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Saxagliptin efficacy and safety in patients with type 2 diabetes receiving concomitant statin therapy
Journal of Diabetes and Its Complications 28 (2014) 887–893
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Saxagliptin efficacy and safety in patients with type 2 diabetes receiving concomitant statin therapy Brian Bryzinski a,⁎, Elsie Allen b, 1, William Cook a, Boaz Hirshberg a a b
AstraZeneca, Wilmington, DE, USA Novo Nordisk, New York, NY, USA
a r t i c l e
i n f o
Article history: Received 1 April 2014 Received in revised form 27 June 2014 Accepted 10 July 2014 Available online 17 July 2014 Keywords: Cardiovascular disease Dipeptidyl peptidase-4 inhibitor Dyslipidemia Incretin Statin
a b s t r a c t Aims: To examine whether concomitant statin therapy affects glycemic control with saxagliptin 2.5 and 5 mg/d in patients with type 2 diabetes mellitus (T2DM). Methods: Efficacy and safety were analyzed post hoc for pooled data from 9 saxagliptin randomized, placebocontrolled trials with a primary 24-week treatment period (4 monotherapy, 2 add-on to metformin, 1 each add-on to a sulfonylurea, thiazolidinedione, or insulin ± metformin). Safety was also assessed in an 11-study, 24-week pool and an extended 20-study pool, which included 9 additional 4- to 52-week randomized studies. Comparisons were performed for patient groups defined by baseline statin use. Results: Saxagliptin produced greater mean reductions in glycated hemoglobin than placebo, with no interaction between treatment and baseline statin use (P = 0.47). In patients receiving saxagliptin 2.5 and 5 mg and placebo, the proportion of patients with ≥1 adverse event (AE) was 78.1%, 64.0%, and 63.2%, respectively, in patients with any statin use and 70.6%, 57.9%, and 55.0% in patients with no statin use. Serious AEs, deaths, and symptomatic confirmed hypoglycemia (fingerstick glucose ≤ 50 mg/dL) were few and similar, irrespective of baseline statin use. Conclusions: Saxagliptin improves glycemic control and is generally well tolerated in patients with T2DM, irrespective of concomitant statin therapy. © 2014 Elsevier Inc. All rights reserved.
1. Introduction The risk of cardiovascular (CV) mortality is 3-fold higher in patients with type 2 diabetes mellitus (T2DM), compared with those without diabetes (Taylor et al., 2013). Low-density lipoprotein cholesterol (LDL-C) is considered the most important modifiable risk factor for CV disease (CVD) in patients with diabetes (Matikainen & Taskinen, 2012). Lifestyle modification and statin therapy are the cornerstones of lipid management in patients with diabetes (American Diabetes Association, 2013). Statin therapy has been demonstrated to significantly reduce CV and all-cause mortality in patients with diabetes, including those with no
Conflict of Interest: Dr. Bryzinski, Dr. Cook, and Dr. Hirshberg are employees of AstraZeneca. Dr Allen was an employee of Bristol-Myers Squibb at the time of the study. Funding statement: Bristol-Myers Squibb and AstraZeneca funded this study. Medical writing support for the preparation of this manuscript was provided by Nicole Strangman, PhD, and Janet Matsuura, PhD, from Complete Healthcare Communications, with funding from Bristol-Myers Squibb and AstraZeneca. Data were presented at the American Diabetes Association 73rd Scientific Sessions; June 21–25, 2013; Chicago, IL. ⁎ Corresponding author at: AstraZeneca, 1800 Concord Pike, Wilmington, DE 19850. Tel.: +1 302 885 1873; fax: +1 302 885 7603. E-mail address: [email protected] (B. Bryzinski). 1 Employed by Bristol-Myers Squibb, Princeton, NJ at the time of the study. http://dx.doi.org/10.1016/j.jdiacomp.2014.07.006 1056-8727/© 2014 Elsevier Inc. All rights reserved.
history of vascular disease (Kearney et al., 2008). The American Diabetes Association (ADA) recommends statin therapy regardless of baseline lipid levels in patients with overt CVD and in patients N40 years of age with ≥ 1 other CVD risk factor (American Diabetes Association, 2013). The ADA also recommends that statin therapy be considered in patients ≤ 40 years of age with multiple CVD risk factors and in lower-risk patients if LDL-C remains N100 mg/dL. However, questions have emerged about the possible impact of statin therapy on glycemic control (Banach et al., 2013; Katsiki & Banach, 2012). Clinical trials (Culver et al., 2012; Ridker, Pradhan, MacFadyen, Libby, & Glynn, 2012; Ridker et al., 2008), observational studies (Carter et al., 2013; Danaei, Garcia Rodriguez, Fernandez Cantero, & Hernan, 2013), and meta-analyses (Preiss et al., 2011; Sattar et al., 2010) have reported an increased risk for development of diabetes with statin treatment in some patients. In addition, several studies have demonstrated deterioration of glycemic control after initiation of statin therapy in patients with T2DM (Bellia et al., 2012; Simsek, Schalkwijk, & Wolffenbuttel, 2012). Saxagliptin is a dipeptidyl peptidase-4 DPP-4 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM (2012). Saxagliptin is weight neutral and has a low rate of hypoglycemia when used as monotherapy (Barnett, 2006). In 24-week controlled clinical trials, saxagliptin was generally well
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tolerated and effective in improving glycemic control as monotherapy (Frederich, McNeill, Berglind, Fleming, & Chen, 2012; Rosenstock et al., 2009) and as add-on therapy to other antidiabetic medications (Barnett, Charbonnel, Donovan, & Fleming, 2012; Chacra et al., 2009; DeFronzo et al., 2009; Hollander, Li, Allen, Chen, & CV181-013 Investigators, 2009). It is not known whether glycemic control with saxagliptin is affected by concomitant statin therapy. To address this question, we conducted post hoc analyses of pooled data from 9 randomized, placebo-controlled trials with saxagliptin 2.5 and 5 mg/d. In addition, we assessed safety of concomitant statin use with saxagliptin in an 11study pool and an extended 20-study pool. Efficacy and safety were compared for patients with and without concomitant statin therapy at baseline (Bryzinski, Allen, Cook, & Hirshberg, 2013). 2. Methods 2.1. Study design This was a post hoc analysis conducted using pooled data from the randomized controlled trials listed in Supplementary Table S1. Study methodology and primary efficacy and safety findings were previously reported for all but 1 of these trials. Efficacy analyses were performed using pooled data for patients treated with saxagliptin 2.5 or 5 mg/d or control in 9 phase 3, randomized studies with a primary 24-week treatment period, including 4 studies of saxagliptin as monotherapy (ClinicalTrials.gov identifier: (NCT00121641 (Rosenstock et al., 2009, 2013), NCT00316082 (Frederich et al., 2012), NCT00698932 (Pan, Yang, Tou, Gause-Nilsson, & Zhao, 2012), and NCT00918879 (Prasanna Kumar, Jain, Tou, & Schutzer, 2014)), 2 studies of saxagliptin as add-on to metformin (NCT00121667 (DeFronzo et al., 2009; Rosentock et al., 2013) and NCT00661362 (Yang, Pan, Tou, Zhao, & Gause-Nilsson, 2011)), and 1 study each of saxagliptin as add-on to a sulfonylurea (NCT00313313 (Chacra et al., 2009; Doucet et al., 2011)), thiazolidinedione (NCT00295633 (Hollander et al., 2009, 2011)), and insulin with and without metformin (NCT00757588 (Barnett et al., 2012)). Safety analyses were performed in an 11-study, 24-week pool and an extended 20-study pool. The 11-study, 24-week safety pool included data for saxagliptin 2.5 and 5 mg/d and control from the 9 studies in the efficacy pool plus two 24-week randomized,
