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XELEVIA - VELMETIA - XELEVIA - VELMETIA - CT 8855 & 8856 - Version anglaise

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Présentation VELMETIA 50 mg/1000 mg, comprimé pelliculé B/56 - Code CIP : 3867797 XELEVIA 100 mg, comprimés pelliculés B/28 - Code CIP : 3793308 B/50 - Code CIP : 5707448 Mis en ligne le 19 mars 2013 Substance active (DCI) sitagliptine/metformine sitagliptine Code ATC A10BD07 A10BH01 Laboratoire / fabricant Laboratoire PIERRE FABRE MEDICAMENT VELMETIA 50 mg/1000 mg, comprimé pelliculé B/56 - Code CIP : 3867797 XELEVIA 100 mg, comprimés pelliculés B/28 - Code CIP : 3793308 B/50 - Code CIP : 5707448 Mis en ligne le 19 mars 2013
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The legally binding text is the original French version
TRANSPARENCY COMMITTEE  OPINION
 18 July 2012   XELEVIA 100 mg, film-coated tablets  B/28 (CIP: 379 330-8) B/50 (CIP: 570 744-8) sitagliptin List I ATC Code: A10BH01 (DPP-4 inhibitor, or gliptin) Date of MA (centralised procedure): 21 March 2007 XELEVIA is a co-marketing of JANUVIA 100 mg.  VELMETIA 50 mg/1 000 mg, film-coated tablet B/56 (CIP: 386 779-7) sitagliptin/metformin List I ATC Code: A10BD07 (combination of oral antidiabetic agents) Date of MA (centralised procedure): 16 July 2008 XELEVIA is a co-marketing of JANUMET 50 mg/1,000 mg.  Applicant: PIERRE FABRE MEDICAMENT  Reason for request:  Inclusion on the list of medicines refundable by National Health Insurance (B/28) and approved for hospital use (B/28 and B/50) in the following extensions of indication for XELEVIA:  “For patients with type 2 diabetes mellitus, XELEVIA is indicated to improve glycaemic control: - as monotherapy, in patients inadequately controlled by diet and exercise alone and  for whom metformin is inappropriate due to contraindications or intolerance. - as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycaemic control.” (date of extensions of indication: 9 November 2009 – centralised procedure)  Inclusion on the list of medicines refundable by National Health Insurance and approved for hospital use (B/56) in the following extension of indication for VELMETIA: “VELMETIA is indicated as an adjunct to diet and exercise to improve glycaemic control in type 2 diabetic patients - as add-on to insulin (triple therapy) when stable dose of insulin and metformin alone do not provide adequate glycaemic control” (date fo extension of indication: 28 October 2009 – centralised procedure)  The companies are only requesting inclusion on the list of medicines refundable by National Health Insurance and hospital use list for the indication in combination with insulin. The Transparency Committee, however, has decided to produce a review for all of the extensions of indications for the correct use of the medicine in the management of type 2 diabetic patients.  Medical, Economic and Public Health Assessment Division   1/22  
1.
CHARACTERISTICS OF THE MEDICINAL PRODUCT
  1.1. Active ingredients  sitagliptin for XELEVIA sitagliptin/metformin for VELMETIA   1.2. Indications  For XELEVIA  “XELEVIA is indicated for use in type 2 diabetic patients to improve glycaemic control:  As monotherapy:   in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.  As dual oral therapy in combination · metformin when diet and exercise  withplus metformin alone do not provide adequate glycaemic control. already evaluated by the TC - cf opinion of 19 December (Indication 2007) · 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 by the TC - cf opinion of 24 June 2009) · a PPAR withγa thiazolidinedione) when its use is appropriate, andreceptor agonist (i.e., when diet and exercise plus the PPARγagonist alone do not provide adequate glycaemic control. (Indication already evaluated by the TC - cf opinion of 6 June 2007 although obsolete as the glitazones are no longer available in France).  As oral triple therapy in combination: · a sulphonylurea and metformin, when diet and physical exercise plus dual therapy with with these medicinal products do not provide adequate glycaemic control. (Indication already evaluated by the TC cf opinion of 24 June 2009). · with a PPARγreceptor agonist and metformin, when use of a PPARγreceptor agonist is appropriate and when diet and physical exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control. (This indication cannot be evaluated by the TC as the glitazones are no longer available in France).  XELEVIA is also indicated as add-on to insulin (with or without metformin) when diet and physical exercise plus a stable dose of insulin do not provide adequate glycaemic control.”  For VELMETIA “VELMETIA is indicated as an adjunct to diet and exercise to improve glycaemic control in type 2 diabetic patients   in patients inadequately controlled on their maximal tolerated dose of metformin alone or · those already being treated with the combination of sitagliptin and metformin. (Indication already evaluated by the TC - cf opinion of 29 April 2009).   in combination with a sulphonylurea (i.e., triple combination therapy) in patients · inadequately controlled on their maximal tolerated dose of metformin and a sulphonylurea. (Indication already evaluated by the TC - cf opinion of 29 April 2009)  
 
