The importance of good glycaemic control constitutes the cornerstone of every therapeutic modality in patients with diabetes. Prospective randomised studies have clearly shown that effective diabetes control, as judged by HbA1c, is associated with lower incidence of chronic complications, especially microangiopathy, both in patients with type 1 and type 2 diabetes[6, 7]. The same applies to satisfactory targeting of postprandial hyperglycaemia that constitutes an independent risk factor for the development of diabetic complications.
The therapeutic goals in terms of HbA1c level s and of fasting and post prandial blood glucose values have been based on large epidemiological studies associating glucose control with the incidence of diabetic complications, although the therapeutic target and timing of intervention for the prevention of macroangiopathic complications have not been well documented compared to relevant action for the reduction of microangiopathy complications[9–11].
The need for effective glycaemic control in the early stages of the disease has modified treatment of T2DM in patients not adequately controlled with life style changes and oral hypoglycaemic agents, bringing insulin into prominence as an effective therapeutic intervention even in the early stages of the disease and before secretory failure of β-cells occurs. The combination of oral hypoglycaemic agents and insulin administration has become a favourable type of treatment achieving effective control with lower insulin dosage in T2DM. The benefits of insulin administration on preservation of β-cell secretory capacity, the antinflammatory action and the dose dependent hypoglycaemic activity are combined with the favourable effects of some OAD like metformin on insulin resistance and glucagon-like-peptide-1 (GLP-1) agonists and dipeptyl-peptidase-4 (DPP-4) inhibitors on β-cell mass preservation and appetite as well as on weight control[12, 13].
The advent of insulin analogues and especially the basal insulins have facilitated initiation of insulin treatment and reduced the incidence of hypoglycaemic episodes which was a certain barrier for insulin therapy in the early stages of T2DM. The treatment guidelines suggested by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)[1, 2, 15] and the introduction of simple instructions for insulin titration[14–18] resulted in an increase of the use of insulin in patients with T2DM.
Insulin may be given in different therapeutic schemes either alone or in combination with OAD depending on the severity of the disease and appointed glycaemic targets. It can be administered once daily as basal insulin usually in combination with 1 or 2 OAD, basal insulin in combination with fast acting insulin, premeal bolus short acting insulin or in the form of a premixed intermediate acting/fast acting combinations (biphasic) insulin.
In the present study we assessed the efficacy and safety of two insulin regimens in subjects with T2DM who had been already on treatment with biphasic human insulin in combination with OAD, without achieving optimal glycaemic control.
A total of 142 patients who had switched treatment from biphasic human insulin to insulin glargine daily were included in the active group and compared to 159 patients who continued treatment with biphasic human insulin bd and were included in the control group. We have shown that the reduction in HbA1c and fasting BG values achieved were significantly greater in the active than in the control group. In particular, HbA1c declined by 1.13% in the active and by 0.59% in the control group and fasting BG declined by 47 mg/dl in the active and 20 mg/dl in the control group.
It must also be emphasized that despite more intensive management in the active group, the number of hypoglycaemic episodes did not differ and body weight did not increase in comparison with the control group. Moreover, only one third of the patients in the active treatment group required three injections of fast acting insulin in addition to basal insulin glargine, the dosage of which was considerably reduced at the end of the monitoring period as a consequence of the addition of fast acting insulin.
Well controlled studies on the comparative evaluation of the effectiveness and safety of the different insulin schemes are limited. Raskin et al. in a 28-week parallel group randomized study involving 233 insulin-naïve patients with T2DM on treatment with metformin, found that biphasic insulin twice daily was more effective in lowering HbA1c compared to treatment with once daily insulin glargine. However, weight gain was greater and minor hypoglycaemic episodes were more often in the group treated with biphasic insulin. Similar results were presented by Holman et al. in an open label one year controlled study involving 708 patients on metformin and sulfonylurea treatment randomized in three insulin treatment groups, biphasic insulin twice daily, fast acting insulin three times daily or basal insulin once daily (or twice if required). However, their results were modified three years after randomization and patients who added a basal or fast acting insulin-based regimen had better glycaemic control than patients who added biphasic insulin.
