Efficacy of Pioglitazone/Metformin Combination Therapy in Subjects With Type 2 Diabetes Mellitus and Dyslipidemia.

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00770653
• Collaborator: (none)
• Enrollment: 305
• Locations: 64
• Arms: 2
• Duration (Months): 25
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to compare pioglitazone and metformin combination therapy, twice daily (BID), to glimepiride and metformin combination therapy for treating diabetic subjects with dyslipidemia.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus; Dyslipidemias	Drug: Pioglitazone and Metformin; Drug: Glimepiride and Metformin	Phase 3

Detailed Description

Insulin resistance is a major endocrinopathy preceding the development of hyperglycemia, diabetic dyslipidemia and cardiovascular disease in type 2 diabetes. The most common pattern of dyslipidemia in patients with type 2 diabetes are elevated triglyceride levels, decreased hih-density lipoprotein cholesterol and a predominance of small dense low-density lipoprotein particles. Each of these dyslipidemia features is associated with an increased risk of cardiovascular events.

Pioglitazone and Metformin are established drugs which can be used for the treatment of type 2 diabetes. This study will investigate the effects of treatment with fixed Pioglitazone/Metformin combination therapy of Metformin and Glimepiride in Metformin-pretreated type 2 diabetic patients with dyslipidemia.

Total participation time in this study is anticipated to be approximately 24 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 305 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effects of a Pioglitazone/Metformin Fixed Combination in Comparison to Metformin in Combination With Glimepiride on Diabetic Dyslipidemia
• Study Start Date: Apr 1, 2007
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pioglitazone 15 mg and Metformin 850 mg BID	Drug: Pioglitazone and Metformin; Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.; Other Names: ACTOS® AD-4833 OPIMET
Active Comparator: Glimepiride 2 mg and Metformin 850 mg BID	Drug: Glimepiride and Metformin; Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.; Other Names: Amaryl Glista

Outcome Measures

Primary Outcome Measures

1. The Mean Increase From Baseline in High-Density Lipoprotein Cholesterol. [Baseline and Week 24.]

   The increase in High-Density Lipoprotein (HDL) Cholesterol collected at week 24 or final visit and HDL-Cholesterol collected at baseline.

Secondary Outcome Measures

1. Change From Baseline in High-Density Lipoprotein Cholesterol. [Baseline and Week 24.]

   The change between HDL-Cholesterol collected at week 24 or final visit and HDL-Cholesterol collected at baseline.

2. Change From Baseline in High-Density Lipoprotein/Low-Density Lipoprotein Ratio. [Baseline and Week 24.]

   The change between High-Density Lipoprotein/Low-Density Lipoprotein Ratio collected at week 24 or final visit and High-Density Lipoprotein/Low-Density Lipoprotein Ratio collected at baseline.

3. Change From Baseline in Triglycerides. [Baseline and Week 24.]

   The change between the value of Triglycerides collected at week 24 or final visit and Triglycerides collected at baseline.

4. Change From Baseline in Low-Density Lipoprotein Subfractions. [Baseline and Week 24.]

   The change between the value of Low-Density Lipoprotein Subfractions collected at week 24 or final visit and Low-Density Lipoprotein Subfractions collected at baseline.

5. Change From Baseline in Low-Density Lipoprotein Cholesterol. [Baseline and Week 24.]

   The change between Low-Density Lipoprotein Cholesterol collected at week 24 or final visit and Low-Density Lipoprotein Cholesterol collected at baseline.

6. Change From Baseline in Glycosylated Hemoglobin. [Baseline and Week 24.]

   The change between the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 24 or final visit and Glycosylated Hemoglobin collected at baseline.

7. Change From Baseline in Fasting Intact Proinsulin. [Baseline and Week 24.]

   The change between Fasting Intact Proinsulin collected at week 24 or final visit and Fasting Intact Proinsulin collected at baseline.

8. Change From Baseline in Fasting Glucose. [Baseline and Week 24.]

   The change between Fasting Glucose collected at week 24 or final visit and Fasting Glucose collected at baseline.

9. Change From Baseline in Adiponectin. [Baseline and Week 24.]

   The change between Adiponectin collected at week 24 or final visit and Adiponectin collected at baseline.

10. Change From Baseline in High Sensitivity C-reactive Protein (Original). [Baseline and Week 24.]

    The change between the value of High Sensitivity C-reactive Protein collected at week 24 or final visit and High Sensitivity C-reactive Protein collected at baseline.