controlled studies of saxagliptin as add-on therapy to metformin (NCT01006590 (Hermans et al., 2012) and NCT00327015 (Jadzinsky et al., 2009; Pfützner et al., 2011) [only the saxagliptin plus metformin and metformin plus placebo arms were included in the analyses]). The 20-study pool included data for all saxagliptin doses (2.5, 5, 10, 20, 40, and 100 mg/d) and control from the 11 studies in the 24-week safety pool (24-week and controlled long-term extension data ranging from 28 weeks to 42 months) as well as nine 4- to 52-week randomized studies of saxagliptin as monotherapy (NCT00614939 (Nowicki et al., 2011a, 2011b), NCT00950599 (Rosenstock, Sankoh, & List, 2008), NCT00374907 (Henry et al., 2011)) or as add-on to metformin (NCT00575588 (Göke, Gallwitz, Eriksson, Hellqvist, & Gause-Nilsson, 2010, 2013), NCT00666458 (Scheen, Charpentier, Ostgren, Hellqvist, & Gause-Nilsson, 2010), NCT00683657 (Stenlof et al., 2010), NCT00885378 (White, Buchanan, Li, & Frederich, 2014) NCT00918138 (Neutel, Zhao, & Karyekar, 2013), NCT00960076 (Fonseca, Zhu, Karyekar, & Hirshberg, 2012)). Study protocols were approved by an institutional review board/ independent ethics committee and conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation. All patients provided written informed consent. 2.2. Study end points Efficacy end points were change from baseline at week 24 in glycated hemoglobin (HbA1c), 120-minute postprandial glucose (PPG), and fasting plasma glucose (FPG) and the proportion of patients achieving a therapeutic glycemic response (HbA1c b7%) at week 24. Safety and tolerability assessments included adverse events (AEs), all reported hypoglycemia, confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL with associated symptoms), myopathy (standardized Medical Dictionary for Regulatory Activities [version 15.0] query: rhabdomyolysis/myopathy; 45 preferred terms), and creatinine kinase (CK) elevation. 2.3. Statistical analyses Efficacy was analyzed in all randomized patients who received ≥1 dose of study medication and had nonmissing values at baseline and week 24 (last observation carried forward, excluding post-rescue assessments). Changes from baseline HbA1c, FPG, and PPG levels at week 24 were analyzed in the pooled patient populations using
Table 1 Demographic and baseline clinical characteristics in the 24-week safety pool. Characteristic⁎
Age, y Men, n (%) Race, n (%) White Asian Black Other BMI, kg/m2 b30, n (%) ≥30, n (%) Duration of T2DM, y HbA1c, % FPG, mg/dL 120-min PPG, mg/dL Fasting insulin, μU/mL
Any statin use
No statin use
SAXA 2.5 mg/d n = 192
SAXA 5 mg/d n = 436
Control n = 418
SAXA 2.5 mg/d n = 690
SAXA 5 mg/d n = 1891
Control n = 1676
58 (8.3) 108 (56.3)
58 (9.3) 219 (50.2)
58 (9.4) 227 (54.3)
54 (10.2) 314 (45.5)
53 (10.5) 934 (49.4)
53 (10.6) 823 (49.1)
148 (77.1) 27 (14.1) 5 (2.6) 12 (6.3) 32 (5.3) 78 (40.6) 114 (59.4) 6 (5.3) n = 192 8.1 (0.90) n = 192 166 (38.8) n = 179 294 (73.3) n = 192 15 (9.9)
308 (70.6) 98 (22.5) 16 (3.7) 14 (3.2) 31 (5.7)† 195 (44.7)† 240 (55.0)† 7 (6.8) n = 435 8.1 (0.94) n = 431 142 (69.6) n = 292 272 (74.4) n = 322 12 (8.9)
283 (67.7) 110 (26.3) 14 (3.3) 11 (2.6) 31 (5.0) 198 (47.4) 220 (52.6) 7 (6.7) n = 417 8.2 (0.95) n = 623 143 (67.9) n = 262 282 (79.7) n = 338 13 (10.5)
455 (65.9) 127 (18.4) 25 (3.6) 83 (12.0) 30 (5.0) 354 (51.3) 336 (48.7) 5 (5.2) n = 689 8.2 (1.01) n = 690 170 (46.0) n = 649 300 (79.3) n = 688 12 (9.3)
919 (48.6) 823 (43.5) 51 (2.7) 98 (5.2) 29 (5.1) 1180 (62.4) 711 (37.6) 4 (5.5) n = 1887 8.4 (1.09) n = 1888 166 (57.1) n = 1246 297 (83.2) n = 1683 12 (12.2)
756 (45.1) 778 (46.4) 31 (1.8) 111 (6.6) 29 (5.1)† 1072 (64.0) 603 (36.0)† 4 (5.1) n = 1674 8.4 (1.12) n = 1672 167 (58.4) n = 1065 304 (85.6) n = 1586 12 (12.1)
BMI = body mass index; FPG = fasting plasma glucose; HbA1c = glycated hemoglobin; PPG = postprandial glucose; SAXA = saxagliptin; T2DM = type 2 diabetes mellitus. ⁎ Mean (SD) unless otherwise noted. † Not reported for 1 patient.
B. Bryzinski et al. / Journal of Diabetes and Its Complications 28 (2014) 887–893
analysis of covariance with terms for treatment group, baseline statin use, study, and treatment by baseline statin use as effects and baseline HbA1c as a covariate. An interaction contrast was used to test the average difference between saxagliptin 2.5 and 5 mg/d and control across subgroups of baseline statin use. Comparisons between any statin use (rosuvastatin, atorvastatin, simvastatin, or other [eg, pravastatin, lovastatin, fluvastatin, pitavastatin]) versus no statin use at baseline were performed for HbA1c, FPG, and PPG. Comparisons between individual statin use (rosuvastatin, atorvastatin, and simvastatin) versus no statin use at baseline were performed for HbA1c only. For interaction tests, P b 0.1 was considered statistically significant. The Mantel-Haenszel proportion difference estimate was used to compare the proportions of patients who achieved HbA1c level b7% at week 24. Analyses were performed using SAS version 8.2 (SAS Institute, Inc., Cary, NC). Adverse events were analyzed in all randomized patients who received ≥ 1 dose of study medication. They were included up to 1 day following the last treatment day or up to the last visit day in the
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short-term plus long-term period, whichever was later. Serious AEs (SAEs) were included up to 30 days following the last treatment day or the last visit day in the short-term plus long-term period, whichever was later. The study of saxagliptin plus metformin versus sitagliptin plus metformin (Scheen et al., 2010) was excluded from the myopathy analysis because of possible confounding due to reports associating concomitant sitagliptin and statin use with rhabdomyolysis (Bhome & Penn, 2012; Matsumae, Abe, Murakami, Ueda, & Saito, 2008). Laboratory values (24-week safety pool) were analyzed in all patients who had a baseline value and ≥1 laboratory value during the 24-week treatment period. Safety end points for the 24-week safety pool were analyzed descriptively. For the 20-study extended safety pool, AEs were analyzed as the number of patients with the event, the total personyears of exposure, the incidence rate (IR), and the incidence rate ratio (IRR). The IR (number of patients with events per 100 person-years) and IRR (IR saxagliptin divided by IR control), with 95% CI, were calculated using the Mantel-Haenszel method.
Fig. 1. HbA1c adjusted mean change from baseline at week 24 (LOCF) in subgroups with (A) no statin use, (B) any statin use, (C) atorvastatin use, (D) rosuvastatin use, and (E) simvastatin use at baseline. HbA1c = glycated hemoglobin; LOCF = last observation carried forward; SAXA = saxagliptin.
