ORIGINAL PAPER
A comparison of glycaemic effects of sitagliptin and sulfonylureas in elderly patients with type 2 diabetes mellitus R. R. Shankar, L. Xu, G. T. Golm, E. A. O’Neill, B. J. Goldstein,* K. D. Kaufman, S. S. Engel
SUMMARY
What’s known
Introduction: In the USA, 45% of patients with type 2 diabetes mellitus (T2DM) are elderly (≥ 65 years old). In general, use of sulfonylurea increases with patient age as does the associated risk for hypoglycaemia, and the consequences of hypoglycaemia can be more pronounced in elderly patients. Sitagliptin, a DPP-4 inhibitor, improves glycaemic control in adult patients of all ages with T2DM, with a low risk of hypoglycaemia when used alone or in combination with other antidiabetic agents that are not generally associated with hypoglycaemia when used independently. Methods: In a post hoc analysis, pooled data from elderly patients who participated in one of three double-blind studies comparing the effects of therapy with sitagliptin (100 mg/day) vs. sulfonylurea (in titrated doses) were analysed for changes from baseline in HbA1c, fasting plasma glucose (FPG), and body weight and for the incidence of reported symptomatic hypoglycaemia. In these studies, patients on diet alone or metformin were randomised to sitagliptin or glipizide for 104 weeks (studies 1 and 2) or glimepiride for 30 weeks (study 3). The analysis included 372 elderly patients who completed a trial through 25 or 30 weeks. Results: Both HbA1c and FPG decreased from baseline with each treatment, with no statistically significant differences between treatments. A significantly lower incidence of reported hypoglycaemia was observed with sitagliptin compared with sulfonylurea (6.2% vs. 27.8%; p < 0.001). Body weight decreased significantly with sitagliptin but not with sulfonylurea. Significantly more patients on sitagliptin than on sulfonylureas achieved a composite end-point of >0.5% HbA1c reduction with no reported hypoglycaemia or increase in body weight (44.1% vs. 16.0%; p < 0.001). Conclusion: In this analysis of elderly patients with T2DM, compared with sulfonylurea, sitagliptin provided similar glycaemic efficacy with less hypoglycaemia and with body weight loss.
Introduction The global prevalence of type 2 diabetes mellitus (T2DM) in the population aged 20–79 years is expected to increase from 8.3% (382 million patients) in 2013 to 10.1% (592 million patients) in 2035 (1). The fraction of these patients who are elderly (≥ 65 years of age) is anticipated to increase disproportionately because of increases in the proportion of elderly people in the overall population (2), the prevalence of T2DM in elderly people population (3), and the longevity of patients diagnosed with T2DM at ages < 65 years (4). It is predicted that the number of elderly patients with T2DM will ª 2015 John Wiley & Sons Ltd Int J Clin Pract doi: 10.1111/ijcp.12607
Sulfonylureas are commonly used to treat T2DM in elderly patients, but they are associated with an increased risk of hypoglycaemia. The DPP-4 inhibitor sitagliptin is associated with a low rate of hypoglycaemia.
What’s new This article provides evidence that, in the treatment of T2DM in the elderly, sitagliptin provides similar efficacy to SU but with a significantly lower incidence of hypoglycaemia and with weight loss.
Merck & Co., Inc., Whitehouse Station, NJ, USA *Present address: Covance, Inc., Princeton, NJ, USA Correspondence to: Ravi Shankar, MD, Merck Research Laboratories, RY34A260, Rahway, NJ 07065, USA Tel.: + 732 594 3046 Fax: + 732 594 9868 Email: ravi.shankar3@merck. com
Disclosures All authors are, or were, employees of Merck & Co. Inc., and may own shares of Merck & Co., Inc. stock or stock options.
