1 and 20.9 % [-11.7 (-19.0 to -4.7)].
Sitagliptin vs. Glimepiride in Elderly Patients Fig. 2 Patient disposition
Screened (N=1140) Excluded (N=660)
Randomized (N=480) Sitagliptin (N=241)
Glimepiride (N=239)
Discontinued (N=37) Adverse Event (3) Lack of Efficacy (7) Lost to Follow-up (1) Protocol Violation (1) Withdrawal by Subject (15) Non-compliance (0) Physician Decision (5) Hyperglycemia Discontinuation Criteria (5)
Completed (N=204)
Table 1 Characteristics of the per-protocol patient population
Discontinued (N=39) Adverse Event (4) Lack of Efficacy (2) Lost to Follow-up (7) (5) Protocol Violation Withdrawal by Subject (11) Non-compliance (1) Physician Decision (4) Hyperglycemia Discontinuation Criteria (5)
Completed (N=200)
Characteristic
Sitagliptin (n = 197)
Glimepiride (n = 191)
Age (years) [mean (± SD)]
70.6 (4.8)
70.8 (4.9)
Sex [n (%)] Male
93 (47.2)
77 (40.3)
Female
104 (52.8)
114 (59.7)
White
121 (61.4)
103 (53.9)
Multi-racial
48 (24.4)
61 (31.9)
Native American/Alaska Native
18 (9.1)
15 (7.9)
Asian
5 (2.5)
12 (6.3)
African American
4 (2.0)
0 (0.0)
Native Hawaiian/Pacific Islander
1 (0.5)
0 (0.0)
76.9 (15.1)
75.3 (16.3)
Race [n (%)]
Body weight (kg) [mean (± SD)] Body mass index (kg/m2) [mean (±SD)]
29.7 (4.0)
29.7 (5.1)
Duration of diabetes mellitus (years) [mean (±SD)]
8.0 (5.6)
9.4 (7.3)
HbA1c (%) [mean (±SD)] Range
7.8 (0.7) 6.4–10.6
7.8 (0.7) 5.7–9.9
HbA1c distribution [n (%)] \8.0 %
131 (66.5)
125 (65.4)
C8.0 %
66 (33.5)
66 (34.6)
168.4 (31.0)
169.7 (35.5)
Fasting plasma glucose (mg/dL) [mean (±SD)] HbA1c glycated hemoglobin, SD standard deviation
The LS mean change in FPG from baseline in the PP population was -14.5 mg/dL with sitagliptin and -21.2 mg/dL with glimepiride, for a between-group difference (95 % CI) of 6.7 mg/dL (0.7–12.7). 3.3 Safety and Tolerability The mean duration of exposure to study medication was similar for the two treatment groups (193 days for
sitagliptin vs. 192 days for glimepiride). The mean dose of glimepiride following the titration period (i.e., after week 18) was 2.6 mg/day. The mean compliance rates for all randomized patients who took at least one dose of study medication were 98.3 % in the sitagliptin and 97 % in the glimepiride group. The incidences of overall clinical AEs and clinical AEs that were assessed as serious (i.e., life threatening, required hospitalization, or resulted in death) or leading to
P. Hartley et al.
discontinuation were similar between treatment groups (Table 2). No patients died or experienced any serious drug-related AEs. There were no cases of pancreatitis. Symptomatic hypoglycemia was reported for two patients (0.8 %; two total events) in the sitagliptin group and 11 patients (4.7 %; 33 total events) in the glimepiride group, for a between-group difference (95 % CI) of -3.9 % (-7.5 to -1.2) (p = 0.009); all events were reported as AEs, as specified in the protocol. One (0.4 %) patient (one event) in the sitagliptin group and three (1.3 %) patients (four events) in the glimepiride group experienced AEs of severe symptomatic hypoglycemia requiring non-medical assistance; no patient in either group experienced a hypoglycemic event that required medical assistance. Asymptomatic hypoglycemia was reported for 16 (6.6 %) patients (41 total events) in the sitagliptin group and 35 (14.8 %) patients (106 total events) in the glimepiride group; in these patients, one or more AEs of asymptomatic hypoglycemia were reported for one patient in the sitagliptin group and six patients in the glimepiride group. Overall, one or more AEs of hypoglycemia (symptomatic or asymptomatic) were reported for a total of 18 patients: three (1.2 %) in the sitagliptin group and 15 (6.4 %) in the glimepiride group, for a between-group difference (95 % CI) of -5.2 (-9.2 to -2.0) (Table 2). The LS mean change in body weight from baseline at week 30 was 0.4 kg with sitagliptin and 1.1 kg with Table 2 Safety results
glimepiride, for a between-group LS mean difference of -0.7 kg (p = 0.011).