11. Change From Baseline in High Sensitivity C-reactive Protein (≤ 10 mg/L). [Baseline and Week 24.]

    The change between the value of High Sensitivity C-reactive Protein less than or equal to 10 mg/L collected at week 24 or final visit and High Sensitivity C-reactive Protein less than or equal to 10 mg/L collected at baseline.

12. Change From Baseline in Systolic Blood Pressure. [Baseline and Week 24.]

    The change between Systolic Blood Pressure measured at week 24 or final visit and Systolic Blood Pressure measured at baseline.

13. Change From Baseline in Diastolic Blood Pressure. [Baseline and Week 24.]

    The change between Diastolic Blood Pressure measured at week 24 or final visit and Diastolic Blood Pressure measured at baseline.

14. Intake of Study Medication Greater Than 80% and Less Than 120%. [Baseline and Week 24.]

    The change between the Intake of study medication greater than 80% at week 24 or final visit and Baseline and the Intake of study medication greater than 80% at baseline.

15. Change From Baseline in Nitrotyrosine. [Baseline and Week 24.]

    The change between the value of Nitrotyrosine collected at week 24 or final visit and Nitrotyrosine collected at baseline.

16. Change From Baseline in Soluble CD40 Ligand. [Baseline and Week 24.]

    The change between the value of Soluble CD40 Ligand collected at week 24 or final visit and Soluble CD40 Ligand collected at baseline.

17. Change From Baseline in Matrix Metallo Proteinase-9. [Baseline and Week 24.]

    The change between the value of Baseline in Matrix Metallo Proteinase-9 collected at week 24 or final visit and Baseline in Matrix Metallo Proteinase-9 collected at baseline.

18. Change From Baseline in Soluble Intracellular Adhesion Molecule. [Baseline and Week 24.]

    The change between the value of Baseline in Soluble Intracellular Adhesion molecule at week 24 or final visit and Baseline in Soluble Intracellular Adhesion molecule collected at baseline.

19. Change From Baseline in Soluble Vascular Cell Adhesion Molecule. [Baseline and Week 24.]

    The change between the value of Soluble Vascular Cell Adhesion Molecule collected at week 24 or final visit and Soluble Vascular Cell Adhesion Molecule collected at baseline.

20. Change From Baseline in Thromboxane B2. [Baseline and Week 24.]

    The change between the value of Thromboxane B2 collected at week 24 or final visit and Thromboxane B2 collected at baseline.

21. Change From Baseline in Platelet Function. [Baseline and Week 24.]

    The change between the value of Platelet Function by PFA 100 collected at week 24 or final visit and Platelet Function by PFA 100 collected at baseline.

22. Change From Baseline in E-Selectin. [Baseline and Week 24.]

    The change between the value of E-Selectin collected at week 24 or final visit and E-Selectin collected at baseline.

23. Change From Baseline in Von-Willebrand Factor. [Baseline and Week 24.]

    The change between the value of Von-Willebrand Factor collected at week 24 or final visit and Von-Willebrand Factor collected at baseline.

24. Change From Baseline in Erythrocyte Deformability (0.30%). [Baseline and Week 24.]

    The change between the 0.30 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.

25. Change From Baseline in Erythrocyte Deformability (0.60%) [Baseline and Week 24.]

    The change between the 0.60 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.

26. Change From Baseline in Erythrocyte Deformability (1.20). [Baseline and Week 24.]

    The change between the 1.20 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.

27. Change From Baseline in Erythrocyte Deformability (3.00). [Baseline and Week 24.]

    The change between the 3.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.

28. Change From Baseline in Erythrocyte Deformability (6.00). [Baseline and Week 24.]

    The change between the 6.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.

29. Change From Baseline in Erythrocyte Deformability (12.00). [Baseline and Week 24.]

    The change between the 12.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.

30. Change From Baseline in Erythrocyte Deformability (30.00). [Baseline and Week 24.]

    The change between the 30.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.

31. Change From Baseline in Erythrocyte Deformability (60.00). [Baseline and Week 24.]

    The change between the 60.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 2 diabetes according to the American Diabetes Association Criteria.

• Treatment with individual maximal tolerated dose of metformin (850 - 2000 mg) as monotherapy within the last 12 weeks.

• Glycosylated Hemoglobin greater than or equal to 6.5% and less than or equal to 9%.