 
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· as triple combination therapy with a peroxisome proliferator-activated receptor gamma (PPARγ) agonist (i.e., a thiazolidinedione) in patients inadequately controlled on their maximal tolerated dose of metformin and a PPARγ agonist.(This indication cannot be evaluated by the TC as the glitazones are no longer available in France).  · as add-on to insulin (i.e., triple combination therapy) when stable doses of insulin and metformin alone do not provide adequate glycaemic control.”   1.3. Dosage  For XELEVIA "The dose of XELEVIA is 100 mg once daily. When XELEVIA is used in combination with metformin, the dose of metformin should be maintained, and XELEVIA administered concomitantly.   When XELEVIA is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see section 4.4 of the SPC).  If a dose of XELEVIA is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day. XELEVIA may be taken with or without food.  Renal impairment When considering the use of sitagliptin in combination with another antidiabetic product, its conditions for use in patients with renal impairment should be checked. For patients with mild renal impairment (creatinine clearance [CrCl] 50 ml/min), no dose adjustment for XELEVIA is required. For patients with moderate renal impairment (CrCl to <50 mL/min), the dose of 30 XELEVIA is 50 mg once daily. For patients with severe renal impairment (CrCl <30 mL/min) or with end-stage renal disease (ESRD) requiring haemodialysis or peritoneal dialysis, the dose of XELEVIA is 25 mg once daily. XELEVIA may be administered without regard to the timing of dialysis. Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of XELEVIA and periodically thereafter.  Hepatic impairment No dose adjustment is necessary for patients with mild to moderate hepatic impairment. XELEVIA has not been studied in patients with severe hepatic impairment.  Elderly No dose adjustment is necessary based on age. Limited safety data are available in patients 75 years old and care should be exercised.  Children XELEVIA is not recommended for use in children below 18 years of age due to a lack of data on its safety and efficacy.”  For VELMETIA in the extension to indication being examined The dose of antihyperglycaemic therapy with VELMETIA should be individualised on the basis of the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin.  For patients inadequately controlled on maximal tolerated dose of metformin monotherapy The usual starting dose of VELMETIA should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) plus the dose of metformin already being taken. When VELMETIA
 
 
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is used in combination with insulin, the dosage of insulin may be reduced to reduce the risk of hypoglycaemia (see section 4.4 of the SPC). All patients should continue their diet with an adequate distribution of carbohydrate intake regularly during the day. Overweight patients should continue their energy-restricted diet.  Special populations Renal impairment VELMETIA should not be used in patients with moderate or severe renal impairment (creatinine  clearance < 60 ml/min) (see sections 4.3 and 4.4 of the SPC).  Hepatic impairment VELMETIA should not be used in patients with hepatic impairment (see sections 4.3 and 5.2 of the SPC).  Elderly As metformin and sitagliptin are excreted by the kidney, VELMETIA should be used with caution as age increases. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly (see sections 4.3 and 4.4 of the SPC). Limited safety data is available in patients 75 years of age and care should be exercised.  Paediatric population VELMETIA is not recommended for use in children below 18 years of age due to a lack of data on its safety and efficacy in this population.  Method of administration  VELMETIA should be given twice daily with meals to reduce the gastrointestinal undesirable effects associated with metformin.”   1.4. Warnings and precautions for use (cf SPC)  “Hypoglycaemia when used in combination with other anti-hyperglycaemic agents In clinical trials of XELEVIA as monotherapy and as part of combination therapy with medicinal products not known to cause hypoglycaemia (for example, metformin), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo. When sitagliptin was added to a sulphonylurea or to insulin, the incidence of hypoglycaemia was increased over that of placebo.Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered   Renal impairment XELEVIA is renally excreted. To achieve plasma concentrations of XELEVIA similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal impairment, as well as in end stage renal disease patients requiring haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2). When considering the use of sitagliptin in combination with another anti-diabetic product, its conditions for use in patients with renal impairment should be checked.  Hypersensitivity reactions Post-marketing reports of serious hypersensitivity reactions in patients treated with XELEVIA have been reported.These reactions include anaphylaxis, angioedema, and exfoliating skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with XELEVIA,with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue XELEVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes.”  
 