increase from nearly 60 million in 2000 to over 120 million by 2030 (5). As in all patients with T2DM, poor glucose control is associated with microvascular complications in elderly patients (6) necessitating the achievement and maintenance of glycaemic control in this population. However, improving glycaemic control in elderly people with T2DM presents unique challenges, in part because of the increased risk of hypoglycaemia in older patients (7–9). Hypoglycaemia is associated with increased morbidity and, in some studies, with increased mortality (10) and is known to have a deleterious effect on patients’ quality of life (11). Elderly patients have compromised counter-regulatory
1
2
Sitagliptin in elderly patients with T2DM
hormone response to hypoglycaemia (12) and decreased awareness of hypoglycaemia (8). This may make the use of sulfonylureas, which lower glucose in a non-glucose-dependent manner and thus causing hypoglycaemia (8), particularly problematic for elderly patients. In an observational study of 3810 patients in primary care, Bramlage et al. (9) found that patients ≥ 70 years of age with T2DM were more frequently treated with sulfonylurea and less frequently treated with metformin, thiazolidinediones or DPP-4 inhibitors, that higher rates of hypoglycaemia were observed in the oldest group of patients analysed, and that use of sulfonylurea was associated with hypoglycaemic events (9). In addition, in a study of 130 hospitalised patients, Deusenberry et al. (13) observed that elderly patients were at increased risk, compared with younger patients, for sulfonylurearelated hypoglycaemia during hospitalisation. Many effective oral antihyperglycaemic medications, including metformin, thiazolidinediones and sulfonylureas, may be contraindicated in some elderly patients because of comorbid conditions (14). Thus, there is a clear need for improvement in the glycaemic control of hyperglycaemia in elderly patients with T2DM using safe and effective agents, and in particular, agents that improve glycaemic control with a low incidence of hypoglycaemia. Sitagliptin is a selective, oral, DPP-4 inhibitor (15) that improves glycaemic control with a low risk of hypoglycaemia when used alone, or in combination with metformin (16–24) or pioglitazone (25,26). Here, we used pooled data from three clinical trials to compare glycaemic efficacy, reported adverse events of hypoglycaemia, and changes in body weight in elderly (≥ 65 years of age) patients with T2DM who received either sitagliptin or a sulfonylurea.
Methods Data sources In this post hoc analysis, data from all patients ≥ 65 years of age who were randomised to receive either sitagliptin 100 mg (total daily dose) or a sulfonylurea, who had HbA1c data at the analysis time point, and who had no major protocol violations were pooled from three randomised double-blind studies (16,18,22,27) (Table 1). In the three original studies, key exclusion criteria included: a history of type 1 diabetes mellitus; renal impairment inconsistent with the use of metformin (Studies 2 and 3); and a fasting plasma glucose (FPG) (or a fasting fingerstick glucose) at or just prior to randomisation > 270 mg/dl (15.0 mmol/l) (Study 2) or < 110 or < 240 mg/dl (< 6.1 or > 13.3 mmol/l) (Study 3) [baseline FPG ≥ 130 and ≤ 240 mg/dl (≥ 7.22 mmol/l and ≤ 13.32 mmol/l) was an inclusion criterion for Study 1]. In all three studies, all patients provided written informed consent to participate, and study protocols were reviewed and approved by the appropriate committees and authorities for each study site. Each study was performed in accordance with the Declaration of Helsinki.
Analysis end-points The end-points presented here include change from baseline in HbA1c, fasting plasma glucose (FPG), and body weight. The percentages of patients with at least one adverse event (AE) of symptomatic hypoglycaemia during the period evaluated were calculated. An AE of symptomatic hypoglycaemia was defined as any episode with symptoms consistent with hypoglycaemia (e.g. weakness, dizziness, shakiness, increased sweating, palpitations or confusion)
Table 1 Key features of studies from which analysis population was drawn
Study
Duration (weeks)
Sample size (N)
Age (years)
Baseline HbA1c (%)
Background therapy
Treatment group sizes (N)
Treatment doses (mg/day)*
Study 1 NCT00482079
12 extended to 104
743
21–76
6.5– 0.5% with no symptomatic hypoglycaemia and no body weight gain at the end of the study periods were also calculated.
Statistical analysis The time point chosen for the analyses reported here was the latest time point approximately common to all three studies. For glycaemic end-points and hypoglycaemia, the time point analysed was Week 25 in Study 1 and Week 30 in Studies 2 and 3. For body weight, the time point analysed was Week 25 in Study 1, Week 24 in Study 2 and Week 30 in Study 3. The population chosen for analysis was the subset of patients ≥ 65 years of age from the primary study population (per-protocol) for Study 2 and Study 3 and the analogous population for Study 1 (i.e. who had HbA1c measurements at baseline and at the analysis time point for the respective study and no major protocol violations). Analysis of covariance was used to compare the change from baseline for continuous end-points at the time points described. The model controlled for treatment, study and baseline value. Percentages and event rates were assessed using the method of Miettinen and Nurminen (28) stratified by study. Event rates were calculated as number of events divided by the total patient-years of exposure.