• Dyslipidemia defined as high-density lipoprotein cholesterol less than or equal to 1.03 mmol/l (40 mg/dL) and/or triglycerides greater than or equal to 1.7 mmol/l (150 mg/dL).

• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.

Exclusion Criteria:

• Type 1 diabetes mellitus.

• Insulin-dependent type 2 diabetes mellitus.

• Treatment or history of treatment with any insulin formulation other than emergency for more than 2 weeks.

• Treatment with other oral antidiabetic drugs in addition to metformin within the last 12 weeks.

• Anamnestic history of hypersensitivity to the study drugs or to drugs with similar chemical structures.

• Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:

• Heparin (and heparin-like drugs)

• coumarin

• phenprocoumon

• hirudin

• Protein C

• Fondaparinux

• antithrombin III

• Peroxisome Proliferation Activating Receptor (gamma) agonists

• Treatment within the last 12 weeks with:

• fibrates

• gemfibrozil

• niacin

• months

• Rifampicin

• Changes in dosage of any statin treatment to lower low-density lipoprotein within 2 weeks before study entry and during study participation interval.

• Changes in dosage of any anticoagulant treatment with acetyl salicylic acid and/or clopidogrel within 2 weeks before study entry and during study participation interval.

• Start of statin and/or anticoagulant treatment during study participation interval.

• History of severe or multiple allergies and/ or acute severe infections.

• Have had more than one unexplained episode of severe hypoglycemia (defined as requiring assistance of another person due to disabling hypoglycemia) within 6 months prior to screening visit.

• Progressive fatal disease.

• Any elective surgery during study participation.

• History of drug or alcohol abuse within the last 5 years.

• A history of significant cardiovascular (New York Heart Association stage I - IV), respiratory, gastrointestinal, hepatic (alanine aminotransferase and/or aspartate aminotransferase greater than 2.5 times the upper limit of the normal reference range), renal (serum creatinine greater than 1.2 mg/dL in women and greater than 1.5 mg/dL in men, glomerular filtration rate less than 60 ml/min as estimated by the Cockroft-Gault formula), neurological, psychiatric and/or hematological disease as judged by the investigator, history of macular edema.

• Blood donation within the last 30 days.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Bretten	Baden-Württemberg	Germany
2		Deggingen	Baden-Württemberg	Germany
3		Dettenheim	Baden-Württemberg	Germany
4		Künzelsau	Baden-Württemberg	Germany
5		Rottweil	Baden-Württemberg	Germany
6		Spaichingen	Baden-Württemberg	Germany
7		Stockach	Baden-Württemberg	Germany
8		Wangen	Baden-Württemberg	Germany
9		Augsburg	Bayern	Germany
10		Feldafing	Bayern	Germany
11		Furth im Wald	Bayern	Germany
12		Immenstadt	Bayern	Germany
13		Lichtenfels	Bayern	Germany
14		München	Bayern	Germany
15		Schweinfurt	Bayern	Germany
16		Waldkraiburg	Bayern	Germany
17		Wallerfing	Bayern	Germany
18		Weilersbach	Bayern	Germany
19		Würzburg	Bayern	Germany
20		Ketzin	Brandenburg	Germany
21		Rüdersdorf	Brandenburg	Germany
22		Bermerhaven	Bremen	Germany
23		Bensheim	Hessen	Germany
24		Ehrenberg	Hessen	Germany
25		Gersfeld	Hessen	Germany
26		Kassel	Hessen	Germany
27		Kelkheim	Hessen	Germany
28		Offenbach	Hessen	Germany
29		Schwerin	Mecklenburg-Vorpommern	Germany
30		Celle	Niedersachsen	Germany
31		Einbeck	Niedersachsen	Germany
32		Hannover	Niedersachsen	Germany
33		Hildesheim	Niedersachsen	Germany
34		Bad Berleburg	Nordrhein-Westfalen	Germany
35		Bad Laasphe	Nordrhein-Westfalen	Germany
36		Bad Oeynhausen	Nordrhein-Westfalen	Germany
37		Bocholt	Nordrhein-Westfalen	Germany
38		Dinslaken	Nordrhein-Westfalen	Germany
39		Dorsten	Nordrhein-Westfalen	Germany
40		Duisburg	Nordrhein-Westfalen	Germany
41		Essen	Nordrhein-Westfalen	Germany
42		Frechen	Nordrhein-Westfalen	Germany
43		Isselburg	Nordrhein-Westfalen	Germany
44		Kamen	Nordrhein-Westfalen	Germany
45		Köln	Nordrhein-Westfalen	Germany
46		Marl	Nordrhein-Westfalen	Germany
47		Menden	Nordrhein-Westfalen	Germany
48		Münster	Nordrhein-Westfalen	Germany
49		Siegen	Nordrhein-Westfalen	Germany
50		Diez	Rheinland-Pfalz	Germany
51		Mainz	Rheinland-Pfalz	Germany
52		Neuwied	Rheinland-Pfalz	Germany
53		Rodenbach	Rheinland-Pfalz	Germany
54		Simmern	Rheinland-Pfalz	Germany
55		Magdeburg	Sachsen-Anhalt	Germany
56		Borna	Sachsen	Germany
57		Dresden	Sachsen	Germany
58		Meißen	Sachsen	Germany
59		Mittweida	Sachsen	Germany
60		Reinfeld	Schleswig-Holstein	Germany
61		Altenburg	Thüringen	Germany
62		Blankenhain	Thüringen	Germany
63		Berlin		Germany
64		Hamburg		Germany