4 Discussion In this multicenter, double-blind study, elderly patients with T2DM and inadequate glycemic control with diet and exercise were randomized to treatment with either sitagliptin or glimepiride for 30 weeks. The HbA1clowering efficacy of sitagliptin was non-inferior to that of glimepiride. The incidence of symptomatic hypoglycemia was significantly lower in the sitagliptin group than that in the glimepiride group. Sitagliptin was weight-neutral; while the between-group difference in change from baseline in body weight was statistically significant, the modest difference may not be clinically meaningful. Non-inferiority of the addition of sitagliptin compared with sulfonylureas in patients with T2DM and inadequate glycemic control on metformin has previously been established [23–25]. The present prospective study extends the demonstration of non-inferiority of sitagliptin compared with the sulfonylurea glimepiride when administered as monotherapy to elderly patients with T2DM and inadequate glycemic control with diet and exercise. The general consistency of the results from the prior and current studies enhances the robustness of the conclusion regarding
Result
Sitagliptin (n = 241)
Glimepiride (n = 236)
One or more clinical AEs
118 (49.0)
115 (48.7)
Drug-related clinical AEsa
9 (3.7)
9 (3.8)
Serious clinical AEs
7 (2.9)
6 (2.5)
Serious drug-related clinical AEs
0 (0.0)
0 (0.0)
Discontinued because of AEs
3 (1.2)
4 (1.7)
Discontinued because of drug-related AEs
1 (0.4)
0 (0.0)
Discontinued because of serious AEs
0 (0.0)
2 (0.8)
Discontinued because of serious, drug-related AEs
0 (0.0)
0 (0.0)
3 (1.2)
15 (6.4)
Hypoglycemia AEs Asymptomatic or symptomatic Symptomatic
b,c
2 (0.8)
11 (4.7)
Severed
1 (0.4)
3 (1.3)
Requiring non-medical assistance
1 (0.4)
3 (1.3)
Requiring medical assistance
0 (0.0)
0 (0.0)
Data displayed are the number (%) of patients with one or more occurrence of the respective endpoint AE adverse experience a
Determined by the investigator to be related to the drug
b
Episode with clinical symptoms attributed to hypoglycemia, without regard to glucose level
c
Between-treatment difference = -3.9 %, p = 0.009
d
Episode that required assistance, either medical or non-medical. Episodes with a markedly depressed level of consciousness, a loss of consciousness, or seizure were classified as having required medical assistance, whether or not medical assistance was obtained
Sitagliptin vs. Glimepiride in Elderly Patients
non-inferiority of the glycemic efficacy of sitagliptin versus sulfonylurea agents in elderly patients with T2DM and mild-to-moderate hyperglycemia. The titration schedule of glimepiride was intended to avoid excessive hypoglycemia, a concern with sulfonylurea agents [4, 10]. In this study, most patients were not uptitrated to the maximum allowed dose of glimepiride and remained at doses of 1 or 2 mg/day; this may have been a consequence of clinical inertia or because a majority of patients had a baseline HbA1c \8.0 %, which may have been considered to represent adequate glycemic control for this patient population. However, substantial reductions in HbA1c have been reported with even 1 mg/day of glimepiride [26]. Whereas a more aggressive up-titration of glimepiride may have translated to further increases in glycemic efficacy, it would also have been expected to produce a greater rate of hypoglycemia events, especially since patients in this group experienced five times as many AEs of hypoglycemia (symptomatic and asymptomatic) than observed with sitagliptin. Both sitagliptin and glimepiride were generally welltolerated. No patient experienced a serious drug-related AE or an AE resulting in death. No meaningful differences in overall AEs, serious AEs, drug-related AEs, or AEs leading to discontinuation were evident between treatment groups. The low incidence of AEs of symptomatic hypoglycemia observed in both groups compared to previous studies was unexpected. In prior studies that compared sitagliptin to the sulfonylurea glipizide or glimepiride in patients with T2DM and inadequate control on metformin monotherapy, the overall incidence of symptomatic hypoglycemia was higher in both treatment groups (4.9 vs. 32.0 % for sitagliptin vs. glipizide over 52 weeks [24] and 7.0 vs. 22.0 % for sitagliptin vs. glimepiride over 30 weeks [23]) than that observed in the present study, although in all studies, there was a significantly lower incidence in the sitagliptin group relative to the sulfonylurea group. It is possible that the incidence of symptomatic hypoglycemia in this study was underestimated due to an impaired awareness of hypoglycemia, which occurs in elderly patients with T2DM [7]. This is supported by the observation that asymptomatic hypoglycemia was reported by a higher proportion of patients relative to symptomatic hypoglycemia in both groups. Although it is possible that the lower incidence of symptomatic hypoglycemia may have resulted in a slightly higher mean dose of glimepiride at 18 weeks (2.6 mg) in this study relative to a comparable study (2.1 mg) [21], the present study was not designed to assess whether the occurrence of symptomatic hypoglycemia affected glimepiride titration. Changes from baseline in body weight also differed between the treatment groups. Glimepiride treatment resulted in a statistically significant increase in body weight,
relative to sitagliptin. Similar effects on body weight with sulfonylureas compared with sitagliptin have been previously documented [23], and studies of longer treatment duration (1 year) have shown weight gain in sulfonylureatreated patients and weight loss in patients treated with sitagliptin [17, 24]. The finding that sitagliptin provides similar overall glycemic control to glimepiride, but with a lower risk of hypoglycemia, is useful for the management of hyperglycemia in elderly patients with T2DM, as treatment options for this patient population are limited. Whereas glimepiride may have provided better FPG control, sitagliptin has been shown to have a significant effect on post-meal glucose levels in elderly patients [19]; thus, changes in FPG may not capture the full efficacy of sitagliptin versus glimepiride. Metformin, the most commonly used AHA in patients with T2DM, is to be used with caution in patients [80 years of age and is not recommended for use in patients with significant renal compromise [27], thiazolidinediones are not typically used in elderly patients because of the risk of heart failure [28], and the use of a-glucosidase inhibitors is limited by their gastrointestinal adverse effects. Thus, many elderly patients with T2DM are treated with sulfonylureas, despite the associated risk of hypoglycemia.