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3. Results 3.1. Patient demographics and baseline clinical characteristics The 24-week safety pool comprised 1046 patients with any statin use at baseline (atorvastatin, n = 460; rosuvastatin, n = 121; simvastatin, n = 316; other statin, n = 149) and 4257 patients with no statin use at baseline. Patient demographics and clinical characteristics are shown in Table 1. Mean age was 53 to 58 years across groups and was slightly higher in patients with any statin use (users) compared with no statin use (nonusers), as was the proportion of men. Other differences in the statin user subgroup versus nonusers were higher proportions of white patients, lower proportions of Asian patients, higher proportions of patients with a body mass index (BMI) ≥ 30 mg/kg 2, and a longer mean disease duration. Mean HbA1c, FPG, and PPG were lower in statin users versus nonusers at baseline. Among statin nonusers, there were higher proportions of white patients and patients with a BMI ≥ 30 mg/kg 2 in the saxagliptin 2.5 mg/d versus saxagliptin 5 mg/d and control groups. 3.2. Efficacy Irrespective of statin use, significantly greater adjusted mean changes from baseline in HbA1c were observed with saxagliptin 2.5 and 5 mg/d versus placebo; no interaction between treatment and baseline statin use was observed (Fig. 1). Similarly, there were significantly greater adjusted mean changes from baseline in FPG (Supplementary Fig. S1A) and PPG (Supplementary Fig. S1B) and significantly higher proportions of patients achieving HbA1c b7% (Supplementary Fig. S1C) with saxagliptin versus placebo in patients with and without baseline statin use. No interaction between treatment and baseline statin use was observed for FPG (Supplementary Fig. S1A) or PPG (Supplementary Fig. S1B). 3.3. Safety outcomes in the 24-week safety pool Rates of overall AEs, common AEs, and hypoglycemia in the 24-week safety pool are presented in Table 2. Irrespective of saxagliptin or control treatment, the proportion of patients with ≥1 AE appeared slightly higher among patients with any statin use (63–78%) versus those with no statin use at baseline (55–71%). Rates of ≥1 treatment-related AE
also appeared to be elevated among statin users (16–18%) compared with nonusers (12–18%). Irrespective of statin use, the rate of ≥1 AE appeared to be higher with saxagliptin 2.5 mg/d compared with saxagliptin 5 mg/d and control (any statin use, 78.1% vs 64.0% and 63.2%, respectively; no statin use, 70.6% vs 57.9% and 55.0%). In patients with no statin use, the rate of ≥1 treatment-related AE appeared to be higher with saxagliptin 2.5 mg/d compared with saxagliptin 5 mg/d and control (18.1% vs 11.9% and 11.8%). The incidence of deaths and SAEs was low irrespective of statin use and treatment. Common AEs (≥5% of patients in any group) were similar across statin users and nonusers and included upper respiratory tract infection, urinary tract infection, nasopharyngitis, diarrhea, and headache (Table 2). Rates of reported hypoglycemia were similar across treatment groups but somewhat higher in patients with any statin use (range across treatment groups, 9.6–11.5%) compared with patients with no statin use (4.2–6.8%; Table 2). Rates of confirmed hypoglycemia (symptoms with fingerstick glucose ≤ 50 mg/dL) were 0 to 2.4% in patients with any statin use and 0.2% to 1.0% in patients with no statin use. Rates of CK elevation were low across groups. In the subgroup of patients with any statin use, 5 patients (1.2%) receiving saxagliptin 5 mg/d and 2 (0.5%) receiving control had CK N 5 times the upper limit of normal (ULN); no patients had CK N 10 times ULN. Among the statin nonusers, 3 patients (0.4%) receiving saxagliptin 2.5 mg/d, 8 (0.4%) receiving saxagliptin 5 mg/d, and 9 (0.5%) receiving placebo had CK N5 times ULN. Two patients each in the saxagliptin 5 mg/d (0.1%) and placebo (0.1%) groups had CK N 10 times ULN. 3.4. Safety Outcomes in the Extended Safety Pool Safety findings were similar in the extended safety pool (saxagliptin, n = 5701; control, n = 3455); IRRs for deaths, SAEs, discontinuations due to AEs, reported and confirmed hypoglycemia, pancreatitis, and hypersensitivity are shown in Fig. 2. IRRs for SAEs were generally similar across statin subgroups (range, 0.8 [simvastatin] to 1.5 [other statin]). IRRs for deaths (n = 43 [0.5%] overall) were b 1, except for the “other statin” group, in which there were 2 events with saxagliptin and 0 events with control. IRRs for discontinuations due to AEs ranged from 0.3 (atorvastatin) to 2.5 (other statin). Risk ratios for reported hypoglycemia ranged from 0.5 (other statin) to 1.8 (atorvastatin). All outcomes had wide CIs. A total of 34 patients had confirmed hypoglycemia, with comparable rates
Table 2 General AEs, common AEs, and hypoglycemia in the 24-week safety pool. n (%)
Any statin use
No statin use
SAXA 2.5 mg/d (n = 192)
SAXA 5 mg/d (n = 436)
Control (n = 418)
SAXA 2.5 mg/d (n = 690)
SAXA 5 mg/d (n = 1891)
Control (n = 1676)
≥1 AE ≥1 Treatment-related AE Deaths ≥1 SAE ≥1 Treatment-related SAE Discontinuation due to SAEs Discontinuation due to AEs Common AEs⁎
150 (78.1) 31 (16.2) 2 (1.0) 11 (5.7) 0 2 (1.0) 5 (2.6)
279 (64.0) 74 (17.0) 1 (0.2) 19 (4.4) 0 0 13 (3.0)
264 (63.2) 73 (17.5) 2 (0.5) 16 (3.8) 1 (0.2) 2 (0.5) 9 (2.2)
487 (70.6) 125 (18.1) 1 (0.1) 20 (2.9) 2 (0.3) 4 (0.6) 15 (2.2)
1094 225 2 57 4 7 42
(57.9) (11.9) (0.1) (3.0) (0.2) (0.4) (2.2)
921 (55.0) 198 (11.8) 4 (0.2) 38 (2.3) 0 8 (0.5) 31 (1.8)
Upper respiratory tract infection Urinary tract infection Nasopharyngitis Diarrhea Headache Hypoglycemia Reported Confirmed†
16 (8.3) 13 (6.8) 10 (5.2) 7 (3.6) 6 (3.1)
30 22 30 14 19
105 97 89 80 93
(5.6) (5.1) (4.7) (4.2) (4.9)
91 87 69 88 70
22 (11.5) 0
50 (11.5) 9 (2.1)
AE = adverse event; SAE = serious adverse event; SAXA = saxagliptin. ⁎ ≥5% of patients in any group. † Symptomatic hypoglycemia with fingerstick glucose ≤50 mg/dL.
(6.9) (5.0) (6.9) (3.2) (4.4)
24 17 27 25 14
(5.7) (4.1) (6.5) (6.0) (3.3)
40 (9.6) 10 (2.4)
46 32 41 46 52
(6.7) (4.6) (5.9) (6.7) (7.5)
47 (6.8) 7 (1.0)
107 (5.7) 10 (0.5)
(5.4) (5.2) (4.1) (5.3) (4.2)
71 (4.2) 4 (0.2)
B. Bryzinski et al. / Journal of Diabetes and Its Complications 28 (2014) 887–893
Deaths
891
SAEs
Statin Use
Statin Use
No statin use
No statin use
Rosuvastatin*
Rosuvastatin
Atorvastatin
Atorvastatin
Simvastatin
9.13
Other
Simvastatin Other
0
1
2
3
4
5.97
0
Incidence Rate Ratio vs Control
1
2
3
4
Incidence Rate Ratio vs Control
*No events in saxagliptin or control groups.
Discontinuations due to AE
Reported Hypoglycemia
Statin Use
Statin Use
No statin use
No statin use
Rosuvastatin
Rosuvastatin
8.43
Atorvastatin
Atorvastatin
4.50
Simvastatin
Simvastatin
Other
24.55
0
1
2
3
Other
4
0
Incidence Rate Ratio vs Control
1
2
3
4
Incidence Rate Ratio vs Control
Pancreatitis
Confirmed Hypoglycemia Statin Use
Statin Use
No statin use
No statin use
Rosuvastatin
86.67
Atorvastatin Simvastatin
4.94
5.46
Rosuvastatin* Atorvastatin
63.36
Simvastatin
32.66
Other *
Other 0
1
2
3
0
4
1
2
3
4
Incidence Rate Ratio vs Control
Incidence Rate Ratio vs Control
*No events in saxagliptin or control groups.
Hypersensitivity Statin Use No statin use Rosuvastatin Atorvastatin
10.28
Simvastatin
76.49
Other
9.51
0
1
2
3
4
Incidence Rate Ratio vs Control Fig. 2. Adverse event incidence rate ratios in the extended safety pool for statin nonusers and statin users. AE = adverse event; SAE = serious adverse event.