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Adviser Clinical Research, Takeda Pharma Gmbh, Aachen (Germany)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• ACTOPLUS MET® Package Insert

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00770653
• Other Study ID Numbers: ATS K024; 2006-004455-37; D-PIO-114; U1111-1114-1678
• First Posted: Oct 10, 2008
• Last Update Posted: Oct 6, 2010
• Last Verified: Sep 1, 2010

• Keywords provided by , ,: Glucose Metabolism Disorder; Dysmetabolic Syndrome; Type II Diabetes; Diabetes Mellitus, Lipoatrophic; Dyslipidemia; Hyperlipidemias; Drug Therapy
• Additional relevant MeSH terms: Diabetes Mellitus; Dyslipidemias; Metformin; Pioglitazone; Glimepiride

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled at 61 investigative sites in Germany from 03 April 2007 to 13 May 2009.
Pre-assignment Detail	Subjects with type 2 diabetes with diabetic dyslipidemia, inadequately controlled by Metformin monotherapy were enrolled in one of two, twice-daily (BID) combination therapy treatment groups.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Period Title: Overall Study
STARTED	155	150
COMPLETED	123	121
NOT COMPLETED	32	29

Baseline Characteristics

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID	Total
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.	Total of all reporting groups
Overall Participants	153	149	302
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.7 (10.0)	58.5 (9.6)	58.6 (9.8)
Sex: Female, Male (Count of Participants)
Female	54 35.3%	55 36.9%	109 36.1%
Male	99 64.7%	94 63.1%	193 63.9%
Region of Enrollment (participants) [Number]
Germany	153 100%	149 100%	302 100%

Outcome Measures

1. Primary Outcome

Title	The Mean Increase From Baseline in High-Density Lipoprotein Cholesterol.
Description	The increase in High-Density Lipoprotein (HDL) Cholesterol collected at week 24 or final visit and HDL-Cholesterol collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analysis was performed on participants with at least one valid baseline and post-baseline measurement. This condition was not fulfilled in 17 participants who were excluded from the all-participants-randomized set, leading to a full-analysis-set of 288 (146 vs. 142). Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	146	142
Least Squares Mean (Standard Error) [mg/dL]	3.2 (9.7)	-0.3 (11.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments	Null hypothesis (H0) = mean increase of HDL after 24 weeks of treatment of Pio/Met group ≤ the mean increase in the Gli/Met group. Alternate hypothesis (H1) = mean increase of HDL after 24 weeks of treatment of Pio/Met group > the mean increase in the Gli/Met group. The relevant clinical effect size to detect with adequate power was 0.35. With this assumption, a one sided t-test with a type I error rate had 80% power to reject the H0 for the H1 when the sample size was 130 patients per group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.2670
	Confidence Interval	(2-Sided) 95%; 1.2264 to 5.3076
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in High-Density Lipoprotein Cholesterol.
Description	The change between HDL-Cholesterol collected at week 24 or final visit and HDL-Cholesterol collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. This condition was not fulfilled in some participants who were excluded. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	143	137
Least Squares Mean (Standard Error) [mg/dL]	3.3 (9.6)	-0.4 (11.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.2670
	Confidence Interval	(2-Sided) 95%; 1.2264 to 5.3076
	Parameter Dispersion	Type: Value:
	Estimation Comments	Deviation from the normal distribution assumption was detected for original and rank-transformed data for all time-points due to p-value of Shapiro-Wilk test, indicating the normal distribution assumption might be distrusted for HDL-cholesterol data.