5 Conclusion Treatment with sitagliptin in elderly patients with T2DM and inadequate glycemic control with diet and exercise alone provided non-inferior glycemic control after 30 weeks of treatment compared with treatment with glimepiride. Both agents were generally well-tolerated, with a low rate of serious AEs, drug-related AEs, and discontinuations due to an AE. A significantly lower incidence of hypoglycemia was observed with sitagliptin than with glimepiride. Sitagliptin was weight-neutral; while the between-group difference in change from baseline in body weight was statistically significant, the modest difference may not be clinically meaningful. Acknowledgments The authors thank Kristen Lewis of Merck & Co., Inc., Kenilworth, NJ, USA for editorial assistance with preparation of this manuscript for publication. Funding Funding for this study was provided by Merck & Co., Inc., Kenilworth, NJ, USA. Disclosures Paul Hartley reports that his institution has received a research grant from Merck & Co., Inc. for the conduct of this study. Yue Shentu, Patricia Betz-Schiff, Gregory T. Golm, Christine McCrary Sisk, Samuel S. Engel, and R. Ravi Shankar are employed by Merck & Co., Inc., Kenilworth, NJ, USA and may hold stock or stock options in the company. All authors are responsible for the work described in this manuscript. All authors were involved in at least one
P. Hartley et al. of the following: conception, design, acquisition, analysis, statistical analysis, interpretation of data; and drafting the manuscript and/or revising it for important intellectual content. All authors provided final approval of the version to be published.
References 1. Selvin E, Coresh J, Brancati FL. The burden and treatment of diabetes in elderly individuals in the US. Diabetes Care. 2006;29(11):2415–9. 2. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–53. 3. Rosenstock J. Management of type 2 diabetes mellitus in the elderly: special considerations. Drugs Aging. 2001;18(1):31–44. 4. Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycaemia in type 2 diabetes. Diabet Med. 2008;25(3):245–54. 5. Matyka K, Evans M, Lomas J, Cranston I, Macdonald I, Amiel SA. Altered hierarchy of protective responses against severe hypoglycemia in normal aging in healthy men. Diabetes Care. 1997;20(2):135–41. 6. Mathieu C, Bollaerts K. Antihyperglycaemic therapy in elderly patients with type 2 diabetes: potential role of incretin mimetics and DPP-4 inhibitors. Int J Clin Pract Suppl. 2007;154:29–37. 7. 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(8):1513–7. 8. McNay EC. The impact of recurrent hypoglycemia on cognitive function in aging. Neurobiol Aging. 2005;26(Suppl 1):76–9. 9. Singh I, Marshall MC Jr. Diabetes mellitus in the elderly. Endocrinol Metab Clin North Am. 1995;24(2):255–72. 10. Bramlage P, Gitt AK, Binz C, Krekler M, Deeg E, Tschope D. Oral antidiabetic treatment in type-2 diabetes in the elderly: balancing the need for glucose control and the risk of hypoglycemia. Cardiovasc Diabetol. 2012;11:122. 11. Deusenberry CM, Coley KC, Korytkowski MT, Donihi AC. Hypoglycemia in hospitalized patients treated with sulfonylureas. Pharmacotherapy. 2012;32(7):613–7. 12. Meneilly GS, Cheung E, Tuokko H. Counterregulatory hormone responses to hypoglycemia in the elderly patient with diabetes. Diabetes. 1994;43(3):403–10. 13. Chelliah A, Burge MR. Hypoglycaemia in elderly patients with diabetes mellitus: causes and strategies for prevention. Drugs Aging. 2004;21(8):511–30. 14. Hsieh CJ, Shen FC. The durability of sitagliptin in elderly patients with type 2 diabetes. Clin Interv Aging. 2014;9:1905–11. 15. Herman GA, Stein PP, Thornberry NA, Wagner JA. Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: focus on sitagliptin. Clin Pharmacol Ther. 2007;81(5):761–7.
16. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696–705. 17. Arjona Ferreira JC, Marre M, Barzilai N, Guo H, Golm GT, Sisk CM, et al. Efficacy and safety of sitagliptin versus glipizide in patients with type 2 diabetes and moderate-to-severe chronic renal insufficiency. Diabetes Care. 2013;36(5):1067–73. 18. Arjona Ferreira JC, Corry D, Mogensen CE, Sloan L, Xu L, Golm GT, et al. Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis: a 54-week randomized trial. Am J Kidney Dis. 2013;61(4):579–87. 19. Barzilai N, Guo H, Mahoney EM, Caporossi S, Golm GT, Langdon RB, et al. Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Curr Med Res Opin. 2011;27(5):1049–58. 20. Shankar R Engel SS, Xu L, Golm GT, O’Neill E, Kaufman KD, Goldstein BJ. A comparison of glycemic effects of sitagliptin and sulfonylureas in elderly patients with type 2 diabetes mellitus. Int J Clin Pract. 2014 (in press). 21. Merck Sharp & Dohme Corp. Safety and efficacy of sitagliptin compared with glimepiride in elderly participants with type 2 diabetes mellitus (MK-0431-251) [Clinical Trials.gov identifier NCT01189890]. US National Institutes of Health, ClinicalTrials.gov. http://www.clinicaltrials.gov. Accessed 7 May 2015. 22. Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4(2):213–26. 23. Arechavaleta R, Seck T, Chen Y, Krobot KJ, O’Neill EA, Duran L, et al. Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2011;13(2):160–8. 24. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9(2):194–205. 25. Seck T, Nauck M, Sheng D, Sunga S, Davies MJ, Stein PP, et al. Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study. Int J Clin Pract. 2010;64(5):562–76. 26. Goldberg RB, Holvey SM, Schneider J. A dose-response study of glimepiride in patients with NIDDM who have previously received sulfonylurea agents. The Glimepiride Protocol #201 Study Group. Diabetes Care. 1996;19(8):849–56. 27. GLUCOPHAGEÒ [package insert]. http://packageinserts.bms. com/pi/pi_glucophage.pdf. Accessed 12 May 2015. 28. Holstein A, Stumvoll M. Contraindications can damage your health—is metformin a case in point? Diabetologia. 2005;48(12):2454–9.