across statin use subgroups (Fig. 2). Twelve patients had pancreatitis and 104 had hypersensitivity, with no evidence of an increased rate among statin users (Fig. 2). Among patients with any statin use at baseline, 90 treated with saxagliptin (IR, 7.0 per 100 person-years) and 62 treated with control (IR, 10.3 per 100 person-years) had myopathy (IRR [95% CI], 0.68 [0.48–0.97]). In patients with no statin use at baseline, 280 patients treated with saxagliptin (IR, 6.2 per 100 person-years) and 89 treated
with control (IR, 4.7 per 100 person-years) had myopathy (IRR [95% CI], 1.32 [1.03–1.71]). 4. Discussion These post hoc pooled analyses in patients with T2DM demonstrate saxagliptin to be consistently effective in improving glycemic control, as assessed by change from baseline in HbA1c, FPG, and PPG,
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irrespective of baseline statin use. In both the 11-study, 24-week pool and the 20-study, extended safety pool, which included studies of up to 52 weeks in duration, saxagliptin was generally well tolerated in patients with and without baseline statin use, with no new safety signals. Rates of deaths and SAEs were low across groups, with comparable rates of confirmed hypoglycemia in patients with and without statin use at baseline. Common AEs were consistent with the saxagliptin labeling information. Although some AE rates appeared to be higher with saxagliptin 2.5 mg/d compared with saxagliptin 5 mg/d and control, this may be attributable to chance, because the 2.5-mg/d dose was not included in all studies. Baseline differences between treatment groups in the subgroup with no statin use, including a higher proportion of white patients and patients with a BMI ≥30 mg/kg 2 in the saxagliptin 2.5-mg/d group compared with the other treatment groups, were not controlled for in the analyses. Results of the JUPITER trial suggested that statins may increase the risk for development of diabetes (Ridker et al., 2008) and raised questions regarding the benefit-risk of statin therapy (Ridker et al., 2012). A population-based retrospective cohort study demonstrated an increased risk of new-onset diabetes in patients treated with the higher potency statins atorvastatin, rosuvastatin, or simvastatin, compared with pravastatin (Carter et al., 2013). Other data suggest that the risk of incident diabetes with statin therapy may be dose dependent (Preiss et al., 2011). However, a reanalysis of the JUPITER data demonstrated that in those patients who developed diabetes during the trial, rosuvastatin was associated with a CV risk reduction consistent with that observed in the overall study population (Ridker et al., 2012), suggesting that statins have a CV benefit irrespective of any potential effect on glycemic control. The present findings demonstrate saxagliptin to be effective in improving HbA1c irrespective of atorvastatin use, rosuvastatin use, simvastatin use, any statin use, or no statin use. Safety and tolerability were not separately assessed in patients treated with atorvastatin, rosuvastatin, or simvastatin because of small numbers of patients. Irrespective of treatment, there appeared to be an elevated rate of AEs in the subgroup of statin users compared with the nonuser subgroup. This is not unexpected because differences may exist between patients receiving and not receiving statins. For example, older age, smoking, and existing CV conditions are associated with increased likelihood of statin use in patients with T2DM (Fu et al., 2011). Differences in baseline demographics and clinical characteristics (eg, age, sex, race, BMI, disease duration) were not controlled for in the analyses and could have contributed to the differences in the AEs in the statin use subgroups. Myopathy, defined by the American College of Cardiology/American Heart Association/National Heart, Lung, and Blood Institute as muscle disease, including myalgia, myositis, or rhabdomyolysis (muscle symptoms plus CK N10 × ULN and creatinine elevation), is a known side effect of statin therapy (Pasternak et al., 2002). Nichols and Koro reported a 1.3-fold higher risk of myopathy events in patients with diabetes using statin therapy compared with those not using statin therapy (Nichols & Koro, 2007). There are case reports of rhabdomyolysis (Bhome & Penn, 2012) and rhabdomyolysis accompanied by renal failure (Matsumae et al., 2008) in patients receiving concomitant sitagliptin and statin therapy. In the current analysis, rates of CK elevation were low (N5 × ULN, ≤1%; N10 × ULN, ≤0.1%) and comparable across treatment groups in the 24-week safety pool. In the extended safety pool, the myopathy IR was ≤10 per 100 person-years across groups. The myopathy IR was higher with saxagliptin versus control in patients with no statin use at baseline but lower with saxagliptin versus control in patients with any statin use at baseline. These findings suggest that saxagliptin does not increase the risk of myopathy or CK elevation when given in combination with statin therapy. Statins are underprescribed in patients with T2DM, with only 63% of eligible patients receiving prescriptions (Zinman, 2011). Patients
with T2DM using antihyperglycemic medication are more likely to be prescribed statin therapy than those not taking such medication (Zinman, 2011). Better understanding of the CV safety of antihyperglycemic medications and the efficacy and safety of concomitant statin and antihyperglycemic therapy could help to inform prescribing. A pooled analysis of the 6 phase 3 trials of saxagliptin demonstrated changes in lipid parameters generally comparable to those in the control groups (Cobble & Frederich, 2012). This was a post hoc analysis and not a prospective trial. Limitations include the fact that patients were not randomized to statin use, and some of the subgroups (eg, rosuvastatin, simvastatin) were small. Differences in baseline characteristics were identified but not statistically evaluated or controlled for. In addition, most trials were 12 to 52 weeks in duration, which may be insufficient to assess the long-term effects of statin therapy on saxagliptin efficacy. As noted above, the 2.5mg/d dose was not included in all studies, which may confound treatment comparisons in the pooled datasets. Inclusion criteria (eg, HbA1c requirement) were appropriate to assess effects on glycemic control, but the homogeneity of the study populations relative to clinical practice may limit external validity and generalizability. 5. Conclusions The current findings suggest that saxagliptin is effective and generally well tolerated in patients with T2DM who are currently receiving statin therapy, as well as for those not currently receiving statin therapy. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jdiacomp.2014.07.006. Acknowledgments Medical writing support for the preparation of this manuscript was provided by Nicole Strangman, PhD, and Janet E. Matsuura, PhD, from Complete Healthcare Communications, Inc., with funding from Bristol-Myers Squibb and AstraZeneca. References American Diabetes Association (2013). Standards of medical care in diabetes–2013. Diabetes Care, 36, S11–S66. Banach, M., Malodobra-Mazur, M., Gluba, A., Katsiki, N., Rysz, J., & Dobrzyn, A. (2013). Statin therapy and new-onset diabetes: molecular mechanisms and clinical relevance. Current Pharmaceutical Design, 19, 4904–4912. Barnett, A. (2006). DPP-4 inhibitors and their potential role in the management of type 2 diabetes. International Journal of Clinical Practice, 60, 1454–1470. Barnett, A. H., Charbonnel, B., Donovan, M., & Fleming, D. (2012). Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin. Current Medical Research and Opinion, 28, 513–523. Bellia, A., Rizza, S., Lombardo, M. F., Donadel, G., Fabiano, R., Andreadi, K., et al. (2012). Deterioration of glucose homeostasis in type 2 diabetic patients one year after beginning of statins therapy. Atherosclerosis, 223, 197–203. Bhome, R., & Penn, H. (2012). Rhabdomyolysis precipitated by a sitagliptin-atorvastatin drug interaction. Diabetic Medicine, 29, 693–694. Bryzinski, B., Allen, E., Cook, W., & Hirshberg, B. (2013). Saxagliptin reduces HbA1c and is well tolerated in patients with type 2 diabetes receiving concomitant statin therapy. Presented at: American Diabetes Association 73rd Scientific Sessions; June 21-25, 2013; Chicago, IL (abstract 1333-P). Carter, A. A., Gomes, T., Camacho, X., Juurlink, D. N., Shah, B. R., & Mamdani, M. M. (2013). Risk of incident diabetes among patients treated with statins: population based study. BMJ, 346, f2610, http://dx.doi.org/10.1136/bmj.f2610. Chacra, A. R., Tan, G. H., Apanovitch, A., Ravichandran, S., List, J., & Chen, R. (2009). Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial. International Journal of Clinical Practice, 63, 1395–1406. Cobble, M. E., & Frederich, R. (2012). Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data. Cardiovascular Diabetology, 11, 6, http://dx. doi.org/10.1186/1475-2840-11-6. Culver, A. L., Ockene, I. S., Balasubramanian, R., Olendzki, B. C., Sepavich, D. M., Wactawski-Wende, J., et al. (2012). Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Archives of Internal Medicine, 172, 144–152.
