Comparison of thrice daily biphasic human insulin (30/70) versus basal detemir & bolus aspart in patients with poorly controlled type 2 diabetes mellitus – A pilot study

Both Diabetes Control and Complications Trial (DCCT)1 and United Kingdom Prospective Diabetes Study (UKPDS)2, the two large interventional studies, which are testimony to glucose hypothesis have convincingly established the role of good glycaemic control in preventing and/or halting the progression of micro- and possibly macrovascular complications in patients with type 1 and type 2 diabetes, respectively. Good glycaemic control, preferably HbA₁c <7 per cent can remarkably reduce the risk of such complications and this target is currently recommended in clinical practice3.

Majority of the patients with type 2 diabetes mellitus (T2DM) are initially treated with dietary and lifestyle modifications and oral hypoglycaemic agents (OHAs). However, with advancing duration of disease, there is progressive and inexorable loss of β cell function/mass and eventually most of the patients need treatment with exogenous insulin45. This implies a once daily long-acting insulin or twice daily insulin treatment with a pre-mixed preparation. However, even with the above mentioned regimen many patients do not achieve their glycaemic targets and require intensification of insulin therapy such as basal-bolus (BB) regimen, which is near physiological and is considered as standard of care in clinical practice. Basal-bolus regimen can be practiced with either conventional insulin or insulin analogues and require four to five pricks per day. Insulin analogues have advantage over conventional insulin in terms of convenience of administration and decreased risk of nocturnal hypoglycaemia, though these are quite expensive. Biphasic human insulin (BHI) given twice a day even in reasonably high doses to avoid multiple injections is a common clinical practice. However, this is associated with post-lunch and/or pre-dinner hyperglycaemia particularly in late diners. To overcome this, biphasic insulin analogues have been given thrice a day and shown to be as efficacious as basal-bolus regimen6, however, BHI (30:70) has not been tried thrice a day. Therefore, this study was planned to assess the efficacy and safety of biphasic human insulin thrice-daily in comparison to basal bolus analogues regimen in patients with T2DM.

Material & Methods

This was an open-labelled randomized, study comparing BHI thrice daily with BB regimen in subjects with T2DM in whom glycaemic targets were not achieved with the use of BHI twice daily along with insulin sensitizers (metformin 2 g/day and pioglitazone 30 mg/day). The number of patients studied was arbitrarily defined, as it was a pilot study. The patients were recruited from out patient department at Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India between June 2008 and December 2009. The trial was conducted at PGIMER, Chandigarh, India. The trial protocol was approved by the institute ethics committee. Written informed consent was obtained from all the subjects.

Subjects: Patients with T2DM who were inadequately controlled while receiving BHI twice a day, metformin 2 g/day and pioglitazone 30 mg/day were recruited in the study after satisfying the following criteria: HbA₁c > 7 per cent, single time insulin dose exceeding >25 units and having post-lunch and/or pre-dinner hyperglycaemia. Exclusion criteria for the study were patients with deranged liver function tests, serum creatinine >1.5 mg/dl, decompensated heart failure/unstable angina/myocardial infarction within last 6 months, untreated proliferative retinopathy/ maculopathy, pregnancy, any other acute co-morbid illness, drug or alcohol dependence and if he/she was unable to understand the regimen.

Study protocol and treatment: Patients were randomized to either BHI or BB regimen for 12 wk (Fig.). Metformin 2 g/day and pioglitazone 30 mg/day were continued. Lifestyle modifications were reinforced. Hypertension and dyslipidaemia were treated according to the guidelines3. BHI (Mixtard 30:70, Novo Nordisk, Denmark) was administered 30 min before each meal. The total daily dose of BHI being received by the patient was distributed in 40:20:40 ratio (breakfast: lunch: dinner) and was later on adjusted according to self monitoring of blood glucose (SMBG). In basal bolus regimen, aspart (Novorapid, Novo Nordisk, Denmark) was injected immediately before breakfast, lunch and dinner, while detemir (Levemir, Novo Nordisk, Denmark) was administered at the bedtime (2200-2300 h). The total daily dose was split between insulin aspart and detemir as 60 and 40 per cent, respectively. Doses were adjusted throughout the treatment period according to scheduled self monitored 6-point plasma glucose profile using glucometer –Optium Xceed; Abbott Diabetes Care Inc, Alameda CA, USA (fasting, 2 h post-breakfast, 2 h post-lunch, pre-dinner, 2 h post-dinner and at 0300 h) targeting the ranges recommended by the American Association of Clinical Endocrinologist (fasting/pre-prandial plasma glucose: 80-110 mg/dl and 2 h post-prandial plasma glucose <140mg/dl) done on day 4, 7, 14 and then every two weekly3. In BB regimen, if pre-dinner blood glucose target was not achieved, then detemir was administered twice a day.

