Safety and Efficacy of Treatment with Sitagliptin or Glipizide in Patients with Type 2 Diabetes Inadequately Controlled on Metformin: A 2-year Study

T. Seck; M. Nauck; D. Sheng; S. Sunga; M. J. Davies; P. P. Stein; K. D. Kaufman; J. M. Amatruda

Int J Clin Pract. 2010;65(5):562-576.

Abstract and Introduction

Abstract

Objectives: To evaluate the 2-year safety and efficacy of adding sitagliptin or glipizide to ongoing metformin in patients with type 2 diabetes.
Methods: Patients who were on a stable dose of metformin (≥ 1500 mg/day) for at least 8 weeks were randomised in a double-blind manner to receive either sitagliptin 100 mg q.d. (N = 588) or glipizide 5 mg/day (up-titrated up to 20 mg/day based upon prespecified glycaemic criteria) (N = 584). The efficacy analysis assessed the change in HbA_1c from baseline using the per-protocol (PP) population.
Results: For the PP cohort, mean baseline HbA_1c was 7.3% in both groups. After 2 years, the least squares (LS) mean change in HbA_1c from baseline [95% confidence interval (CI)] was −0.54% (−0.64, −0.45) with sitagliptin (n = 248) and −0.51% (−0.60, −0.42) with glipizide (n = 256). The rise in HbA_1c from week 24 to week 104 [i.e. coefficient of durability (COD)] was smaller with sitagliptin [COD (95% CI) 0.16%/year (0.10, 0.21)] compared with glipizide [0.26%/year (0.21, 0.31)]. The proportion of patients with an HbA_1c< 7% was 63% and 59% with sitagliptin and glipizide, respectively. The beta-cell responsiveness to a meal challenge was maintained with sitagliptin and decreased with glipizide. The proportion of patients who reported hypoglycaemia was 5% with sitagliptin and 34% with glipizide [difference in proportions (95% CI) = −29% (−33, −25)]. Relative to baseline, sitagliptin was associated with weight loss (−1.6 kg) compared with weight gain (+0.7 kg) with glipizide.
Conclusion: In patients with type 2 diabetes, adding sitagliptin to metformin monotherapy improved glycaemic control over 2 years, similar to the glucose-lowering efficacy observed with adding glipizide, but with greater durability and generally better maintenance of beta-cell function. Sitagliptin was generally well tolerated with a lower risk of hypoglycaemia and weight loss compared with weight gain observed with glipizide.

Introduction

Due to the progressive nature of the disease, over time, patients with type 2 diabetes often require combinations of medications to maintain glycaemic control.^[1] Metformin is the most commonly prescribed oral antihyperglycaemic agent for initial therapy.^[2–4] Incretin-based therapies (e.g. dipeptidyl peptidase-4 (DPP-4) inhibitors and analogues of glucagon-like peptide-1) are newer antihyperglycaemic agents available for the treatment of type 2 diabetes.^[5] In studies of up to 30 weeks, sitagliptin, a DPP-4 inhibitor, added when metformin alone did not provide adequate glycaemic control, significantly improved fasting and postprandial glucose levels and measures of beta-cell function in patients with type 2 diabetes.^[6–8] A previous clinical study showed that the addition of sitagliptin to ongoing metformin therapy provided similar improvement in HbA_1c relative to the addition of rosiglitazone.^[8] The previously reported results from the first year of the present study^[9] showed that compared with the addition of glipizide therapy, the addition of sitagliptin to metformin provided similar glycaemic efficacy with a markedly lower incidence of hypoglycaemia and with weight loss compared with weight gain with the sulfonylurea. While the primary time point for analysis for the present study was at 1 year, the study continued as a randomised, double-blind, active-controlled study for an additional year. The results over the 2-year treatment period are reported herein.

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Cite this: Safety and Efficacy of Treatment with Sitagliptin or Glipizide in Patients with Type 2 Diabetes Inadequately Controlled on Metformin: A 2-year Study - Medscape - Mar 01, 2010.