Results Of the 500 randomised patients ≥ 65 years of age in the three studies (N = 243 treated with sitagliptin and N = 257 treated with a sulfonylurea), 372
(74.4%) met the criteria outlined above and were included in this analysis [N = 178 (73.3%) treated with sitagliptin and N = 194 (75.5%) treated with a sulfonylurea]. Baseline demographical and anthropometric characteristics of patients in the two arms of the pooled study cohort were similar (Table 2). After 25–30 weeks of treatment, the effects of sitagliptin on HbA1c and FPG changes from baseline were similar to those observed with sulfonylureas [Figures 1A (p = 0.399) and B (p = 0.457), respectively]. Body weight in the sitagliptin group decreased from baseline by 1.7 kg (p < 0.001), while in the sulfonylurea group it increased by 0.5 kg (p = 0.066). The between-group difference of 2.2 kg was statistically significant (p < 0.001). In the three studies, 23 events of symptomatic hypoglycaemia occurred in the sitagliptin group during a cumulative exposure of 102.0 patient-years, and 252 events occurred in the sulfonylurea group during a cumulative exposure of 111.0 patient-years. The proportion of patients in the sitagliptin group who had at least one episode of symptomatic hypoglycaemia reported (6.2%) was significantly lower (p < 0.001) compared to patients in the sulfonylurea group (27.8%). In addition, the event rate of symptomatic hypoglycaemia was significantly lower (p < 0.001) in the sitagliptin group (22.5 events per 100 patient-years of follow-up) compared with the sulfonylurea group (227.0 events per 100 patientyears of follow-up). Of those patients whose baseline HbA1c was ≥ 8.0%, ≥ 7.0% or ≥ 6.5%, the proportion with HbA1c goals of < 8.0% (sitagliptin = 37/46, 80.4%; SU = 39/45, 86.7%), < 7.0% (sitagliptin = 78/136; 57.4%, SU = 80/143, 55.9%) or < 6.5% (sitagliptin = 59/173, 34.1%; SU = 64/184, 34.8%), respectively, were comparable in the two groups.
Table 2 Baseline demographical and anthropometric characteristics of patients in the pooled study cohort
Age, years (min, max) Gender, male, n (%) Body weight (kg) Body mass index (kg/m2) Duration of T2DM, years* HbA1c (%) FPG (mg/dl)
Sitagliptin, n = 178
Sulfonylureas, n = 194
69.1 3.3 (65, 79) 105 (59.0) 84.6 14.6 30.3 4.3 6.0 7.5 0.7 150.6 32.6
69.4 3.8 (65, 80) 126 (64.9) 83.7 15.1 29.8 4.3 6.0 7.5 0.8 157.2 38.5
*Median. Data are mean SD unless otherwise indicated. T2DM, type 2 diabetes mellitus; FPG, fasting plasma glucose; to convert FPG in mg/dl to mmol/l divide by 18.
ª 2015 John Wiley & Sons Ltd Int J Clin Pract
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Sitagliptin in elderly patients with T2DM
HbA1c change from baseline, % (LS mean ± 95% CI)
(A)
0.0 –0.2 –0.4 –0.6 –0.8 –0.72 –1.0 –1.2 –1.4
FPG change from baseline, mg/dl (LS mean ± 95% CI)
–0.77 p = 0.399
Sitagliptin (N = 178) Sulfonylurea (N = 194)
0
(B)
–5 –10 –15 –20 –25 –21.0
–22.9
–30 p = 0.457 –35 –40
Sitagliptin (N = 176) Sulfonylurea (N = 194)
Figure 1 (A) HbA1c change from baseline. (B) FPG change from baseline
A significantly higher percentage of patients in the sitagliptin group than in the sulfonylurea group achieved an HbA1c decrease of > 0.5% with no 60 Percent of patients achieving composite endpoint
4
reported AE of symptomatic hypoglycaemia and no increase in body weight (44.1% with sitagliptin vs. 16.0% with SU, p < 0.001, Figure 2).