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G., Hellqvist, A., & Gause-Nilsson, I. (2013). Saxagliptin vs. glipizide as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: long-term (52-week) extension of a 52-week randomised controlled trial. International Journal of Clinical Practice, 67, 307–316. Henry, R. R., Smith, S. R., Schwartz, S. L., Mudaliar, S. R., Deacon, C. F., Holst, J. J., et al. (2011). Effects of saxagliptin on beta-cell stimulation and insulin secretion in patients with type 2 diabetes. Diabetes, Obesity & Metabolism, 13, 850–858. Hermans, M. P., Delibasi, T., Farmer, I., Lohm, L., Maheux, P., Piatti, P., et al. (2012). Effects of saxagliptin added to sub-maximal doses of metformin compared with uptitration of metformin in type 2 diabetes: the PROMPT study. Current Medical Research and Opinion, 28, 1635–1645. Hollander, P., Li, J., Allen, E., Chen, R., & CV181-013 Investigators (2009). 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M., Blackwell, L., Collins, R., Keech, A., Simes, J., Peto, R., et al. (2008). Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet, 371, 117–125. Matikainen, N., & Taskinen, M. R. (2012). Management of dyslipidemias in the presence of the metabolic syndrome or type 2 diabetes. Current Cardiology Reports, 14, 721–731. Matsumae, T., Abe, Y., Murakami, G., Ueda, K., & Saito, T. (2008). Effects of glucose metabolism on aortic pulse wave velocity in hemodialysis patients with and without diabetes. Hypertension Research, 31, 1365–1372. Neutel, J. M., Zhao, C., & Karyekar, C. S. (2013). Adding saxagliptin to metformin extended release (XR) or uptitration of metformin XR: efficacy on daily glucose measures. Diabetes Therapy, 4, 269–283. Nichols, G. A., & Koro, C. E. (2007). Does statin therapy initiation increase the risk for myopathy? An observational study of 32,225 diabetic and nondiabetic patients. 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Contents lists available at ScienceDirect
Journal of Diabetes and Its Complications journal homepage: WWW.JDCJOURNAL.COM
Saxagliptin efficacy and safety in patients with type 2 diabetes receiving concomitant statin therapy Brian Bryzinski a,⁎, Elsie Allen b, 1, William Cook a, Boaz Hirshberg a a b
AstraZeneca, Wilmington, DE, USA Novo Nordisk, New York, NY, USA
a r t i c l e
i n f o
Article history: Received 1 April 2014 Received in revised form 27 June 2014 Accepted 10 July 2014 Available online 17 July 2014 Keywords: Cardiovascular disease Dipeptidyl peptidase-4 inhibitor Dyslipidemia Incretin Statin
a b s t r a c t Aims: To examine whether concomitant statin therapy affects glycemic control with saxagliptin 2.5 and 5 mg/d in patients with type 2 diabetes mellitus (T2DM). Methods: Efficacy and safety were analyzed post hoc for pooled data from 9 saxagliptin randomized, placebocontrolled trials with a primary 24-week treatment period (4 monotherapy, 2 add-on to metformin, 1 each add-on to a sulfonylurea, thiazolidinedione, or insulin ± metformin). Safety was also assessed in an 11-study, 24-week pool and an extended 20-study pool, which included 9 additional 4- to 52-week randomized studies. Comparisons were performed for patient groups defined by baseline statin use. Results: Saxagliptin produced greater mean reductions in glycated hemoglobin than placebo, with no interaction between treatment and baseline statin use (P = 0.47). In patients receiving saxagliptin 2.5 and 5 mg and placebo, the proportion of patients with ≥1 adverse event (AE) was 78.1%, 64.0%, and 63.2%, respectively, in patients with any statin use and 70.6%, 57.9%, and 55.0% in patients with no statin use. Serious AEs, deaths, and symptomatic confirmed hypoglycemia (fingerstick glucose ≤ 50 mg/dL) were few and similar, irrespective of baseline statin use. Conclusions: Saxagliptin improves glycemic control and is generally well tolerated in patients with T2DM, irrespective of concomitant statin therapy. © 2014 Elsevier Inc. All rights reserved.
1. Introduction The risk of cardiovascular (CV) mortality is 3-fold higher in patients with type 2 diabetes mellitus (T2DM), compared with those without diabetes (Taylor et al., 2013). Low-density lipoprotein cholesterol (LDL-C) is considered the most important modifiable risk factor for CV disease (CVD) in patients with diabetes (Matikainen & Taskinen, 2012). Lifestyle modification and statin therapy are the cornerstones of lipid management in patients with diabetes (American Diabetes Association, 2013). Statin therapy has been demonstrated to significantly reduce CV and all-cause mortality in patients with diabetes, including those with no
Conflict of Interest: Dr. Bryzinski, Dr. Cook, and Dr. Hirshberg are employees of AstraZeneca. Dr Allen was an employee of Bristol-Myers Squibb at the time of the study. Funding statement: Bristol-Myers Squibb and AstraZeneca funded this study. Medical writing support for the preparation of this manuscript was provided by Nicole Strangman, PhD, and Janet Matsuura, PhD, from Complete Healthcare Communications, with funding from Bristol-Myers Squibb and AstraZeneca. Data were presented at the American Diabetes Association 73rd Scientific Sessions; June 21–25, 2013; Chicago, IL. ⁎ Corresponding author at: AstraZeneca, 1800 Concord Pike, Wilmington, DE 19850. Tel.: +1 302 885 1873; fax: +1 302 885 7603. E-mail address: [email protected] (B. Bryzinski). 1 Employed by Bristol-Myers Squibb, Princeton, NJ at the time of the study. http://dx.doi.org/10.1016/j.jdiacomp.2014.07.006 1056-8727/© 2014 Elsevier Inc. All rights reserved.
history of vascular disease (Kearney et al., 2008). The American Diabetes Association (ADA) recommends statin therapy regardless of baseline lipid levels in patients with overt CVD and in patients N40 years of age with ≥ 1 other CVD risk factor (American Diabetes Association, 2013). The ADA also recommends that statin therapy be considered in patients ≤ 40 years of age with multiple CVD risk factors and in lower-risk patients if LDL-C remains N100 mg/dL. However, questions have emerged about the possible impact of statin therapy on glycemic control (Banach et al., 2013; Katsiki & Banach, 2012). Clinical trials (Culver et al., 2012; Ridker, Pradhan, MacFadyen, Libby, & Glynn, 2012; Ridker et al., 2008), observational studies (Carter et al., 2013; Danaei, Garcia Rodriguez, Fernandez Cantero, & Hernan, 2013), and meta-analyses (Preiss et al., 2011; Sattar et al., 2010) have reported an increased risk for development of diabetes with statin treatment in some patients. In addition, several studies have demonstrated deterioration of glycemic control after initiation of statin therapy in patients with T2DM (Bellia et al., 2012; Simsek, Schalkwijk, & Wolffenbuttel, 2012). Saxagliptin is a dipeptidyl peptidase-4 DPP-4 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM (2012). Saxagliptin is weight neutral and has a low rate of hypoglycemia when used as monotherapy (Barnett, 2006). In 24-week controlled clinical trials, saxagliptin was generally well
