Safety and efficacy of nateglinide/metformin combination therapy in the treatment of type 2 diabetes

Figures & data

Table 1 Study designs and efficacy outcomes

Reference	Description of Study				Efficacy (HbA1c)
	Duration	Number of patients	Study design	Treatment groups	Baseline (%)	Endpoint or Δ baseline Mean ± SE or [95% CI]
Horton et al (2000)	24 wk	701 diet-treated pts	multicenter, double-blind, parallel-group, RCT	Nateglinide (120 mg ac) plus metformin (500 mg tid)	8.4 ± 1.1	−1.4 ± 0.1^a,b
				Nateglinide (120 mg ac)	8.3 ± 1.0	−0.5 ± 0.1a
				Metformin (500 mg tid)	8.4 ± 1.2	−0.8 ± 0.1^a,b
				Placebo	8.3 ± 1.1	+0.5 ± 0.1
Marre et al (2002)	24 wk	467 metformin-treated pts	multicenter, double-blind, parallel-group, RCT	Nateglinide (120 mg ac) added to metformin (1000 mg bid)	8.2	−0.5 [−0.6, −0.1]a
				Nateglinide (60 mg ac) added to metformin (1000 mg bid)	8.0	−0.4 [−0.6, −0.1]a
				Placebo added to metformin (1000 mg bid)	8.3	0
French (2001)	16 wk	192 pts previously treated with Glucovance, SU, or metformin	multicenter, randomized, parallel-group, open-label study, following 4-wk washout from previous medication	Nateglinide (120 mg ac) added to metformin (titrated to 1000 mg bid)	8.2 ± 1.3	−0.7 ± 0.1a
				Repaglinide (titrated to ≤4 mg ac) added to metformin (titrated to 1000 mg bid)	8.4 ± 1.3	−1.3 ± 0.1^a,b
Schatz et al (2003)	3 to 4 mo	11,421 metformin-treated pts	observational study under general practice conditions	Nateglinide (120 mg ac) added to ongoing metformin (mean dose 850 mg bid)	8.4 ± 0.01	7.2 ± 0.01a
Horton et al (2004)	24 wk	401 drug-naïve pts	subanalysis of drug-naïve pts enrolled in a multicenter, double-blind, parallel-group, RCT	Nateglinide (120 mg ac) plus metformin (500 mg tid)	8.2 ± 0.1	−1.6 ± 0.1^a,b
				Nateglinide (120 mg ac)	8.1 ± 0.1	−0.8 ± 0.1a
				Metformin (500 mg tid)	8.3 ± 0.1	−0.8 ± 0.1a
				Placebo	8.2 ± 0.1	+0.3 ± 0.1a
Weaver et al (2004)	12 wk	115 diet-treated pts, 214 metformin-treated pts	multicenter, open-label, parallel-group study	Nateglinide (120 mg ac)	8.1 ± 0.06	−0.8 ± 0.07a
				Nateglinide (120 mg ac) added to metformin	8.1 ± 0.04	−0.7 ± 0.05a
Gerich et al (2005)	2 y	428 drug-naïve pts	multicenter, double-blind, parallel-group, RCT	Nateglinide (120 mg ac) plus metformin (titrated to ≤1000 mg bid)	8.4 ± 1.2	−1.4 ± 0.1a
				Glibenclamide (titrated to ≤5 mg bid) plus metformin (titrated to ≤1000 mg bid)	8.3 ± 1.1	−1.6 ± 0.1a
Ristic et al (2006)	24 wk	262 pts, HbA1c = 6.8%–9.0% on metformin monotherapy	multicenter, double-blind, parallel-group, RCT	Nateglinide (titrated to ≤ 120 mg ac) added to metformin (≥1000 mg/d)	7.7 ± 0.6	−0.4 ± 0.1a
				Gliclazide (titrated to ≤240 mg qd) added to metformin (≥1000 mg/d)	7.6 ± 0.6	−0.6 ± 0.1a
Ristic et al (2007)	1 y	213 pts HbA1c = 6.8%–9.0% on metformin monotherapy	6-mo extension of a 6-mo multicenter, double-blind, parallel-group, RCT	Nateglinide (titrated to ≤ 20 mg ac) added to metformin (≥1000 mg/d)	7.65 ± 0.6	−0.14
				Gliclazide (titrated to ≤ 240 mg qd) added to metformin (≥1000 mg/d)	7.55 ± 0.6	−0.27
Derosa et al (2007)	1 y	248 drug naïve pts	multicenter, double-blind, parallel-group, RCT	Nateglinide and metformin (titrated to 120 mg, ac; 1000 mg, tid)	8.1 ± 1.0	6.4 ± 0.4^a,b
				Glibenclamide and metformin (titrated to 5 mg tid, 1000 mg, tid)	8.2 ± 1.1	7.3 ± 0.6a
Schwarz et al (2008)	2 y	66 drug-naïve pts age ≥65 y	subanalysis of elderly patients enrolled in multicenter, double-blind, parallel-group, RCT	Nateglinide and metformin (titrated to 120 mg, ac; 1000 mg, bid)	7.8 ± 0.2	6.6 ± 0.1a
				Glibenclamide and metformin (titrated to 5 mg bid; 1000 mg, bid)	7.7 ± 0.1	6.5 ± 0.1a

a p < 0.05 or better vs baseline;

b p < 0.05 or better vs comparator.