Sitagliptin (N = 177) Sulfonylurea (N = 194) p < 0.001
50 44.1 40 30 20
16.0
10 0
Figure 2 Per cent of patients meeting the composite end-point of A1C decrease > 0.5% with no symptomatic
hypoglycaemia and no body weight gain ª 2015 John Wiley & Sons Ltd Int J Clin Pract
Sitagliptin in elderly patients with T2DM
Discussion In this post hoc, pooled analysis, sitagliptin was compared with sulfonylurea in elderly patients with T2DM. Compared with sulfonylurea, sitagliptin was associated with similar glycaemic efficacy, with decreases in the incidence of symptomatic hypoglycaemia and in body weight, and an increase in the proportion of patients meeting a composite end-point of HbA1c decrease of > 0.5%, no symptomatic hypoglycaemia and no increase in body weight. The results of these analyses in the subset of elderly patients are consistent with the results observed in overall populations of the individual studies (16,18,22,27). In this analysis, the efficacy of sitagliptin and sulfonylureas was similar, while the two agents differed with regard to AEs of hypoglycaemia. This difference is likely because of the two agents’ distinct mechanisms of action (15,29). The higher levels of insulin achieved during treatment with sulfonylureas may also be responsible for the weight gain associated with its use (30). The incidence of hypoglycaemia in this analysis was based on reported AEs (defined as any episode with symptoms consistent with hypoglycaemia regardless of blood glucose levels) and not on mea-
References 1 International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Brussels: International Diabetes Federation, 2013. 2 Kinsella K, Velkoff VA. An Aging World. Washington, DC: Government Printing Office, 2001. 3 Perry HM III. The endocrinology of aging. Clin Chem 1999; 45: 1369–76. 4 Gregg EW, Cheng YJ, Saydah S et al. Trends in death rates among U.S. adults with and without diabetes between 1997 and 2006: findings from the National Health Interview Survey. Diabetes Care 2012; 35: 1252–7. 5 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: 1047–53. 6 Nathan DM, Singer DE, Godine JE, Harrington CH, Perlmuter LC. Retinopathy in older type II diabetics. Association with glucose control. Diabetes 1986; 35: 797–801. 7 Holstein A, Hammer C, Hahn M, Kulamadayil NS, Kovacs P. Severe sulfonylurea-induced hypoglycemia: a problem of uncritical prescription and deficiencies of diabetes care in geriatric patients. Expert Opin Drug Saf 2010; 9: 675–81. 8 Bremer JP, Jauch-Chara K, Hallschmid M, Schmid S, Schultes B. Hypoglycemia unawareness in older compared with middle-aged patients with type 2 diabetes. Diabetes Care 2009; 32: 1513–7. 9 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
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surements of blood glucose levels; therefore, it is possible that the number of hypoglycaemic episodes reported by patients was underestimated because of hypoglycaemia unawareness in elderly people (31). In summary, in this analysis of elderly patients with T2DM, compared with sulfonylurea, sitagliptin provided similar glycaemic efficacy with less hypoglycaemia and with body weight loss.
Acknowledgements This analysis and its publication were funded by Merck & Co., Inc., Whitehouse Station, NJ, USA. The authors acknowledge the contributions of Sheila Erespe of Merck & Co., Inc., for assistance with submission of this article.
Author contributions RRS, SSE, LX, GTG, KDK and BJG contributed to the conception and design of this analysis; LX and GTG were primarily responsible for statistical analysis, RRS and EAO drafted the article, all authors contributed to data interpretation and participated in critical revision and final approval of the article.