ORIGINAL RESEARCH ARTICLE
Efficacy and Tolerability of Sitagliptin Compared with Glimepiride in Elderly Patients with Type 2 Diabetes Mellitus and Inadequate Glycemic Control: A Randomized, Double-Blind, Non-Inferiority Trial Paul Hartley1 • Yue Shentu2 • Patricia Betz-Schiff2 • Gregory T. Golm2 Christine McCrary Sisk2 • Samuel S. Engel2 • R. Ravi Shankar2
•
Ó Springer International Publishing Switzerland 2015
Abstract Objective The aim of this study was to evaluate the efficacy and tolerability of sitagliptin compared with glimepiride in elderly patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control with diet and exercise alone. Methods This was a randomized, parallel-group, multinational, non-inferiority clinical trial with an activecontrolled, double-blind treatment period in which patients C65 and B85 years of age with T2DM were screened at 85 sites. Patients were randomized to once-daily sitagliptin (100 or 50 mg, depending on renal function) or glimepiride (in titrated doses) for 30 weeks. The main outcome measures were change from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight; and the incidence of symptomatic hypoglycemia. Results The mean baseline HbA1c was 7.8 % in both the sitagliptin group (n = 197) and the glimepiride group (n = 191). After 30 weeks, the least squares (LS) mean change in HbA1c baseline was -0.32 % with sitagliptin and -0.51 % with glimepiride, for a between-group difference (95 % CI) of 0.19 % (0.03–0.34). This result met the pre-specified criterion for declaring non-inferiority, which required that the upper 95 % confidence limit lie below 0.4 %. The LS mean change in FPG from baseline was -14.5 mg/dL with sitagliptin and -21.2 mg/dL with Electronic supplementary material The online version of this article (doi:10.1007/s40266-015-0271-z) contains supplementary material, which is available to authorized users. & R. Ravi Shankar [email protected]
glimepiride, for a between-group difference (95 % CI) of 6.7 mg/dL (0.7–12.7). The percentages of patients with adverse events of symptomatic hypoglycemia were 0.8 % in the sitagliptin group and 4.7 % in the glimepiride group (between-treatment difference = -3.9 %, p = 0.009). The LS mean change in body weight from baseline was 0.4 kg with sitagliptin and 1.1 kg with glimepiride, for a betweengroup difference of -0.7 kg (p = 0.011). Conclusion In elderly patients with T2DM and inadequate glycemic control with diet and exercise alone, sitagliptin provided non-inferior glycemic control after 30 weeks of treatment compared with glimepiride. Compared with glimepiride, sitagliptin had a lower risk of hypoglycemia. Sitagliptin was weight-neutral; while the between-group difference in change from baseline in body weight was statistically significant, the modest difference may not be clinically meaningful. Study Identifier ClinicalTrials.gov NCT01189890. Key Points This randomized, double-blind, non-inferiority study compared the efficacy and tolerability of sitagliptin with glimepiride in elderly patients with type 2 diabetes mellitus and inadequate glycemic control with diet and exercise alone. Sitagliptin provided non-inferior glycemic control after 30 weeks of treatment compared with glimepiride.
1
Preferred Primary Care Physicians, Uniontown, PA, USA
The risk of symptomatic hypoglycemia was significantly lower with sitagliptin than with glimepiride.
2
Merck & Co., Inc., Kenilworth, NJ, USA
Sitagliptin was weight-neutral.
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1 Introduction Type 2 diabetes mellitus (T2DM) among the elderly (C65 years) is an important public health concern. Alterations in carbohydrate metabolism with advancing age increase the risk of developing T2DM. Data from the 2009–2012 National Health and Nutrition Examination Survey indicate that 25.9 % of US individuals C65 years of age have diagnosed or undiagnosed diabetes [1]. As life expectancy has increased, the global burden of T2DM among the elderly is projected to more than double from the year 2000 to 2030 [2]. Management of elderly patients with T2DM is a challenge due to the presence of co-morbidities and other factors [3]. In addition to a greater likelihood of impaired renal, cardiovascular, and cognitive function, elderly patients are particularly susceptible to hypoglycemia and its associated untoward effects (e.g., unsteadiness may result in falls and fractures) [4, 5]. Risk factors associated with hypoglycemia in elderly patients with T2DM include disability, poor nutrition, and polypharmacy [6]. In addition, elderly patients often lack the typical symptoms of hypoglycemia, and this reduced awareness places them at risk for under-treatment and resultant neuroglycopenic manifestations [7]. Hypoglycemia may exacerbate cognitive decline in the elderly [8, 9], which, in turn, may result in medication errors, improper glucose monitoring, and irregular/insufficient food intake, further confounding successful disease management. These factors highlight the importance of avoiding hypoglycemia to improve health outcomes, quality of life, and anti-diabetic medication adherence in elderly patients with T2DM. Sulfonylurea treatment is associated with an increased risk for hypoglycemia among elderly patients [4, 10]. A recent study demonstrated that elderly patients were at increased risk for sulfonylurea-related hypoglycemia during hospitalization compared with younger patients [11]. This finding may be related to the compromised counterregulatory hormone responses to hypoglycemia [12] and the decreased awareness of symptoms of hypoglycemia often seen in elderly patients [7]. In addition, some drugs may potentiate sulfonylurea activity and increase the risk of hypoglycemia by displacing sulfonylureas from plasma proteins, reducing hepatic metabolism of sulfonylureas, decreasing urinary excretion of sulfonylureas, or producing hypoglycemic action in addition to the effects of sulfonylureas [13]. Antihyperglycemic agents (AHAs) that provide similar efficacy as sulfonylureas with less hypoglycemia would be an important clinical advance for the management of elderly patients with T2DM. Sitagliptin is an oral AHA with characteristics that may provide particular benefits for the treatment of T2DM
among elderly patients [14]. Sitagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor that inhibits the enzymatic degradation and inactivation of the incretins, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) [15]. Through this mechanism of action, sitagliptin improves glycemic control, with a low risk of hypoglycemia [16]. Sitagliptin has been found to be effective and well-tolerated in patients with moderate/severe renal insufficiency, including end-stage renal disease [17, 18], which is of particular importance to the elderly in view of the decline in renal function with age. In a phase III, randomized, double-blind, placebocontrolled study, treatment with sitagliptin monotherapy produced rapid and sustained glucose lowering in elderly patients with T2DM, without associated hypoglycemia or increased body weight [19]. In a retrospective pooled analysis of data from three randomized, double-blind studies, sitagliptin provided similar glycemic improvement with less hypoglycemia compared with sulfonylurea in the subgroup of T2DM patients aged 65 years or older [20]. The present study prospectively assessed the efficacy and tolerability of sitagliptin compared with glimepiride in elderly patients with T2DM and inadequate glycemic control with diet and exercise alone.