 
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Pancreatitis In post-marketing experience there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, XELEVIA and other potentially suspect medicinal products should be discontinued.  These warnings are found in the VELMETIA SPC.   
 
 
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2.
SIMILAR MEDICINAL PRODUCTS
  2.1. ATC Classification (2012)  A  Gastrointestinal tract and metabolism. A10  Diabetic medicines. A10B  Antidiabetic agents, excluding insulin. A10BH dipeptidylpeptidase-4 (DPP-4) inhibitors. A10BH01 tis nitpilga  A:  Gastrointestinal tract and metabolism. A10:  Medicines for diabetes A10B:  Anti-diabetic agents, excluding insulin. A10BD:  Combination of oral antidiabetic agents. A10BD07:  nimem/nroftgltatiipsi   2.2. Medicines in the same therapeutic category  - Another gliptin has Marketing Authorisation indication as monotherapy.  This is linagliptin (TRAJENTA) indicated for use “in the treatment of type 2 diabetes mellitus to improve glycaemic control in adults as monotherapy in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to intolerance, or contraindicated due to renal impairment.” (Insufficient AB defined by the Commission in its opinion of 20 June 2012)  - No other gliptin has an MA indication for combination with insulin to date.   2.3. Medicines with a similar therapeutic aim  · in monotherapy:  metformin   sulphonylureas  repaglinide  alpha-glucosidase inhibitors intestinal  
·  
  
in combination with insulin:  metformin  sulphonylureas  incretin mimetic (exenatide injectable1)
                                            1BYETTA (exenatide) was approved by the CHMP for the following extension of indication on 16 February 2012: “BYETTA is also indicated for use in combination with basal insulin or with or without metformin and/or pioglitazone in adults who have not achieved adequate glycaemic control with these medicines.”   6/22 
 
3.
ANALYSIS OF AVAILABLE DATA
  The applicant submitted: - a randomised, double-blind, phase III, non-inferiority study (study P0492), which compared sitagliptin to metformin. - a double-blind, randomised, placebo-controlled, phase III study (study P0513), which examined sitagliptin in combination with insulin therapy, with or without metformin, in patients inadequately controlled with stable dose insulin.   3.1. Efficacy   3.1.1. Monotherapy study (study P049)  Objective and methodology: double-blind, randomised, phase III study to demonstrate non-inferiority of sitagliptin monotherapy to metformin, in type 2 diabetic patients inadequately controlled with diet and physical exercise alone after treatment for 24 weeks.  Inclusion criteria: Type 2 diabetic patients at least 18 years old who were inadequately controlled (HbA1c 6.5% andphysical exercise and who had not received any diabetic9%) with diet and treatment for at least 4 months.  Method of administration 1050 patients were randomised to receive: - either sitagliptin, dosage 100 mg/day (n=528) - or metformin, initial dosage 500 mg/day which was increased up to 1000 mg twice daily over a maximum period of 5 weeks4(n=522).  All patients were required to follow the recommended diet and physical exercise programme throughout the study.  Primary efficacy endpoint Mean change in HbA1c at 24 weeks treatment compared to the baseline value. Sitagliptin was deemed to be non-inferior to metformin if the upper limit of the 95% confidence interval of the difference in change in HbA1c between the two treatments (sitagliptin – metformin) was less than 0.4%.5  Main secondary efficacy endpoint after treatment for 24 weeks: - percentage of patients with HbA1c <6.5%  Results:  The patient characteristics were similar at inclusion in both treatment groups. Average patient: - age was 56 years old, - the majority were obese (mean BMI 30.8 kg/m2). The diabetes had been present for an average of 12.4 + 6.6 years. Mean HbA1c on inclusion was 7.2 + 0.7%.                                             2Aschner P, Katzeff H, Guo H, et al. Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes. Diabetes Obes Metab 2010; 12: 252-261. 3Vilsbøll T, Rosenstock J, Yki-Järvinen H, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2010 Feb; 12: 167-77. 4 it was not tolerated. ifThe dose of metformin was reduc 5 met andptinagliS tiy ad/gm 0001 ot de-inferio The nonseohdlu irytt rhd ses wausedere in wformam lpoitht ea  tndmeomec rgesado .AM rieht ni de the standard threshold in evaluating antidiabetic agents.    7/22 
 
