The addition of insulin to metformin and sulphonylureas: results of the 4‐T study

The natural history of type 2 diabetes includes progressive beta-cell failure, resulting in a loss of insulin secretion and hyperglycaemia. This inevitably leads to a steady rise in HbA1c. Maintenance of nearly normal levels of glycaemia (<7%) is associated with a reduced incidence of complications. This can be difficult to achieve in patients with type 2 diabetes with the majority of patients eventually requiring insulin therapy despite the use of metformin, sulphonylurea and even thiazolidinediones. While insulin therapy has been shown to reduce HbA1c in patients who have failed with oral antidiabetic drugs, there are concerns that many patients do not reach their glycaemic targets and develop unacceptable levels of weight gain or hypoglycaemia. Before the 4-T study was performed the optimal insulin regimen to control glycaemia when patients are not controlled on oral antidiabetic drugs was unclear. Many studies, designed and sponsored by insulin manufacturers, contained flaws in study design which favoured a particular product.1 In the UK, commonly used regimens included the addition of basal insulin or the addition of a twice daily fixed mixture. In Germany, the addition of thrice daily basal insulin was a popular option. The results of a three-year, open-label, randomised controlled trial, called the Treat to Target in Type 2 Diabetes (4-T) study, were recently presented at the meeting of the International Diabetes Federation in Montreal, with online publication in the New England Journal of Medicine.2 In this study, 708 men and women over the age of 18 years, with a history of diabetes for greater than one year, and who had inadequate glycaemic control (HbA1c 7–10%) while receiving metformin and sulphonylurea, were randomly assigned to receive prandial insulin aspart, basal detemir, or biphasic aspart 30 during the first year.3 After the first year, sulphonylureas were replaced by an additional type of insulin if they exceeded an HbA1c target of 6.5%, which is a similar target to that in the ADVANCE study.4 In such cases, prandial insulin was added at lunch to the biphasic regimen (which is rather unusual in clinical practice), basal insulin was added to the prandial regimen and, finally, prandial insulin was added with each meal (three times daily) to the basal regimen. The primary outcome at three years was the HbA1c. Secondary outcomes were the proportion of patients with an HbA1c of 6.5% or less, the proportion of patients with an HbA1c of 6.5% or less but without hypoglycaemia of grade 2 or more, weight gain, self-measured capillary glucose profiles, the proportion of patients requiring a second type of insulin, the ratio of albumin to creatinine, and quality of life. Importantly, the study confirms that insulin initiation provides a meaningful and sustainable reduction in HbA1c over a three-year period. The mean reduction from baseline at three years was 1.3% in the biphasic group, 1.4% in the prandial group, and 1.2% in the basal group. It is noteworthy that less than 45% of patients in the study reached the HbA1c target of 6.5% or less, including less than one-third of those in the biphasic group. Moreover, 68–82% of patients received an additional type of insulin to achieve a median HbA1c level of 6.9%. Thus, most patients, regardless of the originally assigned group, actually received ‘sophisticated’ insulin regimens. The median daily units of insulin per kilogram of body weight increased steadily during the second and third years of the study. The dose was similar at three years in the prandial group and the basal group but lower in the biphasic group. Patients gained weight in all three groups; increases in the biphasic group and the prandial group were similar and were more than those in the basal group. The overall hypoglycaemia rates remained highest in the prandial group and lowest in the basal group. After three years, glycaemic control with basal insulin was equivalent to prandial insulin but, in terms of the degree of weight gain and frequency of hypoglycaemia, basal insulin was superior. Thus, the authors of the 4-T study advocate the initial addition of basal insulin to oral therapy, with subsequent intensification to a more sophisticated basal–prandial regimen. Large-scale, direct comparisons of various regimens of insulin analogues in combination with oral antidiabetic agents have been lacking in the literature, and there is no doubt that the 4-T study is an important trial which significantly adds to the available literature on insulin initiation. The undoubted strengths of the study are long duration and the standardised approach to insulin therapy and titration. The short duration of such trials is a frequent weakness and this is reinforced by the striking difference in the results at one and three years. The treatment algorithm is relatively simple to follow based on a treat to target blood glucose and the frequency of visits would certainly be achievable in most outpatient secondary care settings, but might be challenging to replicate in a primary care setting. There are, however, certain factors in the design of the 4-T study that may limit its interpretation into everyday clinical practice. When we closely inspect the inclusion and exclusion criteria we note that patients with a BMI >40, HbA1c >10% or who have previously received a thiazolidinedione or ‘triple therapy’ were excluded. The patient characteristics tell us that the majority of the patients were white males, aged around 60 years of age. The mean BMI and HbA1c were approximately 31 and 8.5% respectively. It is therefore difficult to extend these results for the patients who are morbidly obese, have very poor glycaemic control, have received a thiazolidinedione, are young, or are of other ethnic groups (e.g. South Asian patients). Although the study design was entirely in the hands of the investigators, who also analysed the data, the insulins used were all analogues manufactured by Novo Nordisk, and in terms of basal insulin patients were prescribed once or twice daily insulin detemir rather than any alternatives. Detemir may have particular benefits with regard to lack of weight gain compared to other basal insulins.5 While the efficacy of short and long acting analogues is similar to human insulin in short-term studies, it is unlikely that we will see long-term studies comparing insulin analogues and human insulin, and these factors limit the ability to generalise the results. In the 4-T study, 68–82% of patients received an additional type of insulin to achieve a median HbA1c of 6.9%, and approximately one-third of patients required twice daily rather than once daily insulin. Thus, most patients, regardless of the originally assigned group, actually received ‘sophisticated’ regimens ranging from three injections daily in the biphasic group, to four or five injections daily in the advocated basal group. In many patients with type 2 diabetes this might lead to issues with both insulin initiation and compliance. Indeed, the proportions of patients who withdrew from the 4-T study were significantly lower amongst those who received the biphasic regimen. While the withdrawal rate was acceptable for the duration of the study, clinical experience tells us that this may not be the case outwith the clinical trial setting. The findings of the 4-T study support current guidelines to commence addition of basal insulin to metformin in patients who fail to achieve their target HbA1c despite two oral hypoglycaemic agents.6 For now, the recommendations for starting insulin therapy need not change as a result of this study. This approach appears to be the safest and most pragmatic. The 4-T study does reveal that, if we wish to achieve near normal levels of glycaemia, biphasic, basal or prandial insulin is unlikely to be sufficient and that the addition of other insulin formulations will be necessary. The initial one-year data showed that few patients reached the HbA1c target of 6.5% with less than a third of those randomised to receive basal insulin reaching the target of 7%.3 The challenge for many clinicians is not which type of insulin to start, but identifying the patients who are likely to benefit from insulin and tailoring that therapy to each patient on an individual basis. Although long-term data on dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 mimetics are lacking, many patients who would have previously received insulin will now be considered for these agents. A large-scale, long-term trial is now required to compare analogue insulin therapy with these agents over a variety of important end-points including glycaemia, weight, hypoglycaemia and cardiovascular risk. Finally, it is important that we do not lose sight of the fact that the aggressive treatment of other risk factors such as lifestyle, smoking, blood pressure and dyslipidaemia are perhaps collectively more important than the absolute level of glycaemia. Prof Fisher has served on advisory panels for Eli Lilly, Novo Nordisk and sanofiaventis.

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