3. Secondary Outcome

Title	Change From Baseline in High-Density Lipoprotein/Low-Density Lipoprotein Ratio.
Description	The change between High-Density Lipoprotein/Low-Density Lipoprotein Ratio collected at week 24 or final visit and High-Density Lipoprotein/Low-Density Lipoprotein Ratio collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. This condition was not fulfilled in some participants who were excluded. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	141	132
Least Squares Mean (Standard Error) [mg/dL]	0.1 (0.8)	0.3 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1167
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1311
	Confidence Interval	(2-Sided) 95%; -0.2951 to 0.0329
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Triglycerides.
Description	The change between the value of Triglycerides collected at week 24 or final visit and Triglycerides collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. This condition was not fulfilled in some participants who were excluded. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	146	142
Least Squares Mean (Standard Error) [mg/dL]	-40.9 (113.8)	-16.7 (121.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1012
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.9479
	Confidence Interval	(2-Sided) 95%; -39.4331 to 3.5373
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Low-Density Lipoprotein Subfractions.
Description	The change between the value of Low-Density Lipoprotein Subfractions collected at week 24 or final visit and Low-Density Lipoprotein Subfractions collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from the Mainz, Germany study site. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	11	11
Least Squares Mean (Standard Error) [mg/dL]	6.2 (17.5)	6.1 (26.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7486
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.1292
	Confidence Interval	(2-Sided) 95%; -17.0109 to 23.2693
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Low-Density Lipoprotein Cholesterol.
Description	The change between Low-Density Lipoprotein Cholesterol collected at week 24 or final visit and Low-Density Lipoprotein Cholesterol collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from the Mainz, Germany study site. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	143	132
Least Squares Mean (Standard Error) [mg/dL]	9.7 (34.7)	11.2 (25.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9464
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2355
	Confidence Interval	(2-Sided) 95%; -7.1253 to 6.6543
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin.
Description	The change between the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 24 or final visit and Glycosylated Hemoglobin collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. This condition was not fulfilled in some participants who were excluded. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	139	136
Least Squares Mean (Standard Error) [mg/dL]	-0.83 (0.87)	-0.95 (0.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0807
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.1574
	Confidence Interval	(2-Sided) 95%; -0.0193 to 0.3341
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in Fasting Intact Proinsulin.
Description	The change between Fasting Intact Proinsulin collected at week 24 or final visit and Fasting Intact Proinsulin collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. This condition was not fulfilled in some participants who were excluded. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	144	137
Least Squares Mean (Standard Error) [pmol/L]	-5.18 (11.89)	-0.11 (9.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.5039
	Confidence Interval	(2-Sided) 95%; -6.4222 to -2.5855
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in Fasting Glucose.
Description	The change between Fasting Glucose collected at week 24 or final visit and Fasting Glucose collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. This condition was not fulfilled in some participants who were excluded. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	145	139
Least Squares Mean (Standard Error) [mg/dL]	-21.6 (38.6)	-21.1 (40.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7799
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.0707
	Confidence Interval	(2-Sided) 95%; -6.4665 to 8.6079
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Change From Baseline in Adiponectin.
Description	The change between Adiponectin collected at week 24 or final visit and Adiponectin collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. This condition was not fulfilled in some participants who were excluded. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	146	139
Least Squares Mean (Standard Error) [μg/mL]	6.79 (6.38)	0.72 (2.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.3161
	Confidence Interval	(2-Sided) 95%; 5.0994 to 7.5329
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Change From Baseline in High Sensitivity C-reactive Protein (Original).
Description	The change between the value of High Sensitivity C-reactive Protein collected at week 24 or final visit and High Sensitivity C-reactive Protein collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. This condition was not fulfilled in some participants who were excluded. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	141	135
Least Squares Mean (Standard Error) [mg/L]	-0.21 (8.98)	-0.04 (9.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4131
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.8323
	Confidence Interval	(2-Sided) 95%; -2.8312 to 1.1665
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Change From Baseline in High Sensitivity C-reactive Protein (≤ 10 mg/L).
Description	The change between the value of High Sensitivity C-reactive Protein less than or equal to 10 mg/L collected at week 24 or final visit and High Sensitivity C-reactive Protein less than or equal to 10 mg/L collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. This condition was not fulfilled in some participants who were excluded. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	123	113
Mean (Standard Deviation) [mg/L]	-0.87 (1.88)	0.00 (1.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.8847
	Confidence Interval	(2-Sided) 95%; -1.3067 to -0.4627