2 Patients and Methods 2.1 Patient Selection Criteria Eligible patients were community-dwelling, C65 and B85 years of age, and had T2DM that was inadequately controlled with diet and exercise alone [glycated hemoglobin (HbA1c) C7.0 % and B9.0 %]. Patients who had been previously treated with a DPP-4 inhibitor, or had been treated with insulin or GLP-1 mimetics (e.g., liraglutide, exenatide) within 8 weeks prior to screening, or peroxisome proliferator-activated receptor (PPAR)-c agonists within 16 weeks prior to screening, were excluded. Patients with type 1 diabetes, active liver disease, recent history of cardiovascular disease (acute coronary syndrome, coronary artery intervention, New York Heart Association Class III/ IV heart failure, stroke, transient ischemic neurologic event, or new/worsening symptoms of coronary heart disease), inadequately controlled hypertension, severe peripheral vascular disease, triglycerides [600 mg/dL, history of infection with HIV, history of malignancy or clinically important hematologic disorder, or an estimated glomerular filtration rate (eGFR; calculated using the Modification of Diet in Renal Disease formula) \35 mL/ min/1.73 m2 were also excluded. All patients provided written informed consent to participate, and the study protocol was reviewed and approved
Sitagliptin vs. Glimepiride in Elderly Patients
by the appropriate committees and authorities for each study site. The study was performed in accordance with the Declaration of Helsinki. 2.2 Study Design This was a multinational (patients screened at 85 sites), randomized, parallel-group, non-inferiority study with an active-controlled, double-blind treatment period (Sitagliptin Protocol 251; ClinicalTrials.gov NCT01189890 [21]; Fig. 1, Supplementary Material). Patients who were not receiving an AHA (for C12 weeks prior to Visit 1) with HbA1c C7.0 and B9.0 % directly entered a 2-week placebo run-in period. Patients who were receiving treatment with oral AHAs as either monotherapy or low-dose dualcombination therapy (i.e., B50 % of maximum dose of each agent) with HbA1c C6.5 and B8.5 % were to discontinue their AHA and enter a 2-week placebo run-in period after completing a 6-week AHA wash-off period. Patients with HbA1c C7.0 and B9.0 % at the beginning of the 2-week single-blind placebo run-in period were eligible to be randomized to treatment for 30 weeks with either sitagliptin or glimepiride if they satisfied all other entry criteria. Randomization of allocation numbers was performed using a computer-generated allocation schedule and implemented at the study sites using an Interactive Voice Response System (IVRS). The dose of sitagliptin was based upon the eGFR (patients with an eGFR
C50 mL/min/1.73 m2 received sitagliptin 100 mg once daily or matching placebo, and patients with an eGFR C35 and \50 mL/min/1.73 m2 received sitagliptin 50 mg once daily or matching placebo). Patients who initially received sitagliptin 100 mg once daily were to down-titrate their dose to 50 mg once daily if their eGFR was consistently \50 mL/min/1.73 m2 (and C30 mL/min/1.73 m2). Patients who initially received sitagliptin 50 mg once daily (as well as those for whom the dose was down-titrated from 100 to 50 mg once daily) were to be discontinued from the study if their eGFR was consistently\30 mL/min/1.73 m2. Glimepiride or matching placebo was started at a dose of 1 mg once daily and could be up-titrated to a maximum dose of 6 mg/day over the first 18 weeks, after which the dose was not to be increased for the remainder of the trial. The dose of glimepiride could be down-titrated throughout the trial to avoid or control hypoglycemia. Patients receiving C4 mg/day of glimepiride for at least 2 weeks who met protocol-specified hyperglycemic criteria were to be discontinued. 2.3 Study Endpoints The primary efficacy endpoint was the change from baseline in HbA1c after 30 weeks of treatment. After an overnight fast, blood was collected for the assessment of HbA1c at baseline and at various timepoints during the study. HbA1c was determined by high-performance liquid
Glycemic Discontinuation Criteria (Patients on at least 4 mg of glimepiride or glimepiride placebo for 2 weeks) After Week 3 through Week 6: FPG >270 mg/dL (14.99 mmol/L) After Week 6 through Week 12: FPG >240 mg/dL (13.33 mmol/L) After Week 12 through Week 30: FPG >200 mg/dL (11.11 mmol/L) Sitagliptin 100 mg q.d. or 50 mg q.d. • Patients not on oral AHAs at screening (for ≥12 weeks): A1C 7.0%-9.0% • Patients on oral AHA at screening: A1C 6.5%-8.5%
Screening/Wash-off
Visit 1 Screening
Visit 2 Week -8
R Glimepiride: starting dose 1 mg, up-titrate as needed up to maximum dose of 6 mg q.d. through Week 18
Single-blind Placebo run-in
Visit 3 Week -2
Visit 4 Day 1
Double-blind Treatment Period
Visit 5 Week 6
Visit 6 Week 12
Visit 7 Week 18
Visit 8 Week 24
Visit 9 Week 30
Phone F/U Week 32
Fig. 1 Study design. A1C glycated hemoglobin, AHA antihyperglycemic agent, FPG fasting plasma glucose, F/U follow-up, q.d. once daily, R randomization