Close

Fig

Flow chart showing study plan.

Export to PPT

Subjects were contacted by telephone or visit to the clinic on above days to discuss dose modifications. Subjects were also asked to test glucose whenever they experienced symptoms that might be related to hypoglycaemia and to record the results. Hypoglycaemia are classified as major, documented symptomatic, probable symptomatic, asymptomatic, relative and nocturnal hypoglycaemia (2200 to 0600 h)7.

Baseline height, weight, body mass index, waist circumference and blood pressure were measured and fundus examination was done at the entry of the study. Haemogram, renal and liver function test, lipid profile, urinary albumin excretion and HbA₁c were estimated at baseline. HbA₁c was assayed by high performance liquid chromatography method (Bio-Rad Laboratories Inc, USA) and urinary albumin was done by immunoturbidometry (Hemocue, Sweden). All measurements and investigations were repeated at the end of the study.

Outcome measures: The primary outcome measure was improvement in 6-point plasma glucose profile and HbA₁c level. Secondary outcome measures were change in weight, BMI, hypoglycaemic episodes and cost-effectiveness.

Statistical analysis: The statistical analysis was carried out using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, version 15.0 for Windows). All quantitative variables were estimated using measures of central location (mean, median) and measures of dispersion (standard deviation and standard error). Normality of data was checked by measures of skewness and Kolmogorov Smirnov tests of normality. For normally distributed data means were compared using student's t-test for two groups. For skewed data Mann - Whitney test was applied. For time related comparison paired t-test or Wilcoxon signed rank test was applied. Qualitative or categorical variables were described as frequencies and proportions. Proportions were compared using Chi square or Fisher's exact test whichever was applicable.

Results

One hundred and forty consecutive patients were screened and finally 50 patients were randomized to either the BHI (n = 25) or the BB (n = 25) regimen for 12 wk of treatment (Fig.). The two treatment groups were well matched for the baseline characteristics (Table I). There were no significant difference between the two groups in the mean fasting lipid profile, serum creatinine, liver function tests, haemoglobin and urinary protein excretion (data not shown).

Table I Baseline characteristics of the study population

Patients in both groups had improvement in the overall glycaemic control during the study as evidenced by the decrease in HbA₁c levels from 9.0±0.9 per cent at randomization to 7.9±0.8 per cent (P<0.001) in the BHI group and from 9.4±1.3 per cent to 8.2±1.0 per cent (P<0.001) in the BB regimen after 12 wk of treatment. The difference in HbA₁c at the end of the study from the baseline in the BHI group was -1.1±0.5 per cent and was comparable with HbA₁c reduction of -1.2±0.6 per cent in the BB regimen. Of the total 50 patients, only eight achieved HbA₁c <7 per cent, four in each group.

The mean fasting plasma glucose decreased from 166.7±63.7 to 102.7±18.7 mg/dl (P<0.001) in the BHI regimen and from 186.6±80.8 to 111.7±13.7 mg/dl (P<0.001) in BB regimen.

The 6-point plasma glucose profiles were comparable between both treatment groups at baseline, during the study period and at the end of the study. In either group, the mean plasma glucose values were lower at all points after 12 wk of treatment than at the baseline.

Mean total doses of insulin were similar between the two treatment groups at the start of the study; 0.8±0.15 U/kg in the BHI group and 0.72±0.1 U/kg in the BB regimen. At the end of the study, the subjects required 0.94±0.21 U/kg in the BHI group and 1.18±0.36 U/kg in the BB group. However, the insulin dose increment from the baseline was more in the BB regimen 0.46±0.32 U/kg compared to 0.15±0.21 U/kg in the BHI regimen groups (P<0.001).

The mean body weight significantly increased in both the groups from 74.6±11.9 to 76.0±11.6 kg (P<0.001) in the BHI regimen and from 85.5±14.0 to 86.9±14.4 kg (P<0.001) in the BB regimen. The difference in weight gain between BHI regimen (1.45±0.33 kg) and BB regimen (1.38±0.34 kg) was not statistically significant. The body mass index increased by 0.58±0.61 kg/m² in the BHI group and 0.62±0.6 kg/m² in the BB regimen.

Major hypoglycaemic episodes were reported by two patients (one episode in each) in the BHI group and by three patients (one episode in each) in the BB group. None of the patients required hospital admission for these episodes. There was no statistically significant difference in hypoglycaemic episodes including major, minor or nocturnal episodes between both the groups. However, sub-hoc analysis of minor hypoglycaemic events showed significantly more number of documented symptomatic hypoglycaemic episodes in BHI regimen (P= 0.03) (Table II). No other adverse events were observed during the study. The numbers of hypoglycaemic episodes in both treatment groups are shown in Table III.