glucose control and the risk of hypoglycemia. Cardiovasc Diabetol 2012; 11: 122. Holstein A, Egberts EH. Risk of hypoglycaemia with oral antidiabetic agents in patients with Type 2 diabetes. Exp Clin Endocrinol Diabetes 2003; 111: 405–14. Vexiau P, Mavros P, Krishnarajah G, Lyu R, Yin D. Hypoglycaemia in patients with type 2 diabetes treated with a combination of metformin and sulphonylurea therapy in France. Diabetes Obes Metab 2008; 10(Suppl. 1): 16–24. Meneilly GS, Cheung E, Tuokko H. Counterregulatory hormone responses to hypoglycemia in the elderly patient with diabetes. Diabetes 1994; 43: 403–10. Deusenberry CM, Coley KC, Korytkowski MT, Donihi AC. Hypoglycemia in hospitalized patients treated with sulfonylureas. Pharmacotherapy 2012; 32: 613–7. Mazza AD, Morley JE. Update on diabetes in the elderly and the application of current therapeutics. J Am Med Dir Assoc 2007; 8: 489–92. 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: 761–7. Arechavaleta R, Seck T, Chen Y 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: 160–8. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin
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therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006; 29: 2638–43. 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: 194–205. Raz I, Chen Y, Wu M et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin 2008; 24: 537–50. Reasner C, Olansky L, Seck TL et al. The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2011; 13: 644–52. Scott R, Loeys T, Davies MJ, Engel SS. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2008; 10: 959–69. Seck T, Nauck M, Sheng D 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: 562–76. Williams-Herman D, Johnson J, Teng R et al. Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study. Curr Med Res Opin 2009; 25: 569–83.
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24 Williams-Herman D, Johnson J, Teng R et al. Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes. Diabetes Obes Metab 2010; 12: 442–51. 25 Henry RR, Staels B, Fonseca VA et al. Efficacy and safety of initial combination treatment with sitagliptin and pioglitazone-a factorial study. Diabetes Obes Metab 2014; 16: 223–30. doi:10.1111/dom.12194. 26 Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week,
multicenter, randomized, double-blind, placebocontrolled, parallel-group study. Clin Ther 2006; 28: 1556–68. 27 Scott R, Wu M, Sanchez M, Stein P. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Int J Clin Pract 2007; 61: 171–80. 28 Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985; 4: 213–26. 29 Panten U, Schwanstecher M, Schwanstecher C. Sulfonylurea receptors and mechanism of sulfonylurea action. Exp Clin Endocrinol Diabetes 1996; 104: 1–9.
30 Barnett AH. Complementing insulin therapy to achieve glycemic control. Adv Ther 2013; 30: 557– 76. 31 Segel SA, Paramore DS, Cryer PE. Hypoglycemiaassociated autonomic failure in advanced type 2 diabetes. Diabetes 2002; 51: 724–33.
Paper received May 2014, accepted December 2014
ª 2015 John Wiley & Sons Ltd Int J Clin Pract
A comparison of glycaemic effects of sitagliptin and sulfonylureas in elderly patients with type 2 diabetes mellitus R. R. Shankar, L. Xu, G. T. Golm, E. A. O’Neill, B. J. Goldstein,* K. D. Kaufman, S. S. Engel
SUMMARY
What’s known
Introduction: In the USA, 45% of patients with type 2 diabetes mellitus (T2DM) are elderly (≥ 65 years old). In general, use of sulfonylurea increases with patient age as does the associated risk for hypoglycaemia, and the consequences of hypoglycaemia can be more pronounced in elderly patients. Sitagliptin, a DPP-4 inhibitor, improves glycaemic control in adult patients of all ages with T2DM, with a low risk of hypoglycaemia when used alone or in combination with other antidiabetic agents that are not generally associated with hypoglycaemia when used independently. Methods: In a post hoc analysis, pooled data from elderly patients who participated in one of three double-blind studies comparing the effects of therapy with sitagliptin (100 mg/day) vs. sulfonylurea (in titrated doses) were analysed for changes from baseline in HbA1c, fasting plasma glucose (FPG), and body weight and for the incidence of reported symptomatic hypoglycaemia. In these studies, patients on diet alone or metformin were randomised to sitagliptin or glipizide for 104 weeks (studies 1 and 2) or glimepiride for 30 weeks (study 3). The analysis included 372 elderly patients who completed a trial through 25 or 30 weeks. Results: Both HbA1c and FPG decreased from baseline with each treatment, with no statistically significant differences between treatments. A significantly lower incidence of reported hypoglycaemia was observed with sitagliptin compared with sulfonylurea (6.2% vs. 27.8%; p < 0.001). Body weight decreased significantly with sitagliptin but not with sulfonylurea. Significantly more patients on sitagliptin than on sulfonylureas achieved a composite end-point of >0.5% HbA1c reduction with no reported hypoglycaemia or increase in body weight (44.1% vs. 16.0%; p < 0.001). Conclusion: In this analysis of elderly patients with T2DM, compared with sulfonylurea, sitagliptin provided similar glycaemic efficacy with less hypoglycaemia and with body weight loss.