P. Hartley et al.
chromatography (Tosoh A1c 2.2; Tosoh Medics, Foster City, CA, USA). A secondary efficacy endpoint was the change from baseline in fasting plasma glucose (FPG) after 30 weeks of treatment. Safety and tolerability of sitagliptin compared with glimepiride were evaluated throughout the study by a review of safety parameters, including adverse experiences (AEs), laboratory safety parameters, body weight, and vital signs. The primary safety endpoint was the incidence of AEs of symptomatic hypoglycemia, defined as an episode with clinical symptoms attributed to hypoglycemia, without regard to glucose level. Asymptomatic hypoglycemia, defined as episodes without symptoms of hypoglycemia, but with a glucose level B70 mg/dL, was also reported; these events could be reported as AEs of asymptomatic hypoglycemia at the discretion of the investigator. Two weeks after the final study visit, patients were contacted by telephone to assess for post-study serious AEs. All laboratory efficacy and safety measurements were performed at central laboratories (PPD, Highland Heights, KY, USA, and Brussels, Belgium; Covance, Princeton, NJ, USA). 2.4 Statistical Analyses Analysis of covariance (ANCOVA) was used to compare the treatment groups in terms of the mean change from baseline at week 30 for HbA1c and FPG. The model adjusted for the baseline value (HbA1c or FPG), eGFR (35 B eGFR C50 mL/min/1.73 m2), and age (\75, C75 years). The primary population was the Per-Protocol (PP) population, defined as all randomized patients who had a baseline measurement, a measurement at week 30, and no major protocol violations. A secondary population was the full analysis set (FAS), which included all randomized subjects who took at least one dose of study medication and had outcome measurements both at baseline and at least one post-baseline timepoint. The last-observation-carriedforward method was used for subjects with missing data at week 30. Non-inferiority of sitagliptin to glimepiride was to be declared if the upper boundary of the two-sided confidence interval for the difference in means (sitagliptin minus glimepiride) for HbA1c was less than the non-inferiority margin, d = 0.4 for the analysis in the PP population. The study was designed to have 93 % power to declare non-inferiority based on the expectation that the PP population would have 176 patients per group, and the assumption that the true, underlying difference (sitagliptin minus glimepiride) in HbA1c is 0.1 % and the standard deviation (SD) of the change from baseline in HbA1c is 0.8 %. Safety analyses included all randomized patients who received at least one dose of study medication. For the pre-
specified clinical AE of symptomatic hypoglycemia and for the mean change from baseline in body weight at week 30, inferential testing to compare sitagliptin to glimepiride was pre-specified. The between-treatment difference in the percentages of patients with AEs of symptomatic hypoglycemia was compared using the Miettinen and Nurminen method [22], stratified by eGFR and age. The change from baseline in body weight was analyzed using the same ANCOVA model described above based on all treated subjects with data at baseline and week 30.
3 Results 3.1 Patient Disposition and Characteristics Of the 480 randomized patients, 404 (84.2 %) completed the study and 76 (15.8 %) discontinued from the study (Fig. 2). The percentages of patients who completed and discontinued from the study were similar in both treatment groups. The reasons for discontinuation were generally similar between treatment groups, with a slightly higher percentage of patients in the sitagliptin treatment group who discontinued because of lack of efficacy, and slightly higher percentages of patients in the glimepiride treatment group who discontinued because of lost to follow-up or protocol violations. The treatment groups were wellbalanced for baseline demographics and efficacy variables (Table 1). In the overall population at baseline, the mean (±SD) age was 70.7 (4.9) years and body mass index was 29.7 (4.6) kg/m2; mean HbA1c (±SD) at baseline was 7.78 (0.69) %, reflective of mild-to-moderate hyperglycemia. 3.2 Efficacy In the PP population, the least squares (LS) mean HbA1c change from baseline at week 30 was -0.32 % in the sitagliptin treatment group and -0.51 % in the glimepiride treatment group, for a between-group difference (95 % CI) of 0.19 % (0.03–0.34). The upper limit of the two-sided 95 % CI for the between-group LS mean difference (0.34 %) was less than the pre-specified non-inferiority margin of 0.4 %, which met the criterion for declaring noninferiority of sitagliptin to glimepiride in lowering HbA1c. This result was supported by results in the secondary FAS population, for which the upper limit of the two-sided 95 % CI was 0.396 %. At week 30 in the PP population, the percentages of patients in the sitagliptin and glimepiride groups [between-group differences (95 % CI)], respectively, with HbA1c \7.5 % were 61.9 and 64.9 % [-3.0 (-12.6 to 6.6)], with HbA1c \7.0 % were 33.5 and 46.6 % [-12.8 (-22.3 to -3.1)], and with HbA1c \6.5 % were 9.1 and 20.9 % [-11.7 (-19.0 to -4.7)].
