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ONGLYZA - ONGLYZA - CT 7111 - English version

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18 pages
Introduction ONGLYZA 5 mg, film-coated tablets Pack of 30 (CIP: 397 358-8) Pack of 90 (CIP: 575 956-3) Posted on Apr 14 2011 Active substance (DCI) saxagliptin Diabétologie - Nouveau médicament Pas d’avantage clinique démontré dans le traitement du diabète de type 2 ONGLYZA est indiqué dans le traitement du diabète de type 2 en bithérapie orale, en association à la metformine ou à un sulfamide hypoglycémiant ou à une glitazone.Son effet en termes de réduction du taux d’HbA1c est modeste par rapport aux alternatives, mais du même ordre de grandeur que celui observé avec les autres gliptines.Pour en savoir plus, téléchargez la synthèse ou l'avis complet ci-dessous ATC Code A10BH Laboratory / Manufacturer BRISTOL-MYERS SQUIBB ONGLYZA 5 mg, film-coated tablets Pack of 30 (CIP: 397 358-8) Pack of 90 (CIP: 575 956-3) Posted on Apr 14 2011
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The legally binding text is the original French version  TRANSPARENCY COMMITTEE
 OPINION  2 December 2009   ONGLYZA 5 mg, film-coated tablets Pack of 30 (CIP:397 358-8) Pack of 90 (CIP:575 956-3)   Applicant: BRISTOL-MYERS SQUIBB  Saxagliptin  List I ATC Code: A10BH03  Date of Marketing Authorisation (centralised procedure): 1 October 2009   Reason for request: inclusion on the list of medicines reimbursed by National Insurance (Pack of 30) and approved for use by hospitals (Pack of 30 and Pack of 90).                      Medical, Economic and Public Health Assessment Division
 
 
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1. CHARACTERISTICS OF THE MEDICINAL PRODUCT
 1.1. Active ingredient Saxagliptin  1.2. Indications “ONGLYZA is indicated in adult patients with type 2 diabetes mellitus to improve glycaemic control: - in combination with metformin, when metformin alone, with diet and exercise, does not  provide adequate glycaemic control; - in combination with a sulphonylurea, when the sulphonylurea alone, with diet and exercise, does not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate; - in combination with a thiazolidinedione, when the thiazolidinedione alone with diet and exercise, does not provide adequate glycaemic control in patients for whom use of a thiazolidinedione is considered appropriate.”  1.3. Dosage “The recommended dose of ONGLYZA is 5 mg once daily as add-on combination therapy with metformin, a thiazolidinedione or a sulphonylurea.  The safety and efficacy of saxagliptin as triple oral therapy in combination with metformin and a thiazolidinedione, or with metformin and a sulphonylurea, has not been established.  Special populations Renal impairment  No dose adjustment is recommended for patients with mild renal impairment. Clinical study experience with ONGLYZA in patients with moderate to severe renal impairment is limited. Therefore, use of ONGLYZA is not recommended in this patient population.  Hepatic impairment No dose adjustment is necessary for patients with mild or moderate hepatic impairment. Saxagliptin should be used with caution in patients with moderate hepatic impairment, and is not recommended for use in patients with severe hepatic impairment.  Elderly (65 years) No dose adjustment is recommended based solely on age. Experience in patients aged 75 years and older is very limited and caution should be exercised when treating this population.  Paediatric population ONGLYZA is not recommended for use in children and adolescents due to lack of data on safety and efficacy.  Method of administration ONGLYZA can be taken with or without a meal at any time of the day. If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.“
 