Introduction The global prevalence of type 2 diabetes mellitus (T2DM) in the population aged 20–79 years is expected to increase from 8.3% (382 million patients) in 2013 to 10.1% (592 million patients) in 2035 (1). The fraction of these patients who are elderly (≥ 65 years of age) is anticipated to increase disproportionately because of increases in the proportion of elderly people in the overall population (2), the prevalence of T2DM in elderly people population (3), and the longevity of patients diagnosed with T2DM at ages < 65 years (4). It is predicted that the number of elderly patients with T2DM will ª 2015 John Wiley & Sons Ltd Int J Clin Pract doi: 10.1111/ijcp.12607
Sulfonylureas are commonly used to treat T2DM in elderly patients, but they are associated with an increased risk of hypoglycaemia. The DPP-4 inhibitor sitagliptin is associated with a low rate of hypoglycaemia.
What’s new This article provides evidence that, in the treatment of T2DM in the elderly, sitagliptin provides similar efficacy to SU but with a significantly lower incidence of hypoglycaemia and with weight loss.
Merck & Co., Inc., Whitehouse Station, NJ, USA *Present address: Covance, Inc., Princeton, NJ, USA Correspondence to: Ravi Shankar, MD, Merck Research Laboratories, RY34A260, Rahway, NJ 07065, USA Tel.: + 732 594 3046 Fax: + 732 594 9868 Email: ravi.shankar3@merck. com
Disclosures All authors are, or were, employees of Merck & Co. Inc., and may own shares of Merck & Co., Inc. stock or stock options.
increase from nearly 60 million in 2000 to over 120 million by 2030 (5). As in all patients with T2DM, poor glucose control is associated with microvascular complications in elderly patients (6) necessitating the achievement and maintenance of glycaemic control in this population. However, improving glycaemic control in elderly people with T2DM presents unique challenges, in part because of the increased risk of hypoglycaemia in older patients (7–9). Hypoglycaemia is associated with increased morbidity and, in some studies, with increased mortality (10) and is known to have a deleterious effect on patients’ quality of life (11). Elderly patients have compromised counter-regulatory
1
2
Sitagliptin in elderly patients with T2DM
hormone response to hypoglycaemia (12) and decreased awareness of hypoglycaemia (8). This may make the use of sulfonylureas, which lower glucose in a non-glucose-dependent manner and thus causing hypoglycaemia (8), particularly problematic for elderly patients. In an observational study of 3810 patients in primary care, Bramlage et al. (9) found that patients ≥ 70 years of age with T2DM were more frequently treated with sulfonylurea and less frequently treated with metformin, thiazolidinediones or DPP-4 inhibitors, that higher rates of hypoglycaemia were observed in the oldest group of patients analysed, and that use of sulfonylurea was associated with hypoglycaemic events (9). In addition, in a study of 130 hospitalised patients, Deusenberry et al. (13) observed that elderly patients were at increased risk, compared with younger patients, for sulfonylurearelated hypoglycaemia during hospitalisation. Many effective oral antihyperglycaemic medications, including metformin, thiazolidinediones and sulfonylureas, may be contraindicated in some elderly patients because of comorbid conditions (14). Thus, there is a clear need for improvement in the glycaemic control of hyperglycaemia in elderly patients with T2DM using safe and effective agents, and in particular, agents that improve glycaemic control with a low incidence of hypoglycaemia. Sitagliptin is a selective, oral, DPP-4 inhibitor (15) that improves glycaemic control with a low risk of hypoglycaemia when used alone, or in combination with metformin (16–24) or pioglitazone (25,26). Here, we used pooled data from three clinical trials to compare glycaemic efficacy, reported adverse events of hypoglycaemia, and changes in body weight in elderly (≥ 65 years of age) patients with T2DM who received either sitagliptin or a sulfonylurea.