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tolerated and effective in improving glycemic control as monotherapy (Frederich, McNeill, Berglind, Fleming, & Chen, 2012; Rosenstock et al., 2009) and as add-on therapy to other antidiabetic medications (Barnett, Charbonnel, Donovan, & Fleming, 2012; Chacra et al., 2009; DeFronzo et al., 2009; Hollander, Li, Allen, Chen, & CV181-013 Investigators, 2009). It is not known whether glycemic control with saxagliptin is affected by concomitant statin therapy. To address this question, we conducted post hoc analyses of pooled data from 9 randomized, placebo-controlled trials with saxagliptin 2.5 and 5 mg/d. In addition, we assessed safety of concomitant statin use with saxagliptin in an 11study pool and an extended 20-study pool. Efficacy and safety were compared for patients with and without concomitant statin therapy at baseline (Bryzinski, Allen, Cook, & Hirshberg, 2013). 2. Methods 2.1. Study design This was a post hoc analysis conducted using pooled data from the randomized controlled trials listed in Supplementary Table S1. Study methodology and primary efficacy and safety findings were previously reported for all but 1 of these trials. Efficacy analyses were performed using pooled data for patients treated with saxagliptin 2.5 or 5 mg/d or control in 9 phase 3, randomized studies with a primary 24-week treatment period, including 4 studies of saxagliptin as monotherapy (ClinicalTrials.gov identifier: (NCT00121641 (Rosenstock et al., 2009, 2013), NCT00316082 (Frederich et al., 2012), NCT00698932 (Pan, Yang, Tou, Gause-Nilsson, & Zhao, 2012), and NCT00918879 (Prasanna Kumar, Jain, Tou, & Schutzer, 2014)), 2 studies of saxagliptin as add-on to metformin (NCT00121667 (DeFronzo et al., 2009; Rosentock et al., 2013) and NCT00661362 (Yang, Pan, Tou, Zhao, & Gause-Nilsson, 2011)), and 1 study each of saxagliptin as add-on to a sulfonylurea (NCT00313313 (Chacra et al., 2009; Doucet et al., 2011)), thiazolidinedione (NCT00295633 (Hollander et al., 2009, 2011)), and insulin with and without metformin (NCT00757588 (Barnett et al., 2012)). Safety analyses were performed in an 11-study, 24-week pool and an extended 20-study pool. The 11-study, 24-week safety pool included data for saxagliptin 2.5 and 5 mg/d and control from the 9 studies in the efficacy pool plus two 24-week randomized,
controlled studies of saxagliptin as add-on therapy to metformin (NCT01006590 (Hermans et al., 2012) and NCT00327015 (Jadzinsky et al., 2009; Pfützner et al., 2011) [only the saxagliptin plus metformin and metformin plus placebo arms were included in the analyses]). The 20-study pool included data for all saxagliptin doses (2.5, 5, 10, 20, 40, and 100 mg/d) and control from the 11 studies in the 24-week safety pool (24-week and controlled long-term extension data ranging from 28 weeks to 42 months) as well as nine 4- to 52-week randomized studies of saxagliptin as monotherapy (NCT00614939 (Nowicki et al., 2011a, 2011b), NCT00950599 (Rosenstock, Sankoh, & List, 2008), NCT00374907 (Henry et al., 2011)) or as add-on to metformin (NCT00575588 (Göke, Gallwitz, Eriksson, Hellqvist, & Gause-Nilsson, 2010, 2013), NCT00666458 (Scheen, Charpentier, Ostgren, Hellqvist, & Gause-Nilsson, 2010), NCT00683657 (Stenlof et al., 2010), NCT00885378 (White, Buchanan, Li, & Frederich, 2014) NCT00918138 (Neutel, Zhao, & Karyekar, 2013), NCT00960076 (Fonseca, Zhu, Karyekar, & Hirshberg, 2012)). Study protocols were approved by an institutional review board/ independent ethics committee and conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation. All patients provided written informed consent. 2.2. Study end points Efficacy end points were change from baseline at week 24 in glycated hemoglobin (HbA1c), 120-minute postprandial glucose (PPG), and fasting plasma glucose (FPG) and the proportion of patients achieving a therapeutic glycemic response (HbA1c b7%) at week 24. Safety and tolerability assessments included adverse events (AEs), all reported hypoglycemia, confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL with associated symptoms), myopathy (standardized Medical Dictionary for Regulatory Activities [version 15.0] query: rhabdomyolysis/myopathy; 45 preferred terms), and creatinine kinase (CK) elevation. 2.3. Statistical analyses Efficacy was analyzed in all randomized patients who received ≥1 dose of study medication and had nonmissing values at baseline and week 24 (last observation carried forward, excluding post-rescue assessments). Changes from baseline HbA1c, FPG, and PPG levels at week 24 were analyzed in the pooled patient populations using
Table 1 Demographic and baseline clinical characteristics in the 24-week safety pool. Characteristic⁎
Age, y Men, n (%) Race, n (%) White Asian Black Other BMI, kg/m2 b30, n (%) ≥30, n (%) Duration of T2DM, y HbA1c, % FPG, mg/dL 120-min PPG, mg/dL Fasting insulin, μU/mL
Any statin use
No statin use
SAXA 2.5 mg/d n = 192
SAXA 5 mg/d n = 436
Control n = 418
SAXA 2.5 mg/d n = 690
SAXA 5 mg/d n = 1891
Control n = 1676
58 (8.3) 108 (56.3)
58 (9.3) 219 (50.2)
58 (9.4) 227 (54.3)
54 (10.2) 314 (45.5)
53 (10.5) 934 (49.4)
53 (10.6) 823 (49.1)
148 (77.1) 27 (14.1) 5 (2.6) 12 (6.3) 32 (5.3) 78 (40.6) 114 (59.4) 6 (5.3) n = 192 8.1 (0.90) n = 192 166 (38.8) n = 179 294 (73.3) n = 192 15 (9.9)
308 (70.6) 98 (22.5) 16 (3.7) 14 (3.2) 31 (5.7)† 195 (44.7)† 240 (55.0)† 7 (6.8) n = 435 8.1 (0.94) n = 431 142 (69.6) n = 292 272 (74.4) n = 322 12 (8.9)
283 (67.7) 110 (26.3) 14 (3.3) 11 (2.6) 31 (5.0) 198 (47.4) 220 (52.6) 7 (6.7) n = 417 8.2 (0.95) n = 623 143 (67.9) n = 262 282 (79.7) n = 338 13 (10.5)
455 (65.9) 127 (18.4) 25 (3.6) 83 (12.0) 30 (5.0) 354 (51.3) 336 (48.7) 5 (5.2) n = 689 8.2 (1.01) n = 690 170 (46.0) n = 649 300 (79.3) n = 688 12 (9.3)
919 (48.6) 823 (43.5) 51 (2.7) 98 (5.2) 29 (5.1) 1180 (62.4) 711 (37.6) 4 (5.5) n = 1887 8.4 (1.09) n = 1888 166 (57.1) n = 1246 297 (83.2) n = 1683 12 (12.2)
756 (45.1) 778 (46.4) 31 (1.8) 111 (6.6) 29 (5.1)† 1072 (64.0) 603 (36.0)† 4 (5.1) n = 1674 8.4 (1.12) n = 1672 167 (58.4) n = 1065 304 (85.6) n = 1586 12 (12.1)
BMI = body mass index; FPG = fasting plasma glucose; HbA1c = glycated hemoglobin; PPG = postprandial glucose; SAXA = saxagliptin; T2DM = type 2 diabetes mellitus. ⁎ Mean (SD) unless otherwise noted. † Not reported for 1 patient.
B. Bryzinski et al. / Journal of Diabetes and Its Complications 28 (2014) 887–893
analysis of covariance with terms for treatment group, baseline statin use, study, and treatment by baseline statin use as effects and baseline HbA1c as a covariate. An interaction contrast was used to test the average difference between saxagliptin 2.5 and 5 mg/d and control across subgroups of baseline statin use. Comparisons between any statin use (rosuvastatin, atorvastatin, simvastatin, or other [eg, pravastatin, lovastatin, fluvastatin, pitavastatin]) versus no statin use at baseline were performed for HbA1c, FPG, and PPG. Comparisons between individual statin use (rosuvastatin, atorvastatin, and simvastatin) versus no statin use at baseline were performed for HbA1c only. For interaction tests, P b 0.1 was considered statistically significant. The Mantel-Haenszel proportion difference estimate was used to compare the proportions of patients who achieved HbA1c level b7% at week 24. Analyses were performed using SAS version 8.2 (SAS Institute, Inc., Cary, NC). Adverse events were analyzed in all randomized patients who received ≥ 1 dose of study medication. They were included up to 1 day following the last treatment day or up to the last visit day in the
889
short-term plus long-term period, whichever was later. Serious AEs (SAEs) were included up to 30 days following the last treatment day or the last visit day in the short-term plus long-term period, whichever was later. The study of saxagliptin plus metformin versus sitagliptin plus metformin (Scheen et al., 2010) was excluded from the myopathy analysis because of possible confounding due to reports associating concomitant sitagliptin and statin use with rhabdomyolysis (Bhome & Penn, 2012; Matsumae, Abe, Murakami, Ueda, & Saito, 2008). Laboratory values (24-week safety pool) were analyzed in all patients who had a baseline value and ≥1 laboratory value during the 24-week treatment period. Safety end points for the 24-week safety pool were analyzed descriptively. For the 20-study extended safety pool, AEs were analyzed as the number of patients with the event, the total personyears of exposure, the incidence rate (IR), and the incidence rate ratio (IRR). The IR (number of patients with events per 100 person-years) and IRR (IR saxagliptin divided by IR control), with 95% CI, were calculated using the Mantel-Haenszel method.
Fig. 1. HbA1c adjusted mean change from baseline at week 24 (LOCF) in subgroups with (A) no statin use, (B) any statin use, (C) atorvastatin use, (D) rosuvastatin use, and (E) simvastatin use at baseline. HbA1c = glycated hemoglobin; LOCF = last observation carried forward; SAXA = saxagliptin.