 
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 1.4.Main special warnings and precautions for use (cf. SPC)1 “Skin disorders Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinical toxicology studies. Although skin lesions were not observed at an increased incidence in clinical trials, there is limited experience in patients with diabetic skin complications. Post-marketing reports of rash have been described in the DPP4 inhibitor class. Rash is also noted as an adverse event for ONGLYZA. Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering, ulceration or rash, is recommended.  Cardiac failure Experience in New York Heart Association (NYHA) class I-II patients is limited, and there is no experience in clinical studies with saxagliptin in NYHA class III-IV.“   
2. SIMILAR MEDICINAL PRODUCTS
 2.1. ATC Classification (2009) A: Alimentary tract and metabolism A10: Drugs used in diabetes A10B : Antidiabetics, except insulin A10BH: Dipeptidyl peptidase-4 inhibitors (DPP-4) A10BH03: Saxagliptin  2.2. Medicines in the same therapeutic category - JANUVIA 100 mg and XELEVIA 100 mg (co-marketing with Januvia), tablets (sitagliptin), indicated “in type 2 diabetics to improve glycaemic control: - In combination with metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control.(indication already evaluated, cf. opinion of 6 June 2007 for JANUVIA, 19 December 2007 for XELEVIA) - In combination with a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance.(indication already evaluated, cf. opinion of 24 June 2009) - In combination with a sulphonylurea and metformin, when diet and exercise plus dual  therapy with these agents do not provide adequate glycaemic control.in(cadi itno already evaluated, cf. opinion of 24 June 2009) In type 2 diabetics in whom the use of a PPARγagonist (i.e. a thiazolidinedione) is appropriate, XELEVIA is indicated in combination with this PPARΧagonist, when diet and exercise plus the PPARγ alone do not provide adequate glycaemic control”. agonist(indication already evaluated, cf. opinion of 6 June 2007 for JANUVIA, 19 December 2007 for XELEVIA)  - GALVUS 50 mg, tablets (vildagliptin), indicated “in the treatment of type 2 diabetes mellitus, as dual oral therapy, in combination with:
                                            1The special warnings and precautions for use of vildagliptin (GALVUS) in particular in the case of: - hepatic impairment are not found in the SPC of sitagliptin (JANUVIA) and saxagliptin (ONGLYZA) - and those for heart failure are not found in the SCP of sitagliptin (JANUVIA).    
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 - metformin, in patients with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin, - a sulphonylurea, in patients with insufficient glycaemic control despite maximal tolerated dose of a sulphonylurea and for whom metformin is inappropriate due to contraindications or intolerance, - a thiazolidinedione, in patients with insufficient glycaemic control and for whom the use of a thiazolidinedione is appropriate.“ (indication already evaluated, cf. Committee opinion of 10 December 2008)  NB: the indications of JANUVIA and XELEVIA are not completely identical to those of GALVUS and ONGLYZA which are not indicated as triple oral therapy.   2.3. Medicines with a similar therapeutic aim Oral antidiabetics drugs may be added to metformin, a sulphonylurea or a glitazone (thiazolidinedione) within the framework of dual oral antidiabetic therapy indicated:  - in type 2 diabetics not obtaining adequate glycaemic control at maximum tolerated doses of oral treatment with metformin monotherapy: · Sulphonylureas · Glitazones · lucosidase inhibitors alpha Intestinal · Glinides · InjectableGLP-1 analogues, exenatide (BYETTA) and liraglutide (VICTOZA, listing request under evaluation  - in type 2 diabetics not obtaining adequate glycaemic control with maximum tolerated doses of oral monotherapy with sulphonylureas in whom metformin is contraindicated or poorly tolerated: · Glitazones · al Intestinal inhibitors ha lucosidase · In ectable GLP-1 analo lira BYETTA and exenatide ues, lutide VICTOZA, under evaluation  - in type 2 diabetics not obtaining adequate glycaemic control at maximum tolerated doses of oral treatment with glitazones (thiazolidinediones) as monotherapy : not applicable.   
 
