Intensive Glucose-lowering Therapy for Newly Diagnosed

To achieve optimal glycemic control is of prime importance in the prevention of long-term cardiovascular complications of Type 2 diabetes mellitus, but the level of control required and the methods used to achieve this control are controversial.  

Insulin therapy is mostly advised for patients with inadequate glycemic control after treatment with oral antidiabetic agents. Adverse effects, such as weight gain and hypoglycemic episodes, however, are a great concern to physicians and patients, which frequently delay the start of this treatment. Insulin therapy is at present not advocated for patients with newly diagnosed Type 2 diabetes mellitus, and treatment algorithms currently recommend diet and exercise in combination with or without administration of metformin.  A new study by Lingvay et al. examines two regimens of intensive therapy -- insulin and triple oral therapy -- in patients with newly diagnosed Type 2 diabetes mellitus. Insulin therapy was as safe and as effective as oral therapy in the achievement of glycemic control, treatment compliance, treatment satisfaction and quality of life improvement. The investigators suggest, therefore, that insulin should be considered as a first-line treatment for Type 2 diabetes mellitus.

The study by Lingvay et al. was a randomized, open-label trial designed to compare treatment of 58 drug-naive patients with newly diagnosed Type 2 diabetes with either insulin plus metformin or with triple oral therapy. The improvement in glycemic control seen in this trial was marked; HbA_1c levels dropped from 10.8% to 5.9% in the 3-month lead-in period, during which time all participants received insulin plus metformin. After the lead-in period, patients either continued treatment with insulin plus metformin or were switched to triple oral therapy, which consisted of glibenclamide, metformin and pioglitazone. Glycemic control was maintained at around 6% in both treatment groups throughout the 3 years of the trial. Treatment with triple oral therapy did not alter HbA_1c levels compared with insulin plus metformin treatment and no progressive deterioration of glycemic control could be detected in either group. The investigators attribute this finding to a reduction in glucose toxicity as a result of the initial insulin treatment. Furthermore, rates of hypoglycemia were low in both groups and comparable.

To some extent, the results of Lingvay are comparable to the 3-year data from the United Kingdom Prospective Diabetes Study (UKPDS), a trial that compared conventional therapy (dietary restriction) and intensive therapy (treatment with sulfonylureas, insulin or metformin) in patients with newly diagnosed Type 2 diabetes mellitus. The UKPDS also showed that good glycemic control can be achieved and maintained with insulin or oral agents in the first years after treatment is initiated. Notably, glycemic control eventually deteriorated in both treatment groups. This result was attributed to progressive β-cell failure, which is recognized as part of the natural progression of Type 2 diabetes mellitus. The maintenance or improvement of β-cell function is desirable in the treatment of Type 2 diabetes mellitus, and to date no treatment regime has been associated with long-term β-cell preservation. Further follow-up of the study by Lingvay et al. will hopefully assess β-cell function in both treatment groups, and preservation of β-cell function in response to either treatment will be of great interest.

The benefits of tight glycemic control are increasingly controversial, and although long-term cardiovascular benefits have been demonstrated in the UKPDS, none have been found in the short term. The UKPDS follow-up has shown cardiovascular morbidity and mortality benefits 10 years after completion of the study, whereas three studies of shorter duration, ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) and VADT, (Veterans Affairs Diabetes Trial) did not show any benefit of tight glycemic control on cardiovascular outcomes. Notably, the ACCORD trial was stopped prematurely because of increased mortality in the intensive treatment group of the study. This finding has lead to some anxiety about intensive therapies for Type 2 diabetes mellitus and the possible effects of hypoglycemia, weight gain and medication on mortality. Analysis of the VADT has shown that the greatest benefit on cardiovascular outcomes was seen in patients with diabetes mellitus of shorter duration, which suggests that intensive treatment early on in the disease might be desirable.

A limitation of the study that needs to be taken into consideration is the fact that the population of patients analyzed by Lingvay et al. was not typical of the majority of newly diagnosed patients seen in clinical practice. The trial enrolled obese (mean BMI 36 kg/m²), young patients (mean age 45 years) with very poor diabetic control at diagnosis (mean HbA_1c levels 10.8%). These patients could represent a highly motivated group of participants who showed symptoms of Type 2 diabetes mellitus at an early stage. These characteristics do not, however, apply to the majority of newly diagnosed patients, who are largely asymptomatic in the early years of their illness. Some doubts, therefore, remain as to whether the results of Lingvay et al. could be extrapolated to all patients with Type 2 diabetes.

In clinical practice, to convince patients with Type 2 diabetes to start daily insulin injections remains one of the greatest challenges. Compliance and treatment satisfaction rates were high in both treatment groups in the study by Lingvay and colleagues and these levels were maintained over 3 years. This finding is interesting and important, but needs to be viewed with some caution. Given the nature of the trial, volunteers included in the study were willing to commence insulin treatment, whereas people opposed to insulin injections were excluded. This process is a reality of clinical trial selection bias; the study participants are likely to represent a group of compliant patients who are less resistant to long-term insulin use than other patients. Previous studies have shown that initiation of insulin therapy is often delayed because of patient apprehension. In one survey, about 80% of patients expressed the wish for an alternative insulin administration route and nearly half indicated they would avoid insulin, if at all possible. Compliance and satisfaction with early insulin treatment would, therefore, most probably be lower in clinical practice than the study by Lingvay et al. suggests.

In conclusion, the study by Lingvay and colleagues is a small trial of relatively short duration that shows insulin therapy to be a safe and effective treatment for newly diagnosed Type 2 diabetes patients and comparable to triple oral therapy. Currently, neither of these treatment regimes is recommended for initial treatment of Type 2 diabetes, and although the findings revealed a good compliance and satisfaction with insulin therapy, caution should be used in the recommendation of aggressive glucose-lowering strategies. Follow-up of current outcome studies should answer some of the important questions on intensive therapies and glycemic control that remain. How early should we treat? Which agents should we use? Which patients should be targeted? Is β-cell function preserved by early intensive treatment? Until these issues have been elucidated, insulin should remain an alternative option rather than the preferred first-line treatment in the management of newly diagnosed Type 2 diabetes mellitus.

• Insulin treatment could be as safe and as effective as triple oral therapy in patients with newly diagnosed Type 2 diabetes mellitus.
• The benefits of tight glycemic control in Type 2 diabetes remain controversial, however, and intensive strategies might be associated with increased morbidity and mortality.
• Insulin therapy should be considered as an option rather than the preferred first-line treatment for newly diagnosed Type 2 diabetes mellitus.

Nat Rev Endocrinol. 2010;6(1):9-10.

Nathan, D. M. et al. Medical management of hyperglycemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32, 192–203 (2009).

Lingvay, I. et al. Insulin-based versus triple oral therapy for newly diagnosed Type 2 diabetes: which is better? Diabetes Care 32, 1789–1795 (2009).

Holman, R. R., Paul, S. K., Bethel, M. A., Matthews D. R. & Neil H. A. 10-year follow-up of intensive glucose control in Type 2 diabetes. N. Engl. J. Med. 359, 1577–1589 (2008).