Please select the eligibility criteria that correspond to the clinical trial below.
Title: Effect of Repaglinide Versus Metformin Treatment in Combination With Insulin Biasp30 (Novologmix 70/30) Predinner on Glycemic and Non-Glycemic Cardiovascular Risk-Factors in Non-Obese Patients With Type-2-Diabetes With Unsatisfactory Glycaemic Control With Oral Hypoglycaemic Agents
Brief Summary: Aim:

The United Kingdom Prospective Diabetes Study (UKPDS) showed a reduction in cardiovascular events in obese patients with type-2-diabetes treated with metformin compared with other hypoglycaemic treatments with no difference in glycemic control between treatments. Non-obese patients with type-2-diabetes are usually treated with insulin-secretagogues or insulin when diet fails. Since non-obese patients with type-2-diabetes also carry a high risk of cardiovascular events, the use of metformin for this sub-group of patients might be more beneficial. Moreover, when insulin-treatment is initiated ongoing oral hypoglycaemic agents (OHA) are often continued, but in non-obese patients with type-2 diabetes little evidence exist for choosing the optimal class of OHA to be combined with insulin. The aim of the project is therefore to investigate the effect of metformin vs. an insulin-secretagogue (repaglinide) in combination with insulin on glycemic control and non-glycemic cardiovascular risk-factors in non-obese patients with type-2-diabetes, uncontrolled on diet alone.

Methodology:

Single-center, double-blind, double-dummy, randomized, parallel study involving 100 non-obese (BMI 27 kg/m2 or lower) patients with type-2-diabetes investigating the effect of treatment with metformin vs. repaglinide each in combination with biphasic insulin (Insulin-aspart 30/70, BIAsp30) for a period of 12 months.


Options:
A: Inclusion Criteria:

* Non-obese patients (BMI \< 27 kg/m2)
* Type 2 diabetes
* Age 40 years or older
* HbA1c = 6.5% or higher at baseline.

Exclusion Criteria:

* No known contraindications for either of the study-drugs (known allergy to the study-drugs; heart-, liver- or kidney-failure)
* Pregnancy
* Other serious physical or mental illnesses with a life-shortening prognosis.
* Drug or alcohol abuse.
* Weight-loss of more than 5 kg during the last 6 month prior to enrollment.
B: Inclusion Criteria:

1. A diagnosis of type 2 diabetes mellitus first made at age 30 years or older
2. Age 55 years or older at entry
3. Ability to provide informed consent
4. A substantially elevated risk of cardiovascular disease, indicated by:

   * A history of major macrovascular disease defined as any one of: stroke, myocardial infarction, hospital admission for transient ischaemic attack, hospital admission for unstable angina, coronary artery bypass graft, percutaneous transluminal coronary angioplasty (with or without stenting), peripheral revascularisation (angioplasty or surgery) or amputation secondary to vascular disease or
   * A history of major microvascular disease defined as any one of nephropathy (albumin:creatinine ratio \>300ug/mg), retinal photocoagulation therapy, proliferative retinopathy (new blood vessels on the disc or elsewhere, vitreous haemorrhage, pre-retinal haemorrhage, or fibrous proliferations on the disc or elsewhere), macular oedema (retinal thickening within one disc diameter of the macular centre) or blindness in either eye (corrected visual acuity 6/60 or worse, persisting for three months or more) not known to be due to non-diabetic causes or
   * A first diagnosis of type 2 diabetes made 10 or more years prior to entry or
   * Another major risk factor for vascular disease defined as any one of: current daily cigarette smoking, total cholesterol greater than 6.0 mmol/l (with or without cholesterol lowering treatment), HDL cholesterol \<1.0 mmol/l, microalbuminuria (albumin:creatinine ratio 30-300ug/mg) or
   * Age 65 years or over

Exclusion Criteria:

1. A definite contraindication to treatment with an ACE inhibitor or a thiazide-like diuretic
2. A specific indication for treatment with an ACE inhibitor other than perindopril 2-4 mg daily (see also section 5.2.3) or a thiazide-like diuretic
3. A definite and specific indication for treatment with gliclazide or a haemoglobin A1c control target of 6.5% or less
4. A definite contra-indication to treatment with gliclazide or a haemoglobin A1c control target of 6.5% or less
5. A definite indication for long-term full-dose or bed-time insulin therapy
6. Participation in a trial within the month prior to the Registration Visit or current participation in another trial

Other potential reasons for ineligibility include:

* High probability of non-adherence to study treatment or follow-up
* Current clinical instability (e.g. a major cerebral or coronary event or sight-threatening retinopathy or macular oedema within the previous few weeks)
* Life threatening non-vascular disease other than diabetes and its complications
* Moderate or severe dementia
* Major disability that is likely to prevent regular attendance at study clinics

Final decisions about eligibility were made at the discretion of the study investigator and the potential study participant, in the light of any requirements or guidance from local ethics committees and other regulatory bodies.
C: Inclusion Criteria:

* Patients with confirmed diagnosis of Type2 diabetes mellitus (T2DM) by standard criteria
* C-peptide \>0.6 ng/ml (\>0.20 nmol/L).
* HbA1c ≥7.5 to ≤11% at Visit 1
* Treatment with stable, once or twice daily doses (maximum dose of \< 1 unit/kg/day) of basal (long-acting, intermediate-acting) insulin alone or pre-mixed insulin for at least 12 weeks prior to Visit 1. Stable is defined as ±10% of the Visit 1 dose during the previous 12 weeks
* Patients receiving metformin must be on a stable dose of metformin (at least 1500 mg daily or a maximally tolerated dose) for at least 12 weeks prior to Visit 1
* Body Mass Index (BMI) ≥20 to ≤40 kg/m2 at Visit

Exclusion Criteria:

Patients fulfilling any of the following criteria are not eligible for participation in the study

* Fasting plasma glucose (FPG) ≥240 mg/dl (13.3 mmol/L) at Visit 1
* Pregnant or lactating women
* Acute metabolic diabetes complications such as ketoacidosis or hyperosmolar state (coma) within the past 6 months
* Current diagnosis of congestive heart failure (NYHA III or IV).
* Myocardial infarction (MI) within the past 6 months
* Liver disease such as cirrhosis or chronic active hepatitis

Other protocol defined inclusion/excusion criteria may apply
D: Inclusion Criteria:

* Patients of both sexes (women after menopause, women of child-bearing age after sterilization or if practicing reliable contraception)
* Type 2 DM requiring insulin therapy after failure of maximal oral antidiabetic treatment (glycosylated Hb \> 7.5%) and need for exogenous insulin. (No concomitant use of oral antidiabetic agents)
* Being ambulatory
* Age: 30 to 80 years
* Proven absence of Islet Antibodies, if QI \< 28 kg/m2
* Insulin therapy 4 times daily (21), or insulin therapy 2 times daily using insulin 'mixtures' (rapidly and slowly acting)
* Standard dietary prescription by the dietician
* Absence of keto-acidosis
* Informed consent

Exclusion Criteria:

* Congestive heart failure, NYHA-classes III or IV
* Cardiac failure and/or myocardial infarction in the last four months before enrolment
* Other severe organic / systemic disease
* Metformin-induced lactic-acidosis
* Intolerance to metformin hydrochloride
* Renal disease or renal dysfunction
* Hypoxic states
* Severe hepatic dysfunction
* Excessive alcohol intake, acute or chronic
* Acute or chronic metabolic acidosis

Answer: A