 
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3.
ANALYSIS OF AVAILABLE DATA
 The company submitted the results of four clinical studies in support of its application: - three studies assessing the efficacy of saxagliptin versus placebo ·metformin in patients inadequately controlled by CV181014 in combination with  study metformin alone; · CV181040 in combination with the sulphonylurea, glibenclamide (DAONIL), in study patients inadequately controlled by a sulphonylurea alone;  · studyCV181013 in combination with a glitazone (pioglitazone or rosiglitazone), in patients inadequately controlled by a glitazone alone. - one study assessing the efficacy of saxagliptin versus sitagliptin, · CV181056 in combination with metformin in patients inadequately controlled by study metformin.   3.1. Efficacy results   3.1.1. Placebo-controlled studies: CV181014, CV181040, CV181013  
Design and objective: The primary objective of these three double-blind, randomised comparative studies was to evaluate the efficacy and  in combination with metformin or glibenclamidesafety of saxagliptin or a glitazone compared to placebo, after 24 weeks of treatment in type 2 diabetics (HbA1C levels:7% et10%) insufficiently controlled by monotherapy with metformin, glibenclamide or glitazone.  N.B.: three dosages of saxagliptin were evaluated during these phase III studies: 2.5 mg, 5 mg and 10 mg/day. The 5 mg dosage of saxagliptin gives better glycaemic control than the 2.5 mg dosage and the 10 mg dosage induced no additional benefit. The MA recommends a dosage of 5 mg/day. Only the results with this dosage will be presented. A method for controlling the inflation of the alpha risk due to multiple comparisons was implemented to evaluate the endpoints and prevent over-estimation of the observed effect.  These studies had a double-blind extension phase2 a total duration of follow-up of 3.5 and years in the study in combination with metformin and 1.5 years in the studies in combination with a sulphonylurea or a glitazone. The results of an interim analysis planned by the protocol are available at 102 weeks (i.e. approximately 2 years) for the study in combination with metformin and at 50 weeks (i.e. approximately 1 year) for the studies in combination with a sulphonylurea or a glitazone.  Inclusion criteria:t a HbA1C level withype 2 diabetics, aged over 18 years,7% and 10% ( 10.5% in study CV181013), with no signs of renal failure3, norecent history of cardiac disease4 or hepatic impairment5 treated by metformin monotherapy (at a dosage of 1,500 to 2,500 and mg/day) for at least 8 weeks, or by glibenclamide at a dosage of 7.5 mg/day for at least 8 weeks, or by a glitazone (pioglitazone at a dosage of 30 or 45 mg/day or rosiglitazone at a dosage of 4 or 8 mg/day) for at least 12 weeks.
                                            2 The patients who continued the extension phase are those who completed the 24 weeks of treatment with or without rescue therapy 3 Serum creatinine > 1.5 mg/dl (132 mmol/L) for men, > 2 mg/dl for women or > 1.4mg/dL in study CV181014 4 Myocardial infarction, angioplasty or bypass, valvular heart disease, unstable angina, ministroke or stroke during the 6 months before inclusion, congestive heart failure (NYHA class III or IV) or left ventricular ejection fraction40% : 5 Hepatic disease such as cirrhosis or progressive chronic hepatitis, with significant laboratory abnormalities: ALAT, ASAT > 2 ULN, total bilirubin > 2mg/dl.  5
 Dosing regimen: - In study CV181014, in combination with metformin, 370 patients were randomised to receive either saxagliptin at 5 mg/day + metformin from 1,500 to 2,500 mg/day (n=191) or a placebo + metformin from 1,500 to 2,500 mg/day (n=179). - In study CV181040. in combination with glibenclamide, 520 patients were randomised to receive either saxagliptin 5 mg/day + glibenclamide 7.5 mg/day (n=253) or a placebo + glibenclamide from 10mg/day up to not more than15 mg/day6(n=267). - study CV181013, in combination with a glitazone, 370 patients were randomised to receiveIn either saxagliptin 5 mg/day + pioglitazone mg/day or rosiglitazone at 4 or 8from 30 or 45 mg/day (n=186) or a placebo + pioglitazone or rosiglitazone (n=184).  The dosages of antidiabetics used in combination with saxagliptin complied with the recommended dosages of the respective SPCs.  Primary efficacy endpoint: mean change in HbA1C levels at 24 weeks of treatment compared to baseline. This criterion was the subject of an exploratory analysis planned in the protocol in sub-groups of patients according to age, BMI, baseline HbA1C and duration of diabetes. The results of this analysis will not be described.  Main secondary efficacy endpoints: - mean change in fasting blood glucose levels after 24 weeks of treatment; - percentage of patients with HbA1C levels < 7% at 24 weeks of treatment7.  Other efficacy endpoints : - percentage of patients with HbA1C levels6.5% after 24 weeks of treatment.  This endpoint was the subject ofpost hocin sub-groups of patients (according to ageanalysis and duration of diabetes). No conclusions may be drawn because of the methodology used. The results of these analyses will not be described.  
                                            6of patients were treated by 15 mg glibenclamide (maximum dose recommended by the SPC) in the placebo group.92%  7the endpoint “percentage of patients with HbA1C levels <7%” is debatable as it corresponds to the therapeutic goalThe choice of for triple oral therapy whereas ONGLYZA is only indicated as dual oral therapy.   6
 Results: The results presented in tables 1, 2 and 3 were obtained by analysing all randomised patients and those who received at least one dose of treatment.  Table 1 – Study CV181014: in combination with metformin  Metformin combined with  Saxagliptin 5 mg/day Placebo 191 179 54.7 (9.6) 54.8 (10.2) 83.2 85.5 16.8 14.5 1.0 1.7 31.2 (4.7) 31.6 (4.8) 44.0 42.5 56.0 57.5 6.4 (4.7) 6.7 (5.6)   53.9 50.3 18.8 26.3 1840.3 (379.6) 1820.2 (381.4)   49.7 53.1 32.5 29.1 17.8 17.3 186/191 175/179 8.07 (0.06) 8.06 (0.07)
Number of randomised patients N Average age (years) (SD) < 65 years (% patients) ³65 years (% patients) ³75 years (% patients) Mean BMI (kg/m2) (SD) <30 (% patients) ³30 (% patients) Mean duration of diabetes (years) (SD) ³5 years (% patients) ³10 years (% patients)
Mean previous dosage of metformin (mg/day) ³1500 and < 2000 (% patients) ³2000 and (% patients) 2500 < ³2500 (% patients) Change in HbA1C (%) n/N Mean baseline HbA1c (%)
Change from baseline, adjusted mean
Difference relative to placebo adjusted mean (SD) 95% CI, p Change in fasting blood glucose (g/l) n/N
Mean baseline fasting glucose (g/L)
Change from baseline, adjusted mean
Difference relative to placebo, adjusted mean 95% CI, p Percentage of patients with HbA1c6.5% n/N (%) Difference between treatments(% patients) 95% CI, p  Percentage of patients with HbA1c 7% n/N (%) Difference between treatments(% patients) 95% CI, p  
 