Methods Data sources In this post hoc analysis, data from all patients ≥ 65 years of age who were randomised to receive either sitagliptin 100 mg (total daily dose) or a sulfonylurea, who had HbA1c data at the analysis time point, and who had no major protocol violations were pooled from three randomised double-blind studies (16,18,22,27) (Table 1). In the three original studies, key exclusion criteria included: a history of type 1 diabetes mellitus; renal impairment inconsistent with the use of metformin (Studies 2 and 3); and a fasting plasma glucose (FPG) (or a fasting fingerstick glucose) at or just prior to randomisation > 270 mg/dl (15.0 mmol/l) (Study 2) or < 110 or < 240 mg/dl (< 6.1 or > 13.3 mmol/l) (Study 3) [baseline FPG ≥ 130 and ≤ 240 mg/dl (≥ 7.22 mmol/l and ≤ 13.32 mmol/l) was an inclusion criterion for Study 1]. In all three studies, all patients provided written informed consent to participate, and study protocols were reviewed and approved by the appropriate committees and authorities for each study site. Each study was performed in accordance with the Declaration of Helsinki.
Analysis end-points The end-points presented here include change from baseline in HbA1c, fasting plasma glucose (FPG), and body weight. The percentages of patients with at least one adverse event (AE) of symptomatic hypoglycaemia during the period evaluated were calculated. An AE of symptomatic hypoglycaemia was defined as any episode with symptoms consistent with hypoglycaemia (e.g. weakness, dizziness, shakiness, increased sweating, palpitations or confusion)
Table 1 Key features of studies from which analysis population was drawn
Study
Duration (weeks)
Sample size (N)
Age (years)
Baseline HbA1c (%)
Background therapy
Treatment group sizes (N)
Treatment doses (mg/day)*
Study 1 NCT00482079
12 extended to 104
743
21–76
6.5– 0.5% with no symptomatic hypoglycaemia and no body weight gain at the end of the study periods were also calculated.
Statistical analysis The time point chosen for the analyses reported here was the latest time point approximately common to all three studies. For glycaemic end-points and hypoglycaemia, the time point analysed was Week 25 in Study 1 and Week 30 in Studies 2 and 3. For body weight, the time point analysed was Week 25 in Study 1, Week 24 in Study 2 and Week 30 in Study 3. The population chosen for analysis was the subset of patients ≥ 65 years of age from the primary study population (per-protocol) for Study 2 and Study 3 and the analogous population for Study 1 (i.e. who had HbA1c measurements at baseline and at the analysis time point for the respective study and no major protocol violations). Analysis of covariance was used to compare the change from baseline for continuous end-points at the time points described. The model controlled for treatment, study and baseline value. Percentages and event rates were assessed using the method of Miettinen and Nurminen (28) stratified by study. Event rates were calculated as number of events divided by the total patient-years of exposure.
Results Of the 500 randomised patients ≥ 65 years of age in the three studies (N = 243 treated with sitagliptin and N = 257 treated with a sulfonylurea), 372
(74.4%) met the criteria outlined above and were included in this analysis [N = 178 (73.3%) treated with sitagliptin and N = 194 (75.5%) treated with a sulfonylurea]. Baseline demographical and anthropometric characteristics of patients in the two arms of the pooled study cohort were similar (Table 2). After 25–30 weeks of treatment, the effects of sitagliptin on HbA1c and FPG changes from baseline were similar to those observed with sulfonylureas [Figures 1A (p = 0.399) and B (p = 0.457), respectively]. Body weight in the sitagliptin group decreased from baseline by 1.7 kg (p < 0.001), while in the sulfonylurea group it increased by 0.5 kg (p = 0.066). The between-group difference of 2.2 kg was statistically significant (p < 0.001). In the three studies, 23 events of symptomatic hypoglycaemia occurred in the sitagliptin group during a cumulative exposure of 102.0 patient-years, and 252 events occurred in the sulfonylurea group during a cumulative exposure of 111.0 patient-years. The proportion of patients in the sitagliptin group who had at least one episode of symptomatic hypoglycaemia reported (6.2%) was significantly lower (p < 0.001) compared to patients in the sulfonylurea group (27.8%). In addition, the event rate of symptomatic hypoglycaemia was significantly lower (p < 0.001) in the sitagliptin group (22.5 events per 100 patient-years of follow-up) compared with the sulfonylurea group (227.0 events per 100 patientyears of follow-up). Of those patients whose baseline HbA1c was ≥ 8.0%, ≥ 7.0% or ≥ 6.5%, the proportion with HbA1c goals of < 8.0% (sitagliptin = 37/46, 80.4%; SU = 39/45, 86.7%), < 7.0% (sitagliptin = 78/136; 57.4%, SU = 80/143, 55.9%) or < 6.5% (sitagliptin = 59/173, 34.1%; SU = 64/184, 34.8%), respectively, were comparable in the two groups.