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure.
Description	The change between Systolic Blood Pressure measured at week 24 or final visit and Systolic Blood Pressure measured at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. This condition was not fulfilled in some participants who were excluded. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	146	142
Least Squares Mean (Standard Error) [mmHg]	-2.5 (14.8)	0.5 (13.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0929
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.4903
	Confidence Interval	(2-Sided) 95%; -5.3979 to 0.4172
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline in Diastolic Blood Pressure.
Description	The change between Diastolic Blood Pressure measured at week 24 or final visit and Diastolic Blood Pressure measured at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. This condition was not fulfilled in some participants who were excluded. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	146	142
Least Squares Mean (Standard Deviation) [mmHg]	-1.3 (8.7)	-0.1 (8.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3279
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.8832
	Confidence Interval	(2-Sided) 95%; -2.6571 to 0.8906
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Intake of Study Medication Greater Than 80% and Less Than 120%.
Description	The change between the Intake of study medication greater than 80% at week 24 or final visit and Baseline and the Intake of study medication greater than 80% at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. This condition was not fulfilled in some participants who were excluded. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	146	142
Number [participants]	136 88.9%	137 91.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments	The number and percentage of participants with a calculated compliance >80% and <120% are presented for both treatment groups. In addition, the p-values of Fisher's exact test, the two-sided 95% confidence intervals for the percentage of patients per treatment group and for the difference between the treatment groups are provided.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2895
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Fisher Exact
	Estimated Value	-3.33
	Confidence Interval	(2-Sided) 95%; -14.83 to 8.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Change From Baseline in Nitrotyrosine.
Description	The change between the value of Nitrotyrosine collected at week 24 or final visit and Nitrotyrosine collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from Schwerin, Berlin, Hanover and Münster study sites. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	23	20
Least Squares Mean (Standard Error) [nmol/L]	-2.7 (93.2)	32.5 (147.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3517
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-29.9516
	Confidence Interval	(2-Sided) 95%; -94.1999 to 34.2967
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Change From Baseline in Soluble CD40 Ligand.
Description	The change between the value of Soluble CD40 Ligand collected at week 24 or final visit and Soluble CD40 Ligand collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from Schwerin, Berlin, Hanover and Münster study sites. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	16	18
Least Squares Mean (Standard Error) [pg/mL]	-40.7 (248.6)	102.4 (379.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1979
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-151.4477
	Confidence Interval	(2-Sided) 95%; -386.2256 to 83.3302
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Change From Baseline in Matrix Metallo Proteinase-9.
Description	The change between the value of Baseline in Matrix Metallo Proteinase-9 collected at week 24 or final visit and Baseline in Matrix Metallo Proteinase-9 collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from Schwerin, Berlin, Hanover and Münster study sites. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	23	20
Least Squares Mean (Standard Error) [ng/mL]	31.4 (228.3)	51.6 (216.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7186
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-24.8589
	Confidence Interval	(2-Sided) 95%; -163.3229 to 113.6052
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Change From Baseline in Soluble Intracellular Adhesion Molecule.
Description	The change between the value of Baseline in Soluble Intracellular Adhesion molecule at week 24 or final visit and Baseline in Soluble Intracellular Adhesion molecule collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from Schwerin, Berlin, Hanover and Münster study sites. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	23	20
Least Squares Mean (Standard Error) [ng/mL]	-13.0 (46.9)	-3.2 (50.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5058
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.9728
	Confidence Interval	(2-Sided) 95%; -39.9915 to 20.0459
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Change From Baseline in Soluble Vascular Cell Adhesion Molecule.
Description	The change between the value of Soluble Vascular Cell Adhesion Molecule collected at week 24 or final visit and Soluble Vascular Cell Adhesion Molecule collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from Schwerin, Berlin, Hanover and Münster study sites. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	22	20
Least Squares Mean (Standard Error) [ng/mL]	11.6 (160.6)	3.3 (115.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5230
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	28.3988
	Confidence Interval	(2-Sided) 95%; -60.7193 to 117.5169
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Change From Baseline in Thromboxane B2.
Description	The change between the value of Thromboxane B2 collected at week 24 or final visit and Thromboxane B2 collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from Schwerin, Berlin, Hanover and Münster study sites. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	19	20
Least Squares Mean (Standard Error) [pg/mL]	-216.4 (842.9)	527.8 (1190.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2203
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-367.2639
	Confidence Interval	(2-Sided) 95%; -964.3923 to 229.8646
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Secondary Outcome