 
-0.69 (0.07)
-0.83 (0.10) [-1.02 ; -0.63 p<0.0001] 
187/191
1.79 (0.03)
-0.22 (0.002)
-0.23 (0.04) [-0.30 ; -0.16], p<0.0001  
41/186 (22.0) 14.0 [5.2; 23.6] p<0.0003
81/186 (43.5) 27 [17.0 ; 36.7] p<0.0001
+0.13 (0.07)
 
176/179
1.75 (0.03)
0.01 (0.03)
 
14/175 (8.0)
29/175 (16.6)
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 Table 2 - Study 181040: In combination with glibenclamide  
 
Number of randomised patients N Average age (years) (SD) < 65 years (% patients) ³65 years (% patients) ³  M7e5any eBarMsI  ((k%g /pmat2i)e(ntSsD)) <30 (% patients) ³30 (% patients) Mean duration of diabetes (years) (SD) ³5 years (% patients) ³10 years (% patients)
Change in HbA1c (%) n/N
Mean baseline HbA1c (%)
Change from baseline, adjusted mean
Difference relative to placebo, adjusted mean (SD) 95% CI, p
Change in fasting blood glucose (g/l) n/N
Mean baseline fasting glucose (g/L)
Change from baseline, adjusted mean
Difference relative to placebo, adjusted mean 95% CI, p
Patients with HbA1c < 6.5% n/N (%) Difference between treatments(% patients) 95% CI, p 
Patients with HbA1c levels 7% n/N (%) Difference between treatments(% patients) 95% CI, p  
 
 
Glibenclamide 7.5 mg + saxagliptin 5 mg/day
253 54.9 (10) 83.4 16.6 1.2 29.2 (4.6) 60.5 39.5 6.8 (5.8) 55.3 24.1
250/253 8.48 (0.06)
-0.64 (0.06)
-0.72 (0.08) [-0.88 ; -0.56] p<0.0001 
252/253
1.75 (0.03)
-0.10 (0.02)
-0.10 (0.03) [-0.17 ; -0.04], p=0.002  26/250 (10.4) 5.9 [1.2; 10.8] p =0.0117
57/250 (22.8) 13.7 [7.5 ; 20.1] p<0.0001
Glibenclamide 10 to 15 mg + placebo
267 55.1 (10.7) 80.5 19.5 1.9 28.8 (4.7) 61.8 38.2 6.8 (5.7) 53.6 22.8
264/267 8.44 (0.06)
+0.08 (0.06)
 
265/267
1.74 (0.03)
0.07 (0.02)
 