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3. Results 3.1. Patient demographics and baseline clinical characteristics The 24-week safety pool comprised 1046 patients with any statin use at baseline (atorvastatin, n = 460; rosuvastatin, n = 121; simvastatin, n = 316; other statin, n = 149) and 4257 patients with no statin use at baseline. Patient demographics and clinical characteristics are shown in Table 1. Mean age was 53 to 58 years across groups and was slightly higher in patients with any statin use (users) compared with no statin use (nonusers), as was the proportion of men. Other differences in the statin user subgroup versus nonusers were higher proportions of white patients, lower proportions of Asian patients, higher proportions of patients with a body mass index (BMI) ≥ 30 mg/kg 2, and a longer mean disease duration. Mean HbA1c, FPG, and PPG were lower in statin users versus nonusers at baseline. Among statin nonusers, there were higher proportions of white patients and patients with a BMI ≥ 30 mg/kg 2 in the saxagliptin 2.5 mg/d versus saxagliptin 5 mg/d and control groups. 3.2. Efficacy Irrespective of statin use, significantly greater adjusted mean changes from baseline in HbA1c were observed with saxagliptin 2.5 and 5 mg/d versus placebo; no interaction between treatment and baseline statin use was observed (Fig. 1). Similarly, there were significantly greater adjusted mean changes from baseline in FPG (Supplementary Fig. S1A) and PPG (Supplementary Fig. S1B) and significantly higher proportions of patients achieving HbA1c b7% (Supplementary Fig. S1C) with saxagliptin versus placebo in patients with and without baseline statin use. No interaction between treatment and baseline statin use was observed for FPG (Supplementary Fig. S1A) or PPG (Supplementary Fig. S1B). 3.3. Safety outcomes in the 24-week safety pool Rates of overall AEs, common AEs, and hypoglycemia in the 24-week safety pool are presented in Table 2. Irrespective of saxagliptin or control treatment, the proportion of patients with ≥1 AE appeared slightly higher among patients with any statin use (63–78%) versus those with no statin use at baseline (55–71%). Rates of ≥1 treatment-related AE
also appeared to be elevated among statin users (16–18%) compared with nonusers (12–18%). Irrespective of statin use, the rate of ≥1 AE appeared to be higher with saxagliptin 2.5 mg/d compared with saxagliptin 5 mg/d and control (any statin use, 78.1% vs 64.0% and 63.2%, respectively; no statin use, 70.6% vs 57.9% and 55.0%). In patients with no statin use, the rate of ≥1 treatment-related AE appeared to be higher with saxagliptin 2.5 mg/d compared with saxagliptin 5 mg/d and control (18.1% vs 11.9% and 11.8%). The incidence of deaths and SAEs was low irrespective of statin use and treatment. Common AEs (≥5% of patients in any group) were similar across statin users and nonusers and included upper respiratory tract infection, urinary tract infection, nasopharyngitis, diarrhea, and headache (Table 2). Rates of reported hypoglycemia were similar across treatment groups but somewhat higher in patients with any statin use (range across treatment groups, 9.6–11.5%) compared with patients with no statin use (4.2–6.8%; Table 2). Rates of confirmed hypoglycemia (symptoms with fingerstick glucose ≤ 50 mg/dL) were 0 to 2.4% in patients with any statin use and 0.2% to 1.0% in patients with no statin use. Rates of CK elevation were low across groups. In the subgroup of patients with any statin use, 5 patients (1.2%) receiving saxagliptin 5 mg/d and 2 (0.5%) receiving control had CK N 5 times the upper limit of normal (ULN); no patients had CK N 10 times ULN. Among the statin nonusers, 3 patients (0.4%) receiving saxagliptin 2.5 mg/d, 8 (0.4%) receiving saxagliptin 5 mg/d, and 9 (0.5%) receiving placebo had CK N5 times ULN. Two patients each in the saxagliptin 5 mg/d (0.1%) and placebo (0.1%) groups had CK N 10 times ULN. 3.4. Safety Outcomes in the Extended Safety Pool Safety findings were similar in the extended safety pool (saxagliptin, n = 5701; control, n = 3455); IRRs for deaths, SAEs, discontinuations due to AEs, reported and confirmed hypoglycemia, pancreatitis, and hypersensitivity are shown in Fig. 2. IRRs for SAEs were generally similar across statin subgroups (range, 0.8 [simvastatin] to 1.5 [other statin]). IRRs for deaths (n = 43 [0.5%] overall) were b 1, except for the “other statin” group, in which there were 2 events with saxagliptin and 0 events with control. IRRs for discontinuations due to AEs ranged from 0.3 (atorvastatin) to 2.5 (other statin). Risk ratios for reported hypoglycemia ranged from 0.5 (other statin) to 1.8 (atorvastatin). All outcomes had wide CIs. A total of 34 patients had confirmed hypoglycemia, with comparable rates
Table 2 General AEs, common AEs, and hypoglycemia in the 24-week safety pool. n (%)
Any statin use
No statin use
SAXA 2.5 mg/d (n = 192)
SAXA 5 mg/d (n = 436)
Control (n = 418)
SAXA 2.5 mg/d (n = 690)
SAXA 5 mg/d (n = 1891)
Control (n = 1676)
≥1 AE ≥1 Treatment-related AE Deaths ≥1 SAE ≥1 Treatment-related SAE Discontinuation due to SAEs Discontinuation due to AEs Common AEs⁎
150 (78.1) 31 (16.2) 2 (1.0) 11 (5.7) 0 2 (1.0) 5 (2.6)
279 (64.0) 74 (17.0) 1 (0.2) 19 (4.4) 0 0 13 (3.0)
264 (63.2) 73 (17.5) 2 (0.5) 16 (3.8) 1 (0.2) 2 (0.5) 9 (2.2)
487 (70.6) 125 (18.1) 1 (0.1) 20 (2.9) 2 (0.3) 4 (0.6) 15 (2.2)
1094 225 2 57 4 7 42
(57.9) (11.9) (0.1) (3.0) (0.2) (0.4) (2.2)
921 (55.0) 198 (11.8) 4 (0.2) 38 (2.3) 0 8 (0.5) 31 (1.8)
Upper respiratory tract infection Urinary tract infection Nasopharyngitis Diarrhea Headache Hypoglycemia Reported Confirmed†
16 (8.3) 13 (6.8) 10 (5.2) 7 (3.6) 6 (3.1)
30 22 30 14 19
105 97 89 80 93
(5.6) (5.1) (4.7) (4.2) (4.9)
91 87 69 88 70
22 (11.5) 0
50 (11.5) 9 (2.1)
AE = adverse event; SAE = serious adverse event; SAXA = saxagliptin. ⁎ ≥5% of patients in any group. † Symptomatic hypoglycemia with fingerstick glucose ≤50 mg/dL.
(6.9) (5.0) (6.9) (3.2) (4.4)
24 17 27 25 14
(5.7) (4.1) (6.5) (6.0) (3.3)
40 (9.6) 10 (2.4)
46 32 41 46 52
(6.7) (4.6) (5.9) (6.7) (7.5)
47 (6.8) 7 (1.0)
107 (5.7) 10 (0.5)
(5.4) (5.2) (4.1) (5.3) (4.2)
71 (4.2) 4 (0.2)
B. Bryzinski et al. / Journal of Diabetes and Its Complications 28 (2014) 887–893
Deaths
891
SAEs
Statin Use
Statin Use
No statin use
No statin use
Rosuvastatin*
Rosuvastatin
Atorvastatin
Atorvastatin
Simvastatin
9.13
Other
Simvastatin Other
0
1
2
3
4
5.97
0
Incidence Rate Ratio vs Control
1
2
3
4
Incidence Rate Ratio vs Control
*No events in saxagliptin or control groups.
Discontinuations due to AE
Reported Hypoglycemia
Statin Use
Statin Use
No statin use
No statin use
Rosuvastatin
Rosuvastatin
8.43
Atorvastatin
Atorvastatin
4.50
Simvastatin
Simvastatin
Other
24.55
0
1
2
3
Other
4
0
Incidence Rate Ratio vs Control
1
2
3
4
Incidence Rate Ratio vs Control
Pancreatitis
Confirmed Hypoglycemia Statin Use
Statin Use
No statin use
No statin use
Rosuvastatin
86.67
Atorvastatin Simvastatin
4.94
5.46
Rosuvastatin* Atorvastatin
63.36
Simvastatin
32.66
Other *
Other 0
1
2
3
0
4
1
2
3
4
Incidence Rate Ratio vs Control
Incidence Rate Ratio vs Control
*No events in saxagliptin or control groups.