Table II Sub-hoc analysis of hypoglycaemic episodes during study period

Table III Hypoglycaemic episodes by number of patients affected and number of episodes

The cost for the insulin therapy per day at the baseline [ 23 (0.5 US$)] in BHI and [ 28 (0.61 US$) in BB regimen] was not significantly different between the two groups. But at the end of the study, cost of insulin therapy was [ 216.1 (4.71 US$)] in the BB regimen compared to [ 23.8 (0.52 US$)] for the BHI regimen which is nine times higher (P<0.001). None of the patients required hospital admission for major hypoglycaemia.

Discussion

This pilot study showed the efficacy and the safety of the biphasic human insulin thrice-daily in comparison with the basal detemir and bolus aspart for glycaemic control in patients with T2DM. There was no difference between the groups in glycaemic control, weight gain, major, minor or nocturnal hypoglycaemic episodes except for documented symptomatic hypoglycaemic episodes. The BHI regimen was less expensive as compared to the BB regimen.

With progressive deterioration in β cell mass/function, majority of the patients with T2DM require intensified insulin therapy usually in the form of basal bolus regimen either with analogues or conventional insulin. Alternative to this is use of biphasic insulin analogues twice/thrice daily8 or biphasic human insulin twice a day with rapid acting human insulin before lunch9. Biphasic human insulin twice a day is commonly used in the clinical practice. However, with changing lifestyle, most of the people now dine late at night consequently pre-dinner hyperglycaemia is not uncommon with this twice daily regimen as the effect of the morning NPH wanes off by that time. No studies using biphasic human insulin thrice daily are available as there is a theoretical risk of hypoglycaemia/s due to ‘stacking’ effect10. However, the insulin peaks and troughs seen following a single injection of insulin suspension isophane are attenuated with the use of multiple daily isophane injections and pharmacokinetics and pharmacodynamics become similar to long acting insulin analogues11. With the same analogy, we tried using biphasic human insulin (30:70) thrice a day thereby presuming that short acting insulin will take care of prandial hyperglycaemia and NPH will give a basal cover throughout the day.

The glycaemic control in terms of decline in HbA₁c and mean fasting plasma glucose was comparable between the two groups in the present study. There was a significant decline in fasting plasma glucose in both the groups, however, only eight (16%) patients could achieve HbA₁c < 7 per cent, four in each group at the end of the study possibly due to short duration of follow up.

The insulin doses were adjusted in the two treatment groups according to the 6-point plasma glucose profile. The insulin dose requirement and the dose increment during the study was more in the BB regimen compared to the BHI. As insulin analogues have similar potency as per dose by dose in comparison with conventional insulin, the dose at the end of the study should have been comparable. However, this was not observed in our study probably because of higher content of NPH (70%) in the BHI regimen as compared to detemir (40%) in the BB regimen. The other reason might be the short duration of action of aspart as compared to regular insulin, thereby requiring higher doses of basal insulin to control interprandial hyperglycaemia12.

Intensive insulin therapy in patient with diabetes is usually associated with greater frequency of hypoglycaemic episodes as shown in DCCT1 in T1DM and UKPDS2 in T2 DM. It has also been shown previously that hypoglycaemic episodes were similar between biphasic insulin analogues thrice daily and basal bolus regimen6. But minor hypoglycaemic episodes were more in biphasic analogues thrice daily compared to biphasic human insulin twice daily, but this was not statistically significant10. Our study has shown that BHI thrice daily is equally safe when compared to the BB regimen in terms of hypoglycaemic episodes. The number of hypoglycaemic episodes were 12.1 and 9.2 episodes per patient year for the BHI and BB regimen, respectively, which were comparable to the other studies610. However subgroup analysis of minor hypoglycaemic events in our study showed more episodes of documented symptomatic hypoglycaemia in the patients treated with the BHI regimen, but all these episodes occurred during daytime and were managed by patients themselves.

The weight gain was similar in both the treatment groups. Therapy with detemir usually does not result in weight gain because of decreased risk of hypoglycaemia thereby reducing interprandial snacking and probably due to its selective appetite-modulating effect at hypothalamus1314. Similar increase in weight was observed in both the groups despite significantly higher dose requirement in the BB regimen probably due to the beneficial effect of detemir on appetite. Also BHI thrice daily was much less expensive than the basal bolus analogues with comparable efficacy and safety.

The limitations of our study include less number of patients, higher HbA₁c at baseline and inability to achieve target HbA₁c as duration of the study was short. As patients with near target HbA₁c are more prone for hypoglycaemic episodes, the safety of this BHI thrice a day regimen in such subjects needs to be further explored.

In conclusion, the biphasic insulin thrice daily regimen was found to be similar to the basal bolus analogues regimen in term of safety and efficacy. However, more number of patients and longer duration of follow up are required to further substantiate the safety of this regimen.