12/264 (4.5)
24/264 (9.1)
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 Table 3 – Study CV181013: In combination with a glitazone   
Number of randomised patients N Average age (years) (SD) < 65 years (% patients) ³65 years (% patients) ³75 years (% patients) Mean BMI (kg/m2) (SD) <30 (% patients) ³30 (% patients) Mean duration of diabetes (years) (SD) ³5 years (% patients) ³10 years (% patients) Treatment by glitazone Rosiglitazone (n) Pioglitazone (n) High dose (% patients) Low dose (% patients) Change in HbA1c (%) n/N Mean baseline HbA1c (%)
Change from baseline, adjusted mean
Difference relative to placebo, adjusted mean (SD) 95% CI, p Change in fasting blood glucose (g/l) n/N
Mean baseline fasting glucose (g/L)
Change from baseline, adjusted mean
Difference relative to placebo adjusted mean 95% CI, p
Patients with HbA1c6.5% n/N (%) Difference between treatments(% patients) 95% CI, p 
Glitazone combined with Saxagliptin 5 mg/day Placebo 184 54.0 (10.1) 84.8 15.2 1.1 30.3 (5.8) 51.1 48.9 5.1 (5.4) 42.9 12.0  76 108 36.4 63.6 180/184 8.19 (0.08)
186 53.2 (10.6) 86.6 13.4 0.5 29.8 (5.3) 59.1 40.9 5.2 (5.6) 40.3 14.0  78 108 39.2 60.8 183/186 8.35 (0.08)
-0.94 (0.07)
-0.63 (0.11) [-0.84 ; -0.42 p<0.0001] 
185/186
1.60 (0.03)
-0.173 (0.029)
-0.145 (0.04) [-0.23 ; -0.06], p=0.0005  
38/184 (20.7) 11.2 [3.8 ; 18.7] p=0.0033
-0.30 (0.08)
 
181/184
1.62 (0.03)
-0.028 (0.030)
 
17/180 (9.4)
Patients with HbA1c levels 7% n/N (%) Difference between treatments6. ) (25/1803 46.001]7.50=p 5.6[2 ;  18)3 6.4 181.(4,Ip 7 /7)s9 %5C  patient(%   At baseline, in each study the characteristics of the patients were similar between groups. Overall, the patients had an average age of 54 years and in the study in combination with metformin most were obese. The mean time since diagnosis of diabetes was more than 5 years. Most of the patients were treated by low doses of metformin, glibenclamide and glitazone. It should be pointed out that HbA1C levels were high (> 8% in each group). Nearly 40% patients in each treatment group had HbA1C levels between 8 and 9% in the study in combination with metformin and with glimepiride.  For the primar endpoint: After 24 weeks of treatment, the change in HbA1c levels was higher: 1 in patients receiving metformin + saxagliptin than in those receiving metformin alone (difference between saxagliptin 5 mg/day and placebo: -0.83%, 95% CI [-1.02; -0.63]; p<0.0001) 2 in patients receiving glibenclamide + saxagliptin than in those receiving glibenclamide alone (difference between saxagliptin 5 mg/day and placebo: -0.72%, 95% CI [-0.88; -0.56];
 