Sitagliptin vs. Glimepiride in Elderly Patients Fig. 2 Patient disposition
Screened (N=1140) Excluded (N=660)
Randomized (N=480) Sitagliptin (N=241)
Glimepiride (N=239)
Discontinued (N=37) Adverse Event (3) Lack of Efficacy (7) Lost to Follow-up (1) Protocol Violation (1) Withdrawal by Subject (15) Non-compliance (0) Physician Decision (5) Hyperglycemia Discontinuation Criteria (5)
Completed (N=204)
Table 1 Characteristics of the per-protocol patient population
Discontinued (N=39) Adverse Event (4) Lack of Efficacy (2) Lost to Follow-up (7) (5) Protocol Violation Withdrawal by Subject (11) Non-compliance (1) Physician Decision (4) Hyperglycemia Discontinuation Criteria (5)
Completed (N=200)
Characteristic
Sitagliptin (n = 197)
Glimepiride (n = 191)
Age (years) [mean (± SD)]
70.6 (4.8)
70.8 (4.9)
Sex [n (%)] Male
93 (47.2)
77 (40.3)
Female
104 (52.8)
114 (59.7)
White
121 (61.4)
103 (53.9)
Multi-racial
48 (24.4)
61 (31.9)
Native American/Alaska Native
18 (9.1)
15 (7.9)
Asian
5 (2.5)
12 (6.3)
African American
4 (2.0)
0 (0.0)
Native Hawaiian/Pacific Islander
1 (0.5)
0 (0.0)
76.9 (15.1)
75.3 (16.3)
Race [n (%)]
Body weight (kg) [mean (± SD)] Body mass index (kg/m2) [mean (±SD)]
29.7 (4.0)
29.7 (5.1)
Duration of diabetes mellitus (years) [mean (±SD)]
8.0 (5.6)
9.4 (7.3)
HbA1c (%) [mean (±SD)] Range
7.8 (0.7) 6.4–10.6
7.8 (0.7) 5.7–9.9
HbA1c distribution [n (%)] \8.0 %
131 (66.5)
125 (65.4)
C8.0 %
66 (33.5)
66 (34.6)
168.4 (31.0)
169.7 (35.5)
Fasting plasma glucose (mg/dL) [mean (±SD)] HbA1c glycated hemoglobin, SD standard deviation
The LS mean change in FPG from baseline in the PP population was -14.5 mg/dL with sitagliptin and -21.2 mg/dL with glimepiride, for a between-group difference (95 % CI) of 6.7 mg/dL (0.7–12.7). 3.3 Safety and Tolerability The mean duration of exposure to study medication was similar for the two treatment groups (193 days for
sitagliptin vs. 192 days for glimepiride). The mean dose of glimepiride following the titration period (i.e., after week 18) was 2.6 mg/day. The mean compliance rates for all randomized patients who took at least one dose of study medication were 98.3 % in the sitagliptin and 97 % in the glimepiride group. The incidences of overall clinical AEs and clinical AEs that were assessed as serious (i.e., life threatening, required hospitalization, or resulted in death) or leading to
P. Hartley et al.
discontinuation were similar between treatment groups (Table 2). No patients died or experienced any serious drug-related AEs. There were no cases of pancreatitis. Symptomatic hypoglycemia was reported for two patients (0.8 %; two total events) in the sitagliptin group and 11 patients (4.7 %; 33 total events) in the glimepiride group, for a between-group difference (95 % CI) of -3.9 % (-7.5 to -1.2) (p = 0.009); all events were reported as AEs, as specified in the protocol. One (0.4 %) patient (one event) in the sitagliptin group and three (1.3 %) patients (four events) in the glimepiride group experienced AEs of severe symptomatic hypoglycemia requiring non-medical assistance; no patient in either group experienced a hypoglycemic event that required medical assistance. Asymptomatic hypoglycemia was reported for 16 (6.6 %) patients (41 total events) in the sitagliptin group and 35 (14.8 %) patients (106 total events) in the glimepiride group; in these patients, one or more AEs of asymptomatic hypoglycemia were reported for one patient in the sitagliptin group and six patients in the glimepiride group. Overall, one or more AEs of hypoglycemia (symptomatic or asymptomatic) were reported for a total of 18 patients: three (1.2 %) in the sitagliptin group and 15 (6.4 %) in the glimepiride group, for a between-group difference (95 % CI) of -5.2 (-9.2 to -2.0) (Table 2). The LS mean change in body weight from baseline at week 30 was 0.4 kg with sitagliptin and 1.1 kg with Table 2 Safety results
glimepiride, for a between-group LS mean difference of -0.7 kg (p = 0.011).
4 Discussion In this multicenter, double-blind study, elderly patients with T2DM and inadequate glycemic control with diet and exercise were randomized to treatment with either sitagliptin or glimepiride for 30 weeks. The HbA1clowering efficacy of sitagliptin was non-inferior to that of glimepiride. The incidence of symptomatic hypoglycemia was significantly lower in the sitagliptin group than that in the glimepiride group. Sitagliptin was weight-neutral; while the between-group difference in change from baseline in body weight was statistically significant, the modest difference may not be clinically meaningful. Non-inferiority of the addition of sitagliptin compared with sulfonylureas in patients with T2DM and inadequate glycemic control on metformin has previously been established [23–25]. The present prospective study extends the demonstration of non-inferiority of sitagliptin compared with the sulfonylurea glimepiride when administered as monotherapy to elderly patients with T2DM and inadequate glycemic control with diet and exercise. The general consistency of the results from the prior and current studies enhances the robustness of the conclusion regarding
Result
Sitagliptin (n = 241)
Glimepiride (n = 236)
One or more clinical AEs
118 (49.0)
115 (48.7)
Drug-related clinical AEsa
9 (3.7)
9 (3.8)
Serious clinical AEs
7 (2.9)
6 (2.5)
Serious drug-related clinical AEs
0 (0.0)
0 (0.0)
Discontinued because of AEs
3 (1.2)
4 (1.7)
Discontinued because of drug-related AEs
1 (0.4)
0 (0.0)
Discontinued because of serious AEs
0 (0.0)
2 (0.8)
Discontinued because of serious, drug-related AEs
0 (0.0)
0 (0.0)
3 (1.2)
15 (6.4)
Hypoglycemia AEs Asymptomatic or symptomatic Symptomatic
b,c
2 (0.8)
11 (4.7)
Severed
1 (0.4)
3 (1.3)
Requiring non-medical assistance
1 (0.4)
3 (1.3)
Requiring medical assistance
0 (0.0)
0 (0.0)
Data displayed are the number (%) of patients with one or more occurrence of the respective endpoint AE adverse experience a
Determined by the investigator to be related to the drug
b
Episode with clinical symptoms attributed to hypoglycemia, without regard to glucose level
c
Between-treatment difference = -3.9 %, p = 0.009
d