Table 1. Baseline demographics and efficacy endpoint data for the 2-year per-protocol cohort
Characteristic	Sitagliptin + Metformin (n = 248)	Glipizide + Metformin (n = 256)
Age, years	57.6 (8.5)	57.0 (9.1)
Gender, n (%)
Male	142 (57.3)	161 (62.9)
Female	106 (42.7)	95 (37.1)
Race, n (%)
Caucasian	192 (77.4)	201 (78.5)
Black	9 (3.6)	13 (5.1)
Hispanic	14 (5.6)	13 (5.1)
Asian	23 (9.3)	21 (8.2)
Other	10 (4.0)	8 (3.1)
Body weight, kg	88.5 (16.8)	90.3 (16.5)
Body mass index, kg/m²	30.9 (4.8)	31.3 (5.0)
Duration of type 2 diabetes, years	5.8 (5.7)	5.7 (4.9)
Use of oral AHA at screening, n (%)
Dual therapy	53 (21.4)	48 (18.8)
Monotherapy	183 (73.8)	193 (75.4)
None	12 (4.8)	15 (5.9)
HbA_1c, % (Range)*	7.3 (0.6) (6.1–9.3)	7.3 (0.7) (5.8–9.9)
HbA_1c distribution at baseline, n (%)
HbA_1c < 7%	88 (35.5)	89 (34.8)
HbA_1c ≥ 7 and < 8%	114 (46.0)	121 (47.3)
HbA_1c ≥ 8 to < 9%	40 (16.1)	35 (13.7)
HbA_1c ≥ 9%	6 (2.4)	11 (4.3)
Fasting plasma glucose, mmol/l	8.4 (1.7)	8.5 (1.9)

AHA, antihyperglycaemic agent. Data are expressed as mean (± standard deviation) or frequency [n (%)], unless otherwise indicated.
*HbA_1c eligibility criteria for randomisation into the study were based upon HbA_1c values obtained upon initiation of the 2-week single-blind placebo run-in. Baseline HbA_1c measurements were obtained after this run-in period (i.e. at the randomisation visit), and thus baseline HbA_1c values may have been outside the range specified by the eligibility criteria.

Table 2. Key efficacy results in the per-protocol cohort after 2 years of treatment
	n	Week 0 (Baseline) mean (SD)	Week 104 mean (SD)	LS mean change from baseline (95% CI)	Difference in LS mean change (95% CI)
HbA_1c, %
Glipizide + Metformin	256	7.31 (0.74)	6.80 (0.59)	−0.51 (−0.60, −0.42)	−0.03 (−0.13,0.07)
Sitagliptin + Metformin	248	7.30 (0.64)	6.77 (0.58)	−0.54 (−0.64, −0.45)
Fasting plasma glucose, mmol/l
Glipizide + Metformin	251	8.5 (1.9)	7.7 (1.7)	−1.0 (−1.3, −0.7)		−0.1 (−0.4, 0.2)
Sitagliptin + Metformin	249	8.4 (1.7)	7.6 (1.7)	−1.1 (−1.4, −0.8)
Fasting serum insulin, pmol/l
Glipizide + Metformin	241	78.0 (50.4)	94.8 (69.0)	12.6 (4.2, 20.4)	−18.0 (−26.4, −9.0)
Sitagliptin + Metformin	237	78.6 (56.4)	76.8 (43.8)	−5.4 (−13.8, 3.0)
Fasting serum proinsulin, pmol/l
Glipizide + Metformin	249	22.9 (18.0)	26.5 (20.1)	2.1 (−0.7, 4.8)		−6.9 (−9.7, −4.0)
Sitagliptin + Metformin	242	23.9 (20.7)	20.0 (18.3)	−4.8 (−7.6, −2.0)
Proinsulin/insulin ratio
Glipizide + Metformin	240	0.31 (0.16)	0.30 (0.18)	−0.01 (−0.03, 0.02)	−0.04 (−0.07, −0.01)
Sitagliptin + Metformin	235	0.32 (0.17)	0.26 (0.16)	−0.05 (−0.08, −0.02)
HOMA-β (%)
Glipizide + Metformin	234	59.2 (48.2)	77.5 (107.9)	19.2 (5.7, 32.7)		−6.3 (−20.3, 7.6)
Sitagliptin + Metformin	232	59.8 (50.7)	71.2 (58.0)	12.9 (−0.7, 26.5)
HOMA-IR
Glipizide + Metformin	234	5.0 (3.4)	5.6 (5.1)	0.2 (−0.5, 0.9)	−1.1 (−1.8, −0.4)
Sitagliptin + Metformin	232	4.9 (3.8)	4.4 (3.2)	−0.9 (−1.6, −0.2)
QUICKI
Glipizide + Metformin	234	0.314 (0.033)	0.311 (0.029)	−0.001 (−0.005, 0.003)		0.008 (0.003, 0.012)
Sitagliptin + Metformin	232	0.315 (0.029)	0.319 (0.029)	0.006 (0.002, 0.010)

SD, standard deviation; LS, least squares; CI, confidence interval.