93.7% of patients randomised received a dose of 2000 mg of metformin.  Table 1: characteristics of patients included (Per Protocol population)  Age (years) Treatment group N Mean + SD Median Range Sita li tin 455 56.3 + 10.7 57.0 20.0 to 78.0 Metformin 439 55.7 + 10.3 56.0 28.0 to 78.0 All 894 56.0 + 10.5 57.0 20.0 to 78.0 Body mass index kg/m²)    N Mean + SD Median Range Sita li tin 455 30.7 + 4.7 30.5 20.3 to 40.0 Metformin 437 30.9 + 4.9 30.6 20.3 to 40.6 All 892 30.8 + 4.8 30.5 20.3 to 40.6 HbA1c (%)  N Mean + SD Median Range Sita li tin 455 7.2 + 0.7 7.1 5.7 to 10.4 All 439 7.2 + 0.7 7.1 5.6 to 10.1  894 7.2 + 0.7 7.1 5.6 to 10.4 HbA1c distribution  N Number (%) of patients with HbA1c at inclusion  <7%7 and <8%8% Sita li tin 455 199 43,7 182 40,0 74 16,3 Metformin 439 182 41.5 184 41.9 73 16.6 All 894 381 (42.6) 366 (40.9) 147 (16.4) Fasting blood glucose (mg/dL)  N Mean + SD Median Range Sita li tin 453 142.4 + 31.9 136.0 46.0 to 267.0 Metformin 436 141.9 + 33.1 135.0 63.0 to 319.0 All 889 142.2 + 32.5 136.0 46.0 to 319.0 Time since diagnosis of type 2 diabetes (years)  N Mean + SD Median Range Sita li tin 455 2.6 + 3.9 1.0 0.0 to 27.0 Metformin 439 2.1 + 3.5 0.9 0.0 to 30.0 All 894 2.4 + 3.7 1.0 0.0 to 30.0   Primary efficacy endpoint:  Table 2: change in HbA1c at 24 weeks in the Per Protocol population:  M Mean at 24 Change at week 24 compared to baseline. Treatme nt group N HebanA 1bca (sSelDin) e weeks (SD) Mean (SD) Mean MC (95% CI) † 6.80 (0.71) -0.42 (0.03) -0.43 (-0.48, -0.38) 6.68 (0.62) -0.57 (0.03) -0.57 (-0.62, -0.51)
Sitagliptin Metformin
455 439
Estimated difference Sitagliptinversusmetformin
7.22 (0.73) 7.25 (0.69)
Mean difference in MC (95% CI): 0.14 (0.06, 0.21)
 The difference in HbA1c reduction between sitagliptin and metformin after 24 weeks treatment was 0.14%, 95% CI 0.06; 0.21 . The u er limit of the confidence interval of this difference was below the fixed threshold 0.4% and sita li tin was therefore demonstrated to be non-inferior to metformin. This result was confirmed in the ITT population. It should be noted that the effect of sitagliptin was greatest up to the 12th week of treatment. Beyond that, HbA1c levels rose although continued to fall in the metformin group.   Secondary efficacy endpoint: The treatment goal (HbA1c <6.5%) was achieved by 33.6% of patients on sitagliptin (153/455) and by 39.2% of patients on metformin (172/439).
 