 
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p<0.0001) 3 in patients receiving a glitazone + saxagliptin than in those receiving the glitazone alone (difference between saxagliptin 5 mg/day and placebo: -0.63%, 95% CI [-0.84; -0.42]; <0.0001 .   For the other efficacy endpoints: After 24 weeks of treatment, the reduction in fasting blood glucose was higher in patients in the groups treated by saxagliptin combined with metformin, glibenclamide or glitazone than in the placebo group. The observed differences relative to placebo were statistically significant.  The percentage of patients achieving HbA1c levels was higher in the metformin + 6.5% saxagliptin group than in the metformin monotherapy group (22% versus 8%; p<0.0003), in the glibenclamide + saxagliptin group than in the glibenclamide monotherapy group (10.4% versus 4.5%; p=0.0117) and in the glitazone + saxagliptin group than in the glitazone monotherapy group (20.7% versus 9.4%; p=0.0033).   Interim results of the extension phases For the primary endpoint:  The difference between the 2 treatment groups in terms of reduction in HbA1c levels was: o in the study in combination with metformin (results at 2 years) -0.72 -0.50] [-0.94;8 -o -0.63in combination with glibenclamide at 50 weeks of treatment  0.46] [-0.79;9 o [-0.90;  -0.65-0.41] in combination with a glitazone, at 50 weeks of treatment10.  For the other primary efficacy endpoints: Fasting blood glucose decreased by -0.11 (0.03) in the metformin + saxagliptin group and increased by 0.07 (0.03) in the metformin + placebo group at 2 years i.e. a difference of -0.18 [-0.26 ; 0.10]. -It did not fall in the saxagliptin group but increased by 0.10 (0.03) in the placebo group at 50 weeks in the study in combination with glibenclamide. In combination with a glitazone at 50 weeks, the fasting blood glucose decreased by -0.14 (0.03) in the saxagliptin group and increased by 0.02 (0.04) in the placebo group, i.e. a difference of -0.16 [-0.25 ; -0.06].  The percentage of patients with HbA1c levels6.5% was: - 18.5 % (34/184) in the saxagliptin group and 8.1% (14/172) in the placebo group, at 2 years, in the study in combination with metformin; - 7.4 % (18/243) in the saxagliptin group and 2.4% (6/253) in the placebo group, at 50 weeks, in the study in combination with glibenclamide; - 22.1% (30/136) in the saxagliptin group and 1.5% (15/130) in the placebo group, at 50 weeks,  in the study in combination with a glitazone.
                                            8Results available for n=184 in the saxagliptin group, n=172 in the placebo group (replacement of missing data n the saxa lipti oup (replacement of missing data by LOCF method) 190 531=n rof elbalptliagax she tin31 0 ,=norpunig bo glacehe pin tlts avai Resuuprore (acplenemfo tsim gnistad a by LOCF method)g forable43 i n=2lp eht nrg obecap,ougrn  i53=2 nR lusea stliavy  bCFLOet md)ho  10
 3.1.2 Study versus active comparator: metformin + sitagliptin combination (CV181056)  Design and objective: The primary objective of this randomised, double-blind study was to establish, after 18 weeks of treatment, the non-inferiority of the metformin + saxagliptin combination compared to the metformin + sitagliptin combination for the decrease in HbA1c levels in type 2 diabetics aged over 18 years and insufficiently controlled (HbA1C levels > 6.5% and doses10%) by stable 1500 mg/day of metformin monotherapy11. Patients with heart disease12, renal failure13 or hepatic disorders14were excluded. Dosing regimen: Eight hundred and one patients were randomised to receive for 18 weeks: - saxagliptin at 5 mg/day combined with metformin from 1,500 to 3,000 mg/day (n= 403) or - sitagliptin at 100 mg/day combined with metformin from 1,500 to 3,000 mg/day (n= 398).  Primary endpoint15: change in HbA1C levels at 18 weeks of treatment relative to mean baseline.  The metformin + saxagliptin combination was to be considered non-inferior to the metformin + sitagliptin combination if the upper limit of the 95% confidence interval of the difference in the endpoint, change in HbA1C levels between the two treatments (metformin/saxagliptin combination - metformin/sitagliptin combination ), was lower than 0.3%16 .  Main secondary efficacy endpoints: after 18 weeks of treatment, fasting blood glucose levels and percentage of patients with HbA1c6.5%  Results: Table 4: baseline patient characteristics - Study CV181056 : metformin/saxagliptin versus metformin/sitagliptin (ITT population ) Metformin combined with  saxagliptin 5 mg/day sitagliptin 100mg/day Number of randomised patients N403 398 Average age (years) (SD) (10.3)58.6 (10.1) 58.4 < 65 years (% patients) 72.5 69.8 ³ 30.2 27.565 years (% patients) ³75 years (% patients) 4.5 6.2 BMI (kg/m2)   <30 (% patients) 44.9 47.7 ³30 (% patients) 55.1 52.0 Mean duration of diabetes (years) (SD)6.3 (5.0) (4.7) 6.3 ³5 years (% patients) 51.3 54.6 18.1 21.4 ³10 years (% patients)
Mean previous dosage of metformin (mg/day) ³1500 and < 2000 (% patients) ³2000 and < 2500 (% patients) ³2500 and < 3000 (% patients) Mean HbA1c (%)
Mean baseline fasting glucose (g/L)
1831.5 (463.5) 57.8 24.6 11.2 7.7 (1.0)
1.59 (0.04)
1826.2 (480.7) 61.6 19.1 11.3 7.7 (0.9)
1.61 (0.04)
                                            11 Treated by metformin at the dose of 1,500 mg/day or more for at least 8 weeks 12Myocardial infarction, angioplasty or bypass surgery, valvular disease, unstable angina, ministroke or stroke during the 6 months IV tion fraction40% 1b3S erc mure)  or eft or lirucevtnal r hverteaai freluYN( c AHssalIII efore inculisno ,ocgnseit n > ,m4.1rof nem r fomewomgg l /d >.1 5gmtanini e µmol/L)/dl (132 ejec 14 disease such as cirrhosis or progressive chronic hepatitis, with significant laboratory abnormalities: ALAT, ASAT > 2 Hepatic ULN, total bilirubin > 2mg/dl. 15 24 weeks. atAmendment to the protocol: unblind 16 sen  cho Theion.on-nitSgniin wformusedere tpnigailm tea dnsado rgeomecndme ta  ehtitpo lameting authorizatdeb  yhtie ramkr inferiority threshold, 0.3%, was stricter than that normally used (0.4%).   11