Table 3. Baseline and study endpoint results for indices of beta-cell function and insulin sensitivity from the 9-point meal tolerance tests administered following a 4- to 7-day washoff of study drug after 2 years of treatment with sitagliptin or glipizide added to ongoing metformin therapy (per-protocol cohort)
Treatment	n	Baseline mean ± SD	Study endpoint mean ± SD	Mean change from baseline (95% CI)
3-h Glucose AUC (mmol·h/l)
Glipizide + Metformin	94	38.2 ± 7.88	38.3 ± 9.44	−1.40 (−3.46, 0.66)*
Sitagliptin + Metformin	81	37.3 ± 7.51	36.3 ± 7.34	−2.77 (−4.81, −0.73)*
3-h Insulin AUC (pmol·hr/l)
Glipizide + Metformin	80	968 ± 605	1025 ± 655	−39 (−170, 93)*
Sitagliptin + Metformin	69	1219 ± 972	1290 ± 781	47 (−86, 182)*
3-h C-peptide AUC (nmol·hr/l)
Glipizide + Metformin	93	6.6 ± 2.3	6.5 ± 2.5	−0.17 (−0.63, 0.30)*
Sitagliptin + Metformin	81	7.3 ± 2.5	7.6 ± 2.8	0.33 (−0.13, 0.79)*
HOMA-β (%)
Glipizide + Metformin	99	53.3 ± 37.4	58.2 ± 36.6	5.0 (−0.4, 10.3)
Sitagliptin + Metformin	90	60.4 ± 48.8	67.7 ± 56.1	7.3 (0.7, 14.0)
Insulinogenic index (pmol/mmol)
Glipizide + Metformin	83	90 ± 203	67 ± 103	−22 (−76, 32)
Sitagliptin + Metformin	79	57 ± 449	67 ± 46	9 (−97, 108)
Static beta cell sensitivity to glucose index (Φ_s) (10⁻⁹/min)
Glipizide + Metformin	81	28.5 ± 20.3	23.5 ± 14.5	−5.1 (−8.9, −1.2)
Sitagliptin + Metformin	70	29.5 ± 19.1	32.1 ± 19.1	2.6 (−2.3, 7.5)
Dynamic beta cell sensitivity to glucose index (Φ_d) (10⁻⁹)
Glipizide + Metformin	82	501.3 ± 365.5	425.5 ± 264.2	−75.8 (−148.7, −3.0)
Sitagliptin + Metformin	69	521.5 ± 468.3	470.5 ± 282.4	−51.0 (−162.8, 60.9)
Total beta cell sensitivity to glucose index (Φ_total) (10⁻⁹/min)
Glipizide + Metformin	81	11.3 ± 5.0	10.6 ± 4.4	−0.7 (−1.5, 0.1)
Sitagliptin + Metformin	68	12.0 ± 4.2	13.2 ± 5.1	1.1 (0.3, 1.9)
Basal beta cell sensitivity to glucose index (Φ_b) (10⁻⁹/min)
Glipizide + Metformin	91	6.2 ± 3.0	6.7 ± 3.3	0.5 (0.0, 1.0)
Sitagliptin + Metformin	76	6.8 ± 3.3	7.6 ± 3.4	0.8 (0.3, 1.3)
Insulin sensitivity index (ISI)
Glipizide + Metformin	77	3.5 ± 2.3	3.2 ± 2.1	−0.3 (−0.6, 0.0)
Sitagliptin + Metformin	65	3.3 ± 2.1	3.2 ± 1.9	−0.1 (−0.5, 0.3)
Disposition index (DI)
Glipizide + Metformin	69	35.1 ± 21.6	29.2 ± 15.8	−5.9 (−10.4, −1.4)
Sitagliptin + Metformin	60	34.1 ± 16.9	38.0 ± 20.6	3.9 (−1.3, 9.0)
Delay between static phase insulin secretion and glucose concentration (T) (min)
Glipizide + Metformin	78	29.4 ± 39.6	21.4 ± 14.2	−8.0 (−16.8, 0.8)
Sitagliptin + Metformin	69	25.0 ± 16.1	24.1 ± 17.0	−0.9 (−5.3, 3.6)

SD, standard deviation; CI, confidence interval.
*LS mean change from baseline (95% CI).