Another study examined the efficacy and safety of two treatment regimens (intensified basal-bolus glargine/glulisine regimen and biphasic insulin twice daily) for 52 weeks in 312 patients with long-standing T2DM initially treated with biphasic insulin. The study showed that patients allocated in the basal-bolus regimen had superior glycaemic control vs. those allocated in the premix therapy with no increase in the rates of hypoglycaemia. In addition more patients reached HbA1c ≤ 7% in the basal-bolus than in the biphasic treatment group (46.6% vs. 27.9%).
In a meta-analysis, Lasserson et al. reviewed 22 trials that randomized 4,379 insulin-naïve patients. They found greater HbA1c reductions with biphasic and fast acting insulin compared with basal insulin, but at the end of the study larger doses were needed in the biphasic and fast acting arms with minor hypoglycaemic events being inconsistently higher in biphasic and fast acting groups and weight gain greater in the fast acting group compared to the group on basal insulin.
In our study the addition of fast acting insulin when necessary to basal insulin glargine resulted in greater HbA1c and fasting BG reduction, which almost reached the suggested by the ADA/EASD guidelines levels[1, 2, 15]. This was achieved with no increase in weight or in the rate of hypoglycaemic episodes. The recent guidelines for the management of T2DM suggest that not all patients need or benefit from aggressive glucose management and that it is important to individualize treatment targets. Because most of the T2DM patients maintain some endogenous insulin secretion even in late stages of disease, addition of basal insulin [neutral protamine Hagedorn (NPH) or long-acting insulin glargine or insulin detemir)] to the OAD if glucose control is inadequate is an effective, safe and simple approach, unless the patient is markedly hyperglycemic. Our results showed that almost 30% of the participants managed to achieve glucose targets only with insulin glargine once daily. However, almost 40% of the participants in the control and 54% of the participants in the active group needed 3or more insulin injections per day. Moreover, we found that with basal insulin regimens, the addition of medications-beyond metformin-that increase insulin secretion like sulfonylureas or meglitinides is necessary in some patients for the maintenance of glycaemic control; thus, more patients in the active group received such medications during follow-up. Therefore, our data suggest that addition of basal insulin to OAD is an effective approach for the management of hyperglycaemia in T2DM and intensification of insulin therapy with the addition of fast-acting pre-meal insulin may be necessary to achieve glucose targets.
The combination of basal insulin with fast acting insulin when needed offers greater flexibility and better glycaemic control mimicking the physiologic insulin secretion. Due to its pharmacodynamic profile, insulin glargine substitutes basal insulin secretion effectively controlling morning glycaemia, whereas fast acting insulin reduces postprandial hyperglycaemia.
The strength of this study is that it examined in everyday clinical practice with no intervention at all and with adequate power the effectiveness of intensification of treatment with insulin based on two insulin regimens (basal insulin glargine vs. biphasic human insulin) on glycemic control. In addition, the study has adequate power to support the findings. However, this study being observational and retrospective by design has several limitations. First, the two groups differ significantly at baseline in terms of age, BMI, known duration of diabetes and diabetes control. Moreover, at the end of the monitoring period there were significant differences in concomitant treatments for diabetes; thus the results should be interpreted taking into consideration the changes in medications used for the treatment of diabetes during the study. Second, the number of mild/moderate hypoglycaemic episodes might have been under-reported in medical records and therefore, underestimated. Third, detailed data for documented symptomatic hypoglycaemia, asymptomatic hypoglycaemia, probable symptomatic hypoglycaemia and relative hypoglycaemia were not available and all cases of hypoglycaemia other than severe hypoglycaemia were classified as mild or moderate hypoglycaemia. Fourth, causality between the treatments and the outcomes cannot be established and these findings must be confirmed by a randomized clinical trial.