Table 2 Baseline demographical and anthropometric characteristics of patients in the pooled study cohort
Age, years (min, max) Gender, male, n (%) Body weight (kg) Body mass index (kg/m2) Duration of T2DM, years* HbA1c (%) FPG (mg/dl)
Sitagliptin, n = 178
Sulfonylureas, n = 194
69.1 3.3 (65, 79) 105 (59.0) 84.6 14.6 30.3 4.3 6.0 7.5 0.7 150.6 32.6
69.4 3.8 (65, 80) 126 (64.9) 83.7 15.1 29.8 4.3 6.0 7.5 0.8 157.2 38.5
*Median. Data are mean SD unless otherwise indicated. T2DM, type 2 diabetes mellitus; FPG, fasting plasma glucose; to convert FPG in mg/dl to mmol/l divide by 18.
ª 2015 John Wiley & Sons Ltd Int J Clin Pract
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Sitagliptin in elderly patients with T2DM
HbA1c change from baseline, % (LS mean ± 95% CI)
(A)
0.0 –0.2 –0.4 –0.6 –0.8 –0.72 –1.0 –1.2 –1.4
FPG change from baseline, mg/dl (LS mean ± 95% CI)
–0.77 p = 0.399
Sitagliptin (N = 178) Sulfonylurea (N = 194)
0
(B)
–5 –10 –15 –20 –25 –21.0
–22.9
–30 p = 0.457 –35 –40
Sitagliptin (N = 176) Sulfonylurea (N = 194)
Figure 1 (A) HbA1c change from baseline. (B) FPG change from baseline
A significantly higher percentage of patients in the sitagliptin group than in the sulfonylurea group achieved an HbA1c decrease of > 0.5% with no 60 Percent of patients achieving composite endpoint
4
reported AE of symptomatic hypoglycaemia and no increase in body weight (44.1% with sitagliptin vs. 16.0% with SU, p < 0.001, Figure 2).
Sitagliptin (N = 177) Sulfonylurea (N = 194) p < 0.001
50 44.1 40 30 20
16.0
10 0
Figure 2 Per cent of patients meeting the composite end-point of A1C decrease > 0.5% with no symptomatic
hypoglycaemia and no body weight gain ª 2015 John Wiley & Sons Ltd Int J Clin Pract
Sitagliptin in elderly patients with T2DM
Discussion In this post hoc, pooled analysis, sitagliptin was compared with sulfonylurea in elderly patients with T2DM. Compared with sulfonylurea, sitagliptin was associated with similar glycaemic efficacy, with decreases in the incidence of symptomatic hypoglycaemia and in body weight, and an increase in the proportion of patients meeting a composite end-point of HbA1c decrease of > 0.5%, no symptomatic hypoglycaemia and no increase in body weight. The results of these analyses in the subset of elderly patients are consistent with the results observed in overall populations of the individual studies (16,18,22,27). In this analysis, the efficacy of sitagliptin and sulfonylureas was similar, while the two agents differed with regard to AEs of hypoglycaemia. This difference is likely because of the two agents’ distinct mechanisms of action (15,29). The higher levels of insulin achieved during treatment with sulfonylureas may also be responsible for the weight gain associated with its use (30). The incidence of hypoglycaemia in this analysis was based on reported AEs (defined as any episode with symptoms consistent with hypoglycaemia regardless of blood glucose levels) and not on mea-
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Acknowledgements This analysis and its publication were funded by Merck & Co., Inc., Whitehouse Station, NJ, USA. The authors acknowledge the contributions of Sheila Erespe of Merck & Co., Inc., for assistance with submission of this article.
Author contributions RRS, SSE, LX, GTG, KDK and BJG contributed to the conception and design of this analysis; LX and GTG were primarily responsible for statistical analysis, RRS and EAO drafted the article, all authors contributed to data interpretation and participated in critical revision and final approval of the article.
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Paper received May 2014, accepted December 2014
ª 2015 John Wiley & Sons Ltd Int J Clin Pract