Table 4. Summary of clinical adverse experiences for the all-patients-as-treated cohort over the 2-year treatment period
	Sitagliptin + Metformin (n = 588) n (%)	Glipizide + Metformin (n = 584) n (%)	Difference: Sitagliptin vs. Glipizide % (95% CI)*
One or more AEs	452 (76.9)	480 (82.2)	−5.3 (−9.9, −0.7)
Drug-related AEs†	97 (16.5)	193 (33.0)	−16.6 (−21.4, −11.7)
Serious AEs (SAEs)	64 (10.9)	73 (12.5)	−1.6 (−5.3, 2.1)
Drug-related SAEs†	1 (0.2)	3 (0.5)	−0.3 (−1.3, 0.5)
Deaths	1 (0.2)	8 (1.4)‡	−1.2 (−2.5, −0.2)
Discontinuations due to AEs	23 (3.9)	29 (5.0)	−1.1 (−3.5, 1.3)
Discontinuations due to drug-related AEs	9 (1.5)	9 (1.5)	−0.0 (−1.6, 1.5)
Discontinuations due to SAEs	10 (1.7)	14 (2.4)	−0.7 (−2.5, 1.0)
Discontinuation due to drug-related SAEs	1 (0.2)	1 (0.2)	−0.0 (−0.8, 0.8)

AE, adverse experience.
*Positive differences indicate that the proportion for the sitagliptin group is higher than the proportion for the glipizide group.
†Considered by the investigator as possibly, probably, or definitely related to study drug. ‡Includes one suicide death occurring 41 days following discontinuation from study.

Table 5. Specific clinical adverse experiences with a higher incidence in one group vs. the other and a between-treatment difference in incidence ≥ 1% for the all patients as treated cohort over the 2-year treatment period
Adverse experience	Sitagliptin + Metformin (N = 588) n (%)	Glipizide + Metformin (N = 584) n (%)	Difference: Sitagliptin vs. Glipizide % (95% CI)*
Sitagliptin > Glipizide
Fatigue	18 (3.1)	11 (1.9)	1.2 (−0.7, 3.1)
Non-cardiac chest pain	11 (1.9)	4 (0.7)	1.2 (−0.2, 2.7)
Cystitis	8 (1.4)	1 (0.2)	1.2 (0.2, 2.5)
Nasopharyngitis	71 (12.1)	61 (10.4)	1.6 (−2.0, 5.3)
Sinusitis	26 (4.4)	18 (3.1)	1.3 (−0.9, 3.6)
Urinary tract infection	44 (7.5)	25 (4.3)	3.2 (0.5, 6.0)
Weight decreased	6 (1.0)	0 (0.0)	1.0 (0.2, 2.2)
Osteoarthritis	18 (3.1)	8 (1.4)	1.7 (−0.0, 3.5)
Pain in extremity	21 (3.6)	9 (1.5)	2.0 (0.2, 4.0)
Dizziness	26 (4.4)	19 (3.3)	1.2 (−1.1, 3.5)
Sciatica	9 (1.5)	3 (0.5)	1.0 (−0.2, 2.4)
Asthma	9 (1.5)	2 (0.3)	1.2 (0.0, 2.6)
Contact dermatitis	9 (1.5)	3 (0.5)	1.0 (−0.2, 2.4)
Glipizide > Sitagliptin
Cataract	3 (0.5)	14 (2.4)	−1.9 (−3.5, −0.5)
Dyspepsia	11 (1.9)	20 (3.4)	−1.6 (−3.5, 0.3)
Toothache	2 (0.3)	12 (2.1)	−1.7 (−3.2, −0.5)
Peripheral oedema	13 (2.2)	22 (3.8)	−1.6 (−3.6, 0.4)
Upper respiratory tract infection	73 (12.4)	79 (13.5)	−1.1 (−5.0, 2.7)
Blood glucose decreased	3 (0.5)	16 (2.7)	−2.2 (−3.9, −0.8)
Hypoglycaemia	31 (5.3)	199 (34.1)	−28.8 (−33.0, −24.5)
Hypoaesthesia	1 (0.2)	10 (1.7)	−1.5 (−3.0, −0.4)
Prostatitis	1 (0.2)	7 (1.2)	−1.0 (−2.3, −0.0)
Cough	23 (3.9)	32 (5.5)	−1.6 (−4.1, 0.9)

CI, confidence interval.
*Positive differences indicate that the proportion for the sitagliptin group is higher than the proportion for the glipizide group. '0.0' and '−0.0' represent rounding for values that are slightly greater and slightly less than zero, respectively.

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