The predictive role of HbA1c and previous medications in initiation of insulin treatment

Treatment of patients with type 2 diabetes (T2DM) aims at controlling intestinal glucose absorption, normalize hepatic glucose production, reverse insulin resistance, and at preventing the occurrence of long-term complications [1].

A combination of diet, exercise and metformin is recommended as the first line of therapy for patients with T2DM [2, 3]. However, few patients achieve adequate control of blood glucose levels in time using this approach alone due to the progressive nature of T2DM [4-8].

Sulphonylureas, biguanides and alpha-glucosidase inhibitors are well-known oral antidiabetic drugs (OADs), and nowadays new generation OADs such as dipeptidyl peptidase 4 (DPP-4) inhibitors, amylin mimetics and incretin mimetics have increased the capability of oral therapy [9, 10]. All of the agents mentioned above have a potential therapeutic effect equivalent to an approximately 1-2% decrease in HbA1C levels if used in appropriate doses [1].

Insulin is indicated in patients with T2DM who fail to respond to an adequate dietary regimen and to oral hypoglycaemic agents. While transferring to insulin, many subjects fear injections and such fear may affect their compliance with insulin therapy [11-14]. Consequently, oral therapy has generally been the preferred treatment approach for patients with T2DM.

Patients with type 1 diabetes mellitus (T1DM) who have no endogenous insulin secretion generally require between 0.5 and 1.0 IU/kg insulin per day. Diabetes Control & Complications Trial patients with T1DM on average receive 40 IU insulin per day. Because of insulin resistance in T2DM, especially obese patients with T2DM usually require more insulin. Insulin requirements sometimes reach 2.0 IU/kg per day.

The purpose of this study was to investigate whether the number of oral antidiabetic drugs prescribed before shifting to insulin affects later insulin requirements when the oral therapy failed.

MATERIAL AND METHODS

Subjects were selected randomly among the T2DM patients whose oral antidiabetic treatment had failed. The study population comprised a total of 46 patients divided into two groups each counting 23 patients who were using two OADs (group A) or three OADs (group B). They were all willing to initiate insulin therapy and had previously received at least three months of continuous treatment with failure of either two or three OADs (HbA1C > 8.0%). Categories of OADs previously used were ignored. All participants gave fully informed consent to participation in the study and the investigators declare that the study complies with the Helsinki Declaration.

Insulin therapy was initiated with premixed insulin 30/70 twice a day (starting dose, 0.3 IU/kg per day). At baseline, approximately two thirds of the dose was given before breakfast and the remainder before dinner. To avoid hypoglycaemia, dose adjustments in the form of a 10% increase of the current dose were suggested every other day until reaching pre-prandial glycaemic targets in the morning and evening. For all patients, adequate dietary counselling was provided to facilitate management of the meal-related part of the insulin therapy. Treatment efficacy was evaluated after one year of follow-up. The exclusion criteria were diagnosis of T1DM, having used insulin at any time in life, relatively efficient treatment of diabetes mellitus (DM) (HbA1C ≤ 8.0%), acute complications of DM, diagnosis of an additional disease, using or starting a new drug, fever states, falling outside the 40-65 year-old age span, lactating women, pregnancy, and changing business and life style during the study period.

On the basis of these data obtained in the first part of the study, we compared the two groups in terms of age, gender, duration of diabetes, baseline weight (kg) and weight gain (kg) achieved at the end of the study, body mass indexes (BMI), HbA1C values and insulin requirements. HbA1C values were measured with high-performance liquid chromatography. All results were reported as mean values +/- standard error of the mean. Statistical analysis was done with the use of the unpaired, two-tailed t test; p values of less than 0.05 were considered statistically significant.

RESULTS

Demographics of both groups are shown in Table 1. No significant difference was found in age, gender or duration of diabetes between the two groups. BMIs were similar in the two groups. The increases in weight after insulin therapy were also similar in the two groups.

HbA1C values before insulin therapy were not significantly different between the two groups. One year after the initiation of insulin therapy, HbA1C values had changed markedly in both groups. All of the patients reached HbA1C values below 8%. Insulin doses per kg of body weight per day were significantly higher in group B (p < 0.001) than in group A. We observed no hypoglycaemic attacks or fluctuations in blood glucose concentrations during the study. Two patients in group B transferred into intensive insulin therapy.

The number of oral antidiabetic agents used before insulin therapy correlated with the insulin doses needed at the end of the study (Figure 1).

No subjects were excluded according to the criteria, and no patients refused to participate in the study.

DISCUSSION

We have shown that patients who were previously using double drug therapy (two oral antidiabetic drugs) needed less insulin than patients who were using triple drug therapy. Patients’ pre-insulin HbA1C levels also predicted insulin dosing.

In this study, we hypothesized that pre-insulin therapy may hold clues to the insulin dosing needed when oral agents have failed. We demonstrated that a mean insulin dose of 0.56 IU/kg/day was required in patients who had previously been treated with two OADs as compared to a mean insulin dose of 0.90 IU/kg/day in patients previously treated with three OADs.

The response to the OADs (HbA1C) also correlated with insulin doses at the end of the first year of follow-up. Thus, the HbA1C values of the two groups were similar before insulin treatment began, which implies that double and triple OAD treatment had been equally unsuccessful in the two groups prior to the commencement of insulin therapy.

HbA1C levels were also similar after insulin injections. If the HbA1C values are similar, differences in insulin deficiency between these two groups can therefore be estimated by the number of OADs which had failed.

It would have been better if we had examined the individual oral antidiabetic agents used by the patients, but the aim of the study was to investigate if the number of OADs affected the final insulin doses. And it is well-known that an ordinary OAD causes a 1-2% HbA1C decrease.

The rise in patients’ weights after insulin therapy is a side effect of insulin therapy and an indication for the use of drugs such as glucagon-like peptide 1 analogues. However, due to their non-licensed state, these drugs were not available for use in the country where the study was conducted.

All parameters explored in this study, including baseline weights of the two groups, were statistically similar, except for their demand for insulin.

CONCLUSIONS

In this study we have shown that similar HbA1C values and unsuccessful triple oral drug therapy means that we need more insulin to control diabetes (Figure 1). In conclusion, further investigation is required to ascertain whether this observation is linked to the stage of DM at the time of institution of insulin therapy.

Correspondence: Hakan Demirci, Nilüfer Toplum Sağlığı Merkezi, Department of Family Medicine, Bursa, Turkey. E-mail: drhakandemirci@hotmail.com

Accepted: 2 September 2010

Conflicts of interest: Prof, Dr İhan Satman (University of Istanbul, Department of Endocrinology) was involved in critically revising the manuscript.