Title	Change From Baseline in Platelet Function.
Description	The change between the value of Platelet Function by PFA 100 collected at week 24 or final visit and Platelet Function by PFA 100 collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from the Mainz, Germany study site. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	3	5
Least Squares Mean (Standard Error) [sec]	-30.3 (44.3)	-1.0 (102.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5850
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	28.0794
	Confidence Interval	(2-Sided) 95%; -95.6468 to 151.8057
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Change From Baseline in E-Selectin.
Description	The change between the value of E-Selectin collected at week 24 or final visit and E-Selectin collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from Schwerin, Berlin, Hanover and Münster study sites. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	23	20
Least Squares Mean (Standard Error) [ng/mL]	-3.7 (4.8)	-0.5 (3.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0138
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.4205
	Confidence Interval	(2-Sided) 95%; -4.3207 to -0.5202
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Change From Baseline in Von-Willebrand Factor.
Description	The change between the value of Von-Willebrand Factor collected at week 24 or final visit and Von-Willebrand Factor collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from Schwerin, Berlin, Hanover and Münster study sites. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	24	20
Least Squares Mean (Standard Error) [percent]	-19.5 (32.0)	1.4 (33.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0817
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.0009
	Confidence Interval	(2-Sided) 95%; -30.1139 to 1.8578
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

Title	Change From Baseline in Erythrocyte Deformability (0.30%).
Description	The change between the 0.30 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from the Mainz, Germany study site. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	11	12
Mean (Standard Deviation) [percent]	1.3 (2.1)	-0.4 (1.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1761
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.9935
	Confidence Interval	(2-Sided) 95%; -0.4843 to 2.4712
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Secondary Outcome

Title	Change From Baseline in Erythrocyte Deformability (0.60%)
Description	The change between the 0.60 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from the Mainz, Germany study site. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	11	12
Mean (Standard Deviation) [percent]	2.4 (1.3)	-0.5 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.5263
	Confidence Interval	(2-Sided) 95%; 1.3832 to 3.6695
	Parameter Dispersion	Type: Value:
	Estimation Comments

27. Secondary Outcome

Title	Change From Baseline in Erythrocyte Deformability (1.20).
Description	The change between the 1.20 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from the Mainz, Germany study site. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	11	12
Mean (Standard Deviation) [percent]	3.2 (2.2)	-1.1 (2.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0055
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.2345
	Confidence Interval	(2-Sided) 95%; 1.0675 to 5.4016
	Parameter Dispersion	Type: Value:
	Estimation Comments

28. Secondary Outcome

Title	Change From Baseline in Erythrocyte Deformability (3.00).
Description	The change between the 3.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from the Mainz, Germany study site. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	11	12
Mean (Standard Deviation) [percent]	3.3 (2.8)	-.15 (3.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0264
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.9712
	Confidence Interval	(2-Sided) 95%; 0.3863 to 5.5562
	Parameter Dispersion	Type: Value:
	Estimation Comments

29. Secondary Outcome

Title	Change From Baseline in Erythrocyte Deformability (6.00).
Description	The change between the 6.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from the Mainz, Germany study site. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	11	12
Mean (Standard Deviation) [percent]	3.1 (2.9)	-1.4 (2.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0509
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.5394
	Confidence Interval	(2-Sided) 95%; -0.0114 to 5.0901
	Parameter Dispersion	Type: Value:
	Estimation Comments

30. Secondary Outcome

Title	Change From Baseline in Erythrocyte Deformability (12.00).
Description	The change between the 12.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from the Mainz, Germany study site. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	11	12
Mean (Standard Deviation) [percent]	2.7 (2.8)	-1.3 (2.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1013
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.1718
	Confidence Interval	(2-Sided) 95%; -0.4660 to 4.8097
	Parameter Dispersion	Type: Value:
	Estimation Comments

31. Secondary Outcome

Title	Change From Baseline in Erythrocyte Deformability (30.00).
Description	The change between the 30.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from the Mainz, Germany study site. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	11	12
Mean (Standard Deviation) [percent]	2.5 (2.6)	-1.3 (3.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1363
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.1346
	Confidence Interval	(2-Sided) 95%; -0.7338 to 5.0031
	Parameter Dispersion	Type: Value:
	Estimation Comments

32. Secondary Outcome

Title	Change From Baseline in Erythrocyte Deformability (60.00).
Description	The change between the 60.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Time Frame	Baseline and Week 24.