Abbreviations: RCT, randomized, controlled trial; HbA1c glycosylated hemoglobin.

Figure 1 Adjusted mean change from baseline in glycosylated hemoglobin (HbA_1c), fasting plasma glucose (FPG), and glucose area under the curve (AUC) after Sustacal challenge. All parameters were significantly reduced from baseline (p ≤ 0.0001) in the active treatment groups. All values were significantly reduced compared to placebo (p ≤ 0.0001) except for glucose AUC with metformin monotherapy (not significant, NS). *p ≤ 0.01; **p ≤ 0.001; ***p ≤ 0.0001. Open bars = placebo; light gray bars = nateg-linide monotherapy; dark gray bars = metformin monotherapy; black bars = nateglinide plus metformin (Horton et al 2000). Copyright © 2000 American Diabetes Association. From Diabetes Care®, Vol 23, 2000; 1660–1665. Reprinted with permission from The American Diabetes Association.

Figure 2 Time course of HbA_1c in drug-naïve patients with type 2 diabetes randomized to the nateglinide/metformin combination (closed triangles) or the glyburide/metformin combination (open circles). Mean ± SE, intention-to-treat population (Gerich et al 2005). Copyright © 2005 American Diabetes Association. From Diabetes Care^®, Vol 28, 2005; 2093–2099. Reprinted with permission from The American Diabetes Association.

Table 2 Effects of initial combination therapy with nateglinide (Nate) or glibenclamide (Glyb) plus metformin (Met) on glycemic control and prothrombotic factors during 1-year treatment of overweight and hypertensive patients with type 2 diabetes (Derosa et al 2007)

Mean ± SD	Nate/Met		Glyb/Me
	Baseline	12 months	Baseline	12 months
HbA1c (%)	8.1 ± 1.0	6.4 ± 0.4^b,c	8.2 ± 1.1	7.3 ± 0.6a
FPG (mg/dL)	174 ± 21	138 ± 17b	177 ± 24	136 ± 15b
2-hour PPG (mg/dL)	191 ± 28	150 ± 21b	187 ± 24	166 ± 20a
Lp(a) (mg/dL)	29.3 ± 18.9	20.1 ± 14.2^a,c	28.5 ± 17.4	26.7 ± 16.9
PAI-1 (ng/mL)	44.5 ± 15.9	36.1 ± 13.1^a,c	43.9 ± 16.2	41.3 ± 15.6
Homocysteine (μM)	13.6 ± 2.4	9.2 ± 1.8^a,c	13.9 ± 2.6	12.7 ± 2.2

a p < 0.05 vs baseline,

b p < 0.01 vs baseline,

c p < 0.05 vs glib/met.

Abbreviations: Nate, nateglinide; Glyb, glibenclamide; Met, metformin; FPG, fasting plasma glucose; PPG, postprandial glucose; Lp(a), lipoprotein (a); PAI-1, plasminogen activator inhibitor-1; HbA_1c glycosylated hemoglobin.

HortonESClinkingbeardCGatlinM2000Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetesDiabetes Care231660511092289

 PubMed Web of Science ®Google Scholar

MarreMVan GaalLUsadelK-H2002Nateglinide improves glycaemic control when added to metformin monotherapy: results of a randomized trial with type 2 diabetes patientsDiabetes Obes Metab41778612047396

 PubMed Web of Science ®Google Scholar

FrenchJA2001The role of new antiepileptic drugsAm J Manag Care7S209S21411474769

 PubMed Web of Science ®Google Scholar

SchatzHSchoppelKLehwalderD2003Efficacy, tolerability and safety of nateglinide in combination with metformin. Results from a study under general practice conditionsExp Clin Endocrinol Diabetes111262612951631

 PubMed Web of Science ®Google Scholar

HortonESFoleyJEShenSG2004Efficacy and tolerability of initial combination therapy with nateglinide and metformin in treatment-naive patients with type 2 diabetesCurr Med Res Opin20883915200747

 PubMed Web of Science ®Google Scholar

WeaverJURobertsonDAtkinSL2004Nateglinide alone or with metformin safely improves glycaemia to target in patients up to an age of 84Diabetes Obes Metab63445215287927

 PubMed Web of Science ®Google Scholar

GerichJRaskinPJean-LouisL2005PRESERVE-β: two-year efficacy and safety of initial combination therapy with nateglinide or glyburide plus metforminDiabetes Care282093916123472

 PubMed Web of Science ®Google Scholar

RisticSCollober-MaugeaisCPecherE2006Comparison of nateglinide and gliclazide in combination with metformin, for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum doses of metformin aloneDiabet Med237576216842480

 PubMed Web of Science ®Google Scholar

RisticSCollober-MaugeaisCCressierF2007Nateglinide or gliclazide in combination with metformin for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone: 1-year trial resultsDiabetes Obes Metab95061117587393

 PubMed Web of Science ®Google Scholar

DerosaGD’AngeloAFogariE2007Effects of nateglinide and glibenclamide on prothrombotic factors in naive type 2 diabetic patients treated with metformin: a 1-year, double-blind, randomized clinical trialIntern Med4618374618025765

 PubMed Web of Science ®Google Scholar

SchwarzSLGerichJEMarcellariA2008Nateglinide, alone or in combination with metformin, is effective and well tolerated in treatment-naive elderly patients with type 2 diabetesDiabetes Obes Metab106526017941876

 PubMed Web of Science ®Google Scholar