Please select the eligibility criteria that correspond to the clinical trial below.
Title: Effects on Incidence of Cardiovascular Events of the Addition of Pioglitazone as Compared With a Sulphonylurea in Type 2 Diabetic Patients Inadequately Controlled With Metformin.
Brief Summary: Background: In patients with type 2 diabetes inadequately controlled with metformin, two main therapeutic options are equally plausible: add-on a sulfonylurea (SU) or a thiazolidinedione (TZD). Since the two classes of drugs clearly differ in terms of mechanisms of action, side effects, economic costs and cardiovascular risk factors profile, a direct comparison of the two therapeutic strategies would be most appropriate.

Aims: 1) To evaluate the effects of add-on pioglitazone as compared with add-on a SU on the incidence of cardiovascular events in type 2 diabetic patients inadequately controlled with metformin; 2) To compare the two treatments in terms of glycemic control, safety, and economic costs.

Methods: multicentre, randomised, open label, parallel group trial of 48 months duration. Eligible participants (type 2 diabetic males and females, aged 50-75 years, BMI 20-45 Kg/m2, in treatment for the last two months with metformin 2 gr/die in monotherapy and with HbA1c \> =7.0% and \<= 9.0%) will be randomized to add-on: a SU - glibenclamide (5-15 mg/die), gliclazide (30-120 mg/die), glimepiride (2-6 mg/die), chosen according to local practice - or pioglitazone (15-45 mg/die). A HbA1c value \> 8.0 % on two consecutive occasions will lead to addition of insulin to ongoing oral therapy.

Primary efficacy outcome: a composite endpoint of all-cause mortality, non fatal MI (including silent MI), non fatal stroke, and unplanned coronary revascularization.

Secondary outcomes. Principal secondary outcome: a composite ischemic endpoint of sudden death, fatal and non fatal acute MI (including silent MI), fatal and non fatal stroke, major amputations (above ankle), endovascular or surgical intervention on the coronary, leg or carotid arteries.

Other secondary outcomes

- a composite cardiovascular end point including the primary end point plus hospitalization for heart failure, endovascular or surgical intervention on the coronary, leg or carotid arteries, silent MI, angina - by WHO criteria and confirmed by a new electrocardiogram abnormality - intermittent claudication with an ankle/brachial index lower than 090; events of heart failure; a microvascular endpoint including: plasma creatinine increase of 2 times above the baseline value or creatinine clearance reduction of 20ml/min/1. 73m2 or development of overt nephropathy (dialysis or plasma creatinine \>3,3 mg/dl) or macroalbuminuria; glycemic control (changes from baseline in HBA1c, time to failure of glycemic control, i.e., HBA1c \>8.0% on two consecutive occasions three months apart); major CV risk factors (lipids, blood pressure, microalbuminuria, inflammation markers, waist circumference); safety and side effects; direct and indirect costs.

Data regarding CV endpoints, safety, tolerability, and study conduct will be monitored and analyzed by an independent committee, and will be not available to the study investigators until the closing of data collection. Efficacy end points will be analyzed on an intention-to-treat basis.


Options:
A: Inclusion Criteria:

* Patients with type 2 DM who are no longer responsive to maximum dose of one or more oral agents.

Exclusion Criteria:

* Angina pectoris, Canadian Class I-II,
* congestive heart failure, Class III-IV,
* stroke, incapacitating or in last 6 months,
* Myocardial infarction (MI) or invasive cardiovascular procedure within the past six months,
* ongoing diabetic gangrene,
* BMI \> 40,
* hemoglobinopathy that interferes with A1c monitoring,
* serum creatinine \> 1.6 mg/dL,
* fasting C-peptide \< 0.21 pmol/ml,
* Alanine Amino Transaminase (ALT) \> 3 times normal or serum bilirubin \> 1.9 mg/dL,
* malignancy or noncardiac life-threatening diseases making life expectancy \< 5 years,
* autonomic neuropathy,
* symptomatic pancreatic insufficiency (endocrine or exocrine),
* recurrent seizures within the past year,
* hypopituitarism,
* pregnancy, lactation, or planning a pregnancy,
* active psychosis or substance abuse,
* lack of access to a person who can assist or be called in an emergency,
* underlying conditions that in the site PI's judgment may prevent adherence to protocol,
* current participation in another clinical trial
B: Inclusion Criteria:

Screening study: Every one aged 40-69 years (UK and DK) or 50-69 years(NL). Treatment study: All with screen detected type 2 diabetes.

Exclusion Criteria:

Participants are excluded if they already have diabetes at time of screening, are pregnant or lactating or have a severe psychotic illness, are house bound or have an illness with a likely survival of less than one year.
C: Inclusion Criteria:

* Males and females, age 50-75 years
* Type 2 diabetes of at least 2 years duration
* BMI 20-45 Kg/m2
* Stable treatment for the last two months with metformin in monotherapy (at least 2 gr/die)
* HbA1c \>=7.0% and \<=9.0%

Exclusion Criteria:

* Type 1 diabetes
* Previous treatment with thiazolidinediones in the last six months
* Contraindication/intolerance to metformin or SUs or TZDs
* Documented coronary or cerebrovascular events in the previous 3 months
* Serum creatinine \> 1.5 mg/dl
* History of congestive heart failure, NYHA I or higher
* Chronic use of glucocorticoids
* Ischemic ulcer or gangrene
* Liver cirrhosis or severe hepatic dysfunction (ALT increase of 2.5 times the upper normal limit)
* Pregnancy or breast feeding
* Cancer, substance abuse, or any health problem that may interfere with the compliance to the study protocol or limit life expectancy
D: Inclusion Criteria:

* Clinical diagnosis of Type 2 diabetes mellitus
* HgbA1c between 6,8 - 10,0%
* With or without one or more micro- and macrovascular or neurological complications.

Exclusion Criteria:

* HgbA1c \< 6,8 and \> 10,0 %
* Patients who have attended lifestyle intervention in the past year
* Patients who is planned to start treatment with insulin during intervention period
* Lack of motivation
* Patients with severe heart-, liver or kidney disease or incurable cancer

Answer: C