Outcome Measure Data

Analysis Population Description

Analyses was performed for the full analysis and per-protocol set. The number of participants for analysis was derived from a subgroup of participants from the Mainz, Germany study site. Last observation carried forward was used (LOCF) in case of premature termination.

Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID	Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.	Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
Measure Participants	11	12
Mean (Standard Deviation) [percent]	2.7 (2.6)	-1.3 (3.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pioglitazone 15 mg and Metformin 850 mg BID, Glimepiride 2 mg and Metformin 850 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1165
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.4181
	Confidence Interval	(2-Sided) 95%; -0.6561 to 5.4922
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	1 year and 11 months. Treatment-emergent adverse events are defined as those occurring after signature of consent form and no more than 14 days after the end of the study.
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Irrespective of the relation to study treatment, any event spontaneously reported by the participant or observed by the investigator was recorded.
Arm/Group Title	Pioglitazone 15 mg and Metformin 850 mg BID		Glimepiride 2 mg and Metformin 850 mg BID
Arm/Group Description	Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks.		Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks.
All Cause Mortality
	Pioglitazone 15 mg and Metformin 850 mg BID		Glimepiride 2 mg and Metformin 850 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pioglitazone 15 mg and Metformin 850 mg BID		Glimepiride 2 mg and Metformin 850 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/153 (11.1%)		8/149 (5.4%)
Blood and lymphatic system disorders
Leukocytosis	1/153 (0.7%)		0/149 (0%)
Thrombocytopenia	1/153 (0.7%)		0/149 (0%)
Cardiac disorders
Cardiac failure	2/153 (1.3%)		0/149 (0%)
Cardiomegaly	1/153 (0.7%)		0/149 (0%)
Coronary artery disease	0/153 (0%)		1/149 (0.7%)
Tachycardia	1/153 (0.7%)		0/149 (0%)
Gastrointestinal disorders
Abdominal adhesions	0/153 (0%)		1/149 (0.7%)
Subileus	0/153 (0%)		1/149 (0.7%)
General disorders
Chest pain	1/153 (0.7%)		0/149 (0%)
Hepatobiliary disorders
Hepatic failure	1/153 (0.7%)		0/149 (0%)
Investigations
Tumour marker increased	1/153 (0.7%)		0/149 (0%)
Metabolism and nutrition disorders
Diabetes mellitus	1/153 (0.7%)		0/149 (0%)
Hyperkalaemia	1/153 (0.7%)		0/149 (0%)
Hyponatraemia	1/153 (0.7%)		0/149 (0%)
Lactic acidosis	1/153 (0.7%)		0/149 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign breast neoplasm	1/153 (0.7%)		0/149 (0%)
Prostate cancer	0/153 (0%)		1/149 (0.7%)
Nervous system disorders
Carotid artery stenosis	0/153 (0%)		1/149 (0.7%)
Psychiatric disorders
Depression	1/153 (0.7%)		0/149 (0%)
Mental disorder due to a general medical condition	1/153 (0.7%)		0/149 (0%)
Renal and urinary disorders
Renal failure acute	1/153 (0.7%)		0/149 (0%)
Urinary retention	0/153 (0%)		1/149 (0.7%)
Vascular disorders
Hypertensive crisis	0/153 (0%)		1/149 (0.7%)
Peripheral arterial occlusive disease	0/153 (0%)		1/149 (0.7%)
Other (Not Including Serious) Adverse Events
	Pioglitazone 15 mg and Metformin 850 mg BID		Glimepiride 2 mg and Metformin 850 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/153 (39.9%)		61/149 (40.9%)
Gastrointestinal disorders
Diarrhoea	14/153 (9.2%)		14/149 (9.4%)
General disorders
Oedema peripheral	8/153 (5.2%)		4/149 (2.7%)
Infections and infestations
Nasopharyngitis	24/153 (15.7%)		33/149 (22.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	8/153 (5.2%)		3/149 (2%)
Nervous system disorders
Headache	7/153 (4.6%)		7/149 (4.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 14 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.