Hypersensitivity Statin Use No statin use Rosuvastatin Atorvastatin
10.28
Simvastatin
76.49
Other
9.51
0
1
2
3
4
Incidence Rate Ratio vs Control Fig. 2. Adverse event incidence rate ratios in the extended safety pool for statin nonusers and statin users. AE = adverse event; SAE = serious adverse event.
across statin use subgroups (Fig. 2). Twelve patients had pancreatitis and 104 had hypersensitivity, with no evidence of an increased rate among statin users (Fig. 2). Among patients with any statin use at baseline, 90 treated with saxagliptin (IR, 7.0 per 100 person-years) and 62 treated with control (IR, 10.3 per 100 person-years) had myopathy (IRR [95% CI], 0.68 [0.48–0.97]). In patients with no statin use at baseline, 280 patients treated with saxagliptin (IR, 6.2 per 100 person-years) and 89 treated
with control (IR, 4.7 per 100 person-years) had myopathy (IRR [95% CI], 1.32 [1.03–1.71]). 4. Discussion These post hoc pooled analyses in patients with T2DM demonstrate saxagliptin to be consistently effective in improving glycemic control, as assessed by change from baseline in HbA1c, FPG, and PPG,
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irrespective of baseline statin use. In both the 11-study, 24-week pool and the 20-study, extended safety pool, which included studies of up to 52 weeks in duration, saxagliptin was generally well tolerated in patients with and without baseline statin use, with no new safety signals. Rates of deaths and SAEs were low across groups, with comparable rates of confirmed hypoglycemia in patients with and without statin use at baseline. Common AEs were consistent with the saxagliptin labeling information. Although some AE rates appeared to be higher with saxagliptin 2.5 mg/d compared with saxagliptin 5 mg/d and control, this may be attributable to chance, because the 2.5-mg/d dose was not included in all studies. Baseline differences between treatment groups in the subgroup with no statin use, including a higher proportion of white patients and patients with a BMI ≥30 mg/kg 2 in the saxagliptin 2.5-mg/d group compared with the other treatment groups, were not controlled for in the analyses. Results of the JUPITER trial suggested that statins may increase the risk for development of diabetes (Ridker et al., 2008) and raised questions regarding the benefit-risk of statin therapy (Ridker et al., 2012). A population-based retrospective cohort study demonstrated an increased risk of new-onset diabetes in patients treated with the higher potency statins atorvastatin, rosuvastatin, or simvastatin, compared with pravastatin (Carter et al., 2013). Other data suggest that the risk of incident diabetes with statin therapy may be dose dependent (Preiss et al., 2011). However, a reanalysis of the JUPITER data demonstrated that in those patients who developed diabetes during the trial, rosuvastatin was associated with a CV risk reduction consistent with that observed in the overall study population (Ridker et al., 2012), suggesting that statins have a CV benefit irrespective of any potential effect on glycemic control. The present findings demonstrate saxagliptin to be effective in improving HbA1c irrespective of atorvastatin use, rosuvastatin use, simvastatin use, any statin use, or no statin use. Safety and tolerability were not separately assessed in patients treated with atorvastatin, rosuvastatin, or simvastatin because of small numbers of patients. Irrespective of treatment, there appeared to be an elevated rate of AEs in the subgroup of statin users compared with the nonuser subgroup. This is not unexpected because differences may exist between patients receiving and not receiving statins. For example, older age, smoking, and existing CV conditions are associated with increased likelihood of statin use in patients with T2DM (Fu et al., 2011). Differences in baseline demographics and clinical characteristics (eg, age, sex, race, BMI, disease duration) were not controlled for in the analyses and could have contributed to the differences in the AEs in the statin use subgroups. Myopathy, defined by the American College of Cardiology/American Heart Association/National Heart, Lung, and Blood Institute as muscle disease, including myalgia, myositis, or rhabdomyolysis (muscle symptoms plus CK N10 × ULN and creatinine elevation), is a known side effect of statin therapy (Pasternak et al., 2002). Nichols and Koro reported a 1.3-fold higher risk of myopathy events in patients with diabetes using statin therapy compared with those not using statin therapy (Nichols & Koro, 2007). There are case reports of rhabdomyolysis (Bhome & Penn, 2012) and rhabdomyolysis accompanied by renal failure (Matsumae et al., 2008) in patients receiving concomitant sitagliptin and statin therapy. In the current analysis, rates of CK elevation were low (N5 × ULN, ≤1%; N10 × ULN, ≤0.1%) and comparable across treatment groups in the 24-week safety pool. In the extended safety pool, the myopathy IR was ≤10 per 100 person-years across groups. The myopathy IR was higher with saxagliptin versus control in patients with no statin use at baseline but lower with saxagliptin versus control in patients with any statin use at baseline. These findings suggest that saxagliptin does not increase the risk of myopathy or CK elevation when given in combination with statin therapy. Statins are underprescribed in patients with T2DM, with only 63% of eligible patients receiving prescriptions (Zinman, 2011). Patients
with T2DM using antihyperglycemic medication are more likely to be prescribed statin therapy than those not taking such medication (Zinman, 2011). Better understanding of the CV safety of antihyperglycemic medications and the efficacy and safety of concomitant statin and antihyperglycemic therapy could help to inform prescribing. A pooled analysis of the 6 phase 3 trials of saxagliptin demonstrated changes in lipid parameters generally comparable to those in the control groups (Cobble & Frederich, 2012). This was a post hoc analysis and not a prospective trial. Limitations include the fact that patients were not randomized to statin use, and some of the subgroups (eg, rosuvastatin, simvastatin) were small. Differences in baseline characteristics were identified but not statistically evaluated or controlled for. In addition, most trials were 12 to 52 weeks in duration, which may be insufficient to assess the long-term effects of statin therapy on saxagliptin efficacy. As noted above, the 2.5mg/d dose was not included in all studies, which may confound treatment comparisons in the pooled datasets. Inclusion criteria (eg, HbA1c requirement) were appropriate to assess effects on glycemic control, but the homogeneity of the study populations relative to clinical practice may limit external validity and generalizability. 5. Conclusions The current findings suggest that saxagliptin is effective and generally well tolerated in patients with T2DM who are currently receiving statin therapy, as well as for those not currently receiving statin therapy. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jdiacomp.2014.07.006. Acknowledgments Medical writing support for the preparation of this manuscript was provided by Nicole Strangman, PhD, and Janet E. Matsuura, PhD, from Complete Healthcare Communications, Inc., with funding from Bristol-Myers Squibb and AstraZeneca. References American Diabetes Association (2013). Standards of medical care in diabetes–2013. Diabetes Care, 36, S11–S66. Banach, M., Malodobra-Mazur, M., Gluba, A., Katsiki, N., Rysz, J., & Dobrzyn, A. (2013). Statin therapy and new-onset diabetes: molecular mechanisms and clinical relevance. Current Pharmaceutical Design, 19, 4904–4912. Barnett, A. (2006). DPP-4 inhibitors and their potential role in the management of type 2 diabetes. International Journal of Clinical Practice, 60, 1454–1470. Barnett, A. H., Charbonnel, B., Donovan, M., & Fleming, D. (2012). Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin. Current Medical Research and Opinion, 28, 513–523. Bellia, A., Rizza, S., Lombardo, M. F., Donadel, G., Fabiano, R., Andreadi, K., et al. (2012). Deterioration of glucose homeostasis in type 2 diabetic patients one year after beginning of statins therapy. Atherosclerosis, 223, 197–203. Bhome, R., & Penn, H. (2012). Rhabdomyolysis precipitated by a sitagliptin-atorvastatin drug interaction. Diabetic Medicine, 29, 693–694. Bryzinski, B., Allen, E., Cook, W., & Hirshberg, B. (2013). Saxagliptin reduces HbA1c and is well tolerated in patients with type 2 diabetes receiving concomitant statin therapy. Presented at: American Diabetes Association 73rd Scientific Sessions; June 21-25, 2013; Chicago, IL (abstract 1333-P). Carter, A. A., Gomes, T., Camacho, X., Juurlink, D. N., Shah, B. R., & Mamdani, M. M. (2013). Risk of incident diabetes among patients treated with statins: population based study. BMJ, 346, f2610, http://dx.doi.org/10.1136/bmj.f2610. Chacra, A. R., Tan, G. H., Apanovitch, A., Ravichandran, S., List, J., & Chen, R. (2009). Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial. International Journal of Clinical Practice, 63, 1395–1406. Cobble, M. E., & Frederich, R. (2012). Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data. Cardiovascular Diabetology, 11, 6, http://dx. doi.org/10.1186/1475-2840-11-6. Culver, A. L., Ockene, I. S., Balasubramanian, R., Olendzki, B. C., Sepavich, D. M., Wactawski-Wende, J., et al. (2012). Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Archives of Internal Medicine, 172, 144–152.
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