Biphasic Insulin Aspart Versus NPH Plus Regular Human Insulin in Type 2 Diabetic Patients

Study design and participants This was a randomized controlled clinical trial of 48 weeks on subjects with T2DM between July 2011 and October 2012. Two hundred and four diabetic subjects aged 28-65 years were included in the study. Subjects had A1C >8.0% and had indication for starting insulin. They were randomly allocated to two groups using a simple randomization method. Any current and prior medications were acceptable for inclusion of participant except any type of insulin being evaluated. Demographic and anthropometric variables were recorded. Hypoglycemia events and laboratory data including FPG, HbA1c and lipid profiles were measured every three months. In addition, quality of life was assessed with self-administered standard EQ-5D questionnaire (Brooks, Rabin et al. 2003).

Subjects were excluded for any of the following criteria: Alteration in insulin sensitivity such as major surgery, infection, renal failure (Glomerular Filtration Rate < 50), glucocorticoid treatment, recent (within 2 weeks) serious hypoglycemic episode (requires assistance of another), simultaneous participating in another clinical study, using any type of insulin, sight or hearing impaired, active proliferative retinopathy or maculopathy require treatment within 6 months prior to screening, breast feeding, pregnancy or nursing of the intention of becoming pregnant or not using adequate contraceptive measures.

The study was approved by ethics committee of Tehran University of Medical Sciences and was recorded in IRCT (IRCT code: 201112038282N1). All eligible subjects agreed and signed written informed consent after full explanation of the purpose and nature of all procedures used. All patients were free to withdraw at will at any time.

Assessments and outcome measures The insulin therapies were prescribed by a single physician in the clinic. The starting dose of BIAsp 30 (NovoMix® 30-pen, NovoNordisk) was 0.2-0.6 unit/kg per day in 2 divided doses according to level of glycemia in the intervention group. The control group received NPH/Reg insulin (from Exir pharmaceuticals, Lorestan, Iran) in a Ratio of 2:1 with initiation dose of 0.2-0.6 unit/kg in 2 divided doses. Two-thirds of the dose was given before breakfast and the remainder before dinner in NPH/Reg insulin group. Changes to oral glucose lowering drugs (OGLDs) at the time of starting the insulin analog, or thereafter, were entirely at the discretion of the participant and physician. Para clinical data were measured in a referral laboratory every three months. After an overnight fast of at least 12 hours, blood samples were obtained for measurement of fasting blood sugar (FBS) using a the glucose oxidase method, lipid profileswere determined using enzymatic methods. These measurements were conducted using commercial Parsazmun kits (Tehran, Iran) and a Hitachi 704 automatic analyzer (Tokyo, Japan)(Lentjes, Harff et al. 1987). HbA1c was measured using the high performance liquid chromatography method(Esteghamati, Jamali et al. 2010). Post prandial blood glucose (PPG) was measured two hours after breakfast using a glucose analyzer (YSI 2700 Select, YSI, Inc., Yellow Springs, OH).

Trial visits were defined as 0, 12, 24, 36 and 48 weeks from baseline. All participants were asked to record their 7-point blood glucose values in three consecutive days before each visit. Seven-point self-monitoring blood glucose includes three pre-meals, three post-meals, and bedtime blood glucose values during each day. Insulin doses were adjusted by a titration regimen according to self-monitored blood glucose. For both groups, treatment goals were as follows: fasting blood glucose of 80-120 mg/dl, postprandial glucose <160 mg/dl, A1C<7% and the before dinner blood glucose target for the NPH/Reg insulin group was 100 mg/dl, with a stepwise increase of both type of insulin depending on the pre-meal blood glucose values to achieve targets for plasma glucose (PG)as follows: +2 IU/day where 126 mg/dl < PG < 140 mg/dl, +4 IU/day where 140 mg/dl < PG < 160 mg/dl, +6 IU/day where 160 mg/dl < PG < 180 mg/dl, +8 IU/day where 180 mg/dl < PG < 200 mg/dl and +10 IU/day where PG > 200 mg/dl(Hermansen, Davies et al. 2006; Liebl, Prager et al. 2009), unless symptoms of hypoglycemia occurred. Hypoglycemia was defined as blood glucose <70 mg/dl. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia where the individual required the assistance of another person and was not treated with oral carbohydrate due to confusion or unconsciousness and was associated with a blood glucose level <40 mg/dl with recovery with intravenous glucose, or glucagon administration. Nocturnal hypoglycemia was defined as hypoglycemia occurred at night and which commonly known as hypoglycemia while asleep.