Episode that required assistance, either medical or non-medical. Episodes with a markedly depressed level of consciousness, a loss of consciousness, or seizure were classified as having required medical assistance, whether or not medical assistance was obtained
Sitagliptin vs. Glimepiride in Elderly Patients
non-inferiority of the glycemic efficacy of sitagliptin versus sulfonylurea agents in elderly patients with T2DM and mild-to-moderate hyperglycemia. The titration schedule of glimepiride was intended to avoid excessive hypoglycemia, a concern with sulfonylurea agents [4, 10]. In this study, most patients were not uptitrated to the maximum allowed dose of glimepiride and remained at doses of 1 or 2 mg/day; this may have been a consequence of clinical inertia or because a majority of patients had a baseline HbA1c \8.0 %, which may have been considered to represent adequate glycemic control for this patient population. However, substantial reductions in HbA1c have been reported with even 1 mg/day of glimepiride [26]. Whereas a more aggressive up-titration of glimepiride may have translated to further increases in glycemic efficacy, it would also have been expected to produce a greater rate of hypoglycemia events, especially since patients in this group experienced five times as many AEs of hypoglycemia (symptomatic and asymptomatic) than observed with sitagliptin. Both sitagliptin and glimepiride were generally welltolerated. No patient experienced a serious drug-related AE or an AE resulting in death. No meaningful differences in overall AEs, serious AEs, drug-related AEs, or AEs leading to discontinuation were evident between treatment groups. The low incidence of AEs of symptomatic hypoglycemia observed in both groups compared to previous studies was unexpected. In prior studies that compared sitagliptin to the sulfonylurea glipizide or glimepiride in patients with T2DM and inadequate control on metformin monotherapy, the overall incidence of symptomatic hypoglycemia was higher in both treatment groups (4.9 vs. 32.0 % for sitagliptin vs. glipizide over 52 weeks [24] and 7.0 vs. 22.0 % for sitagliptin vs. glimepiride over 30 weeks [23]) than that observed in the present study, although in all studies, there was a significantly lower incidence in the sitagliptin group relative to the sulfonylurea group. It is possible that the incidence of symptomatic hypoglycemia in this study was underestimated due to an impaired awareness of hypoglycemia, which occurs in elderly patients with T2DM [7]. This is supported by the observation that asymptomatic hypoglycemia was reported by a higher proportion of patients relative to symptomatic hypoglycemia in both groups. Although it is possible that the lower incidence of symptomatic hypoglycemia may have resulted in a slightly higher mean dose of glimepiride at 18 weeks (2.6 mg) in this study relative to a comparable study (2.1 mg) [21], the present study was not designed to assess whether the occurrence of symptomatic hypoglycemia affected glimepiride titration. Changes from baseline in body weight also differed between the treatment groups. Glimepiride treatment resulted in a statistically significant increase in body weight,
relative to sitagliptin. Similar effects on body weight with sulfonylureas compared with sitagliptin have been previously documented [23], and studies of longer treatment duration (1 year) have shown weight gain in sulfonylureatreated patients and weight loss in patients treated with sitagliptin [17, 24]. The finding that sitagliptin provides similar overall glycemic control to glimepiride, but with a lower risk of hypoglycemia, is useful for the management of hyperglycemia in elderly patients with T2DM, as treatment options for this patient population are limited. Whereas glimepiride may have provided better FPG control, sitagliptin has been shown to have a significant effect on post-meal glucose levels in elderly patients [19]; thus, changes in FPG may not capture the full efficacy of sitagliptin versus glimepiride. Metformin, the most commonly used AHA in patients with T2DM, is to be used with caution in patients [80 years of age and is not recommended for use in patients with significant renal compromise [27], thiazolidinediones are not typically used in elderly patients because of the risk of heart failure [28], and the use of a-glucosidase inhibitors is limited by their gastrointestinal adverse effects. Thus, many elderly patients with T2DM are treated with sulfonylureas, despite the associated risk of hypoglycemia.
5 Conclusion Treatment with sitagliptin in elderly patients with T2DM and inadequate glycemic control with diet and exercise alone provided non-inferior glycemic control after 30 weeks of treatment compared with treatment with glimepiride. Both agents were generally well-tolerated, with a low rate of serious AEs, drug-related AEs, and discontinuations due to an AE. A significantly lower incidence of hypoglycemia was observed with sitagliptin than with glimepiride. Sitagliptin was weight-neutral; while the between-group difference in change from baseline in body weight was statistically significant, the modest difference may not be clinically meaningful. Acknowledgments The authors thank Kristen Lewis of Merck & Co., Inc., Kenilworth, NJ, USA for editorial assistance with preparation of this manuscript for publication. Funding Funding for this study was provided by Merck & Co., Inc., Kenilworth, NJ, USA. Disclosures Paul Hartley reports that his institution has received a research grant from Merck & Co., Inc. for the conduct of this study. Yue Shentu, Patricia Betz-Schiff, Gregory T. Golm, Christine McCrary Sisk, Samuel S. Engel, and R. Ravi Shankar are employed by Merck & Co., Inc., Kenilworth, NJ, USA and may hold stock or stock options in the company. All authors are responsible for the work described in this manuscript. All authors were involved in at least one
P. Hartley et al. of the following: conception, design, acquisition, analysis, statistical analysis, interpretation of data; and drafting the manuscript and/or revising it for important intellectual content. All authors provided final approval of the version to be published.
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