 
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 3.1.2. Study in combination with insulin with or without metformin (study P051)  Objective and methodology: This was a double-blind, randomised, phase III study, the aim of which was to compare the efficacy and safety of the insulin + sitagliptin combination with that of the insulin + placebo combination (with or without metformin) after 24 weeks' treatment.  The protocol stratified randomisation according to whether or not metformin was being received concomitantly, the type of insulin received (insulin mix6or intermediary/slow acting insulin) and whether or not a test meal was given to evaluate insulin resistance indices.  Inclusion criteria: Type 2 diabetic patients, at least 21 years old, inadequately controlled (HbA1c7.5% and doses of mixed, slow-acting or intermediary insulins for11%) on insulin with stable 10 weeks, + stable dose metformin1500 mg/day.  Non-inclusion criteria: treatment with sulphonylureas, glinides, alpha-glucosidase inhibitors or exenatide during the previous 3 months, prior exposure to sitagliptin, use of a rapid-acting, preprandial insulin (>1 injection/d).7  Administration regimen: 641 patients were randomised to be given: - either the combination of stable dose insulin + sitagliptin 100 mg/d ± metformin (n=322) - or the combination of stable dose insulin + placebo ± metformin (n=319).  Primary efficacy endpoint: Mean change in HbA1c at 24 weeks’ treatment compared with baseline.  The protocol planned to include 270 patients in both treatment groups to identify a difference of 0.5% ± 1.0% in the change in HbA1c with a power of 99% and statistical threshold of 0.05.  Tests were performed on this endpoint as stipulated in the protocol in the patient subgroups (depending on diabetes treatment at inclusion, baseline HbA1c, BMI, and time since diagnosis of diabetes). No adjustment was made for the multiple comparisons and an overestimation of the effect cannot therefore be excluded. As a result no conclusion can be drawn based on these exploratory tests and they will not be presented.  Mains secondary efficacy endpoints after 24 weeks’ treatment: - mean change in fasting blood glucose (FBG) and Post-prandial glycaemia (GPP)8  glycaemic control in the sub-groups with or without metformin. -- of patients with HbA1c <6.5% and <7%. percentage  Tests were ranked9 and a correction method was used for inflation of probability values because of the multiple comparisons to avoid overestimating the effect.  Other endpoint: Mean change in HbA1c at 24 weeks’ treatment compared with baseline in the groups of patients who were or were not treated with metformin.10                                                 6 Insulin mix = mixture of intermediary and rapid acting insulins 7 using insulin mix (containing a rapid acting insulin) and those who only used occasional rapid acting insulin Patients <3 times/week ould be included. 8o  f,setg 9 hobrardyd an g18f  ot fanoatsec olir 0acf ca g og 75inin fo laem dradnat46y elatimoxprapuoh a srretfs a Me uras 2ed) c( protein. 9The hypotheses for the secondary endpoints were tested in the following rank order: change in HbA1c in the patient subgroup treated with intermediary/slow acting insulin, change in PPG, change in FBG, proportion of patients who achieved HbA1c < 7.0%, proportion of patients who achieved HbA1c < 6.5%. 10defined as a subgroup in the protocol.Some patients were not   9/22  
 
Results:  Results were obtained from the analysis of all patients randomised who did or did not receive at least one dose of the treatment (305/322 patients in the sitagliptin group, 312/319 patients in the placebo group).11  Patient characteristics were similar in both treatment groups at inclusion. Average patient: - was 58 years old (22% of patients were 65 years old or older), age - majority were obese (mean BMI 31.0 kg/m the2).  The diabetes had been present for an average of 12.4 + 6.6 years. Mean HbA1c at inclusion was 8.7 + 0.9%. The majority of patients (42%) had an HbA1c of between 8 and 9%. 23.6% of patients had an HbA1c below 8%, and 23.6% of patients had an HbA1c of between 9 and 10%. It should be noted that HbA1c values were high at inclusion. 27.9% of patients were treated with insulin alone and 72.1% received the combination of insulin + metformin. The majority of patients (73.6%) were using an intermediary or slow-acting insulin and 26.4% were using an insulin mix. Insulin doses had been stable for more than 6 months in 75% of patients.  The mean daily doses of insulin used were: o U/day (44.2 U/day in the sitagliptin group and 44.5 U/day in the placebo group) for 44.3 intermediary insulin or slow-acting insulin analogues, oinsulin mix (67.4 U/day for the sitagliptin group and 74.5 U/day for the U/day for  70.9 placebo group).  The average dose of metformin received was 2010 mg in the sitagliptin group and 1969.5 mg in the placebo group.
                                            11of insulin was adjusted were not included in this analysis. Patients whose dose  There were no changes in average daily insulin doses during the study in the sitagliptin group. Mean changes were +1.6 U/d (7.0) in the placebo group because of inadequate glycaemic control.     10/22 
 
 Table 3: characteristics of the patients included  Age (years) Treatment group N Mean + SD Median Range Sita li tin 322 58.3 + 9.1 58.0 25.0 to 80.0 Placebo 319 57.2 + 9.3 58.0 28.0 to 82.0 All 641 57.8 + 9.2 58.0 25.0 to 82.0 Body mass index (kg/m²)    N Mean + SD Median Range Sita li tin 322 31.4 + 5.4 31.1 20.6 to 43.3 Placebo 319 31.4 + 5.0 30.9 20.3 to 49.3 All 641 31.4 + 5.2 31.1 20.3 to 49.3 HbA1c (%)  N Mean + SD Median Range Sita li tin 322 8.7 + 0.9 8.6 6.6 to 12.1 Placebo 319 8.6 + 0.9 8.6 6.6 to 11.7 All 641 8.7 + 0.9 8.5 6.6 to 12.1 HbA1c distribution  N Number (%) of patients with HbA1c at inclusion  <8%8 and <9%9 and <10%10% Sita li tin 322 68 21,1 137 42.5 80 24.8 37 11.5 Placebo 319 83 26.0 132 41.4 71 22.3 33 10.3 All 641 151 (23.6) 269 (42.0) 151 (23.6) 70 (10.9) Fasting blood glucose (mg/dL) N Mean + SD Median Range 63.0 to 322 175.6 + 51.8 165.0 376.0 319 178.7 + 59.6  170.06710.40 t0o  . 177.1 + 55.8  168.06710.04 t0o   .
 
 
 Sitagliptin
Placebo
All 641 Post-prandial glycaemia (mg/dL)  N Sitagliptin 298
Placebo
301
Mean + SD 295.2 + 72.3  
295.8 + 73.2
  
 
Median 286.0
289.0
All 599 295.5 + 72.7 288.0  Time since diagnosis of type 2 diabetes (years)  N Mean + SD Median Sita li tin 322 12.9 + 7.2 12.0 Placebo 319 12.0 + 5.9 12.0 All 641 12.4 + 6.6 12.0 Treatments for diabetes  insulin alone insulin + metformin  N (%) N (%) Sita li tin 93 28.9 229 71.1 Placebo 86 27.0 233 73.0 All 179 (27.9) 462 (72.1)  insulin mix intermediary or slow-acting insulin  N (%) N (%) Sitagliptin 87 (27.0) 235 (73.0) Placebo 82 (25.7) 237 (74.3) Global 169 (26.4) 472 (73.6) Treatments for diabetes: use for metformin depending on insulin type  insulin mix Intermediary or slow-acting insulin with without  metformin metformin with Nm e(t%fo) rmin withouNt  (m%et)formin N % N % 52 (16.1) 35 (10.9) 177 (55.0) 58 (18.0) 48 15.0 34 10.7 185 (58.0) 52 (16.3) 100 (15.6) 69 (10.8) 362 (56.5) 110 (17.2)
Sitagliptin Placebo All
 
Range 112.0 to 587.0 116.0 to 609.0 112.0 to 609.0
Range 1.0 to 40.0 0.1 to 36.0 0.01 to 40.0
Total N 322 319 641 Total N 322 319 641
Total
N
322 319 641
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