In UKPDS 57, 826 patients with type 2 diabetes were randomized to diet (n=242), ultralente insulin, a long-acting basal insulin (n=245), or sulfonylurea with the addition of ultralente insulin if FPG remained >108 mg/dL at maximal sulfonylurea dosage (n=339). Over 6 years, 53% of those started on sulfonylurea required addition of insulin.26 Patients treated with insulin monotherapy achieved a median A1C of 7.1%, while those on insulin plus sulfonylurea had a median A1C of 6.6% (P<.01). Episodes of major hypoglycemia occurred at a rate of 1.6% per year in the combined therapy group, compared with 3.2% a year in the insulin monotherapy group (P=0.17). In view of the observed progression of β-cell dysfunction and the failure of oral agents to maintain glycemic control, early addition of insulin to existing oral therapy may be a successful strategy in patients with type 2 diabetes.
Surmounting barriers
Insulin therapy may be delayed for a variety of reasons, including concerns about weight gain and hypo-glycemia as well as misconceptions that it increases the risk of cardiovascular disease.27 UKPDS 33 noted that relatively low proportions of patients treated with insulin experienced major (needing third-party help or medical intervention) hypoglycemic events (1.8% per year; intent-to-treat analysis).23 While both hypoglycemia and weight gain may occur with any form of insulin therapy or use of oral secretagogues, the benefits of effective glycemic control should be considered; moreover, tactics that may reduce these problems are available.28 For example, combined therapy with metformin and insulin can reduce or abolish the weight gain that otherwise may occur when insulin monotherapy is started or intensified.29 Treatment-associated hypoglycemia is generally mild to moderate in type 2 diabetes, and can be addressed with self–blood-glucose monitoring and patient education regarding recognition of symptoms and self-treatment. Also, the new long-acting insulin analogue, insulin glargine, causes fewer episodes of hypoglycemia than does neutral protamine Hagedorn (NPH) insulin.30-32
It is sometimes thought that insulin therapy may be associated with increased insulin resistance; however, studies examining peripheral insulin sensitivity have demonstrated that restoration of glycemic control with insulin improved insulin sensitivity.27,33 Also, the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction trial showed that intensive glycemic control with insulin therapy after an MI reduced the risk of adverse cardiovascular outcomes.6,34
Patient barriers to insulin therapy also include fear of needles and injections or a belief that insulin therapy represents failure, punishment, or a worsened prognosis.35 The notion that starting insulin therapy is a penalty for failure may be reinforced by physicians’ misconceptions about the role of insulin in type 2 diabetes.35 Setting the appropriate expectation that type 2 diabetes is a progressive disease that often eventually requires insulin can help to prevent such negative attitudes.
Finally, both patients and physicians may perceive insulin therapy as a complex and time-consuming treatment.27 Lack of office personnel and time to provide appropriate patient education for insulin therapy may contribute to such a perception. Concerns over complexity may be ameliorated by use of devices such as insulin pens and jet injectors that provide a precise dose and simplify self-administration. Premixed insulins are given twice daily and provide a measure of convenience, although flexibility of meal timing is limited in order to prevent hypoglycemia. Newer treatment regimens may also reduce patient apprehension concerning complexity and increase compliance.4 Notably, a simple and effective approach is to add once-daily basal insulin to established oral therapy.
Basal insulin studies
The efficiency and efficacy of adding basal insulin to existing oral antidiabetic agents was demonstrated in the randomized, open-label Treat-to-Target Trial.32 Overweight patients (N=756) who had been inadequately controlled (A1C >7.5%) on 1 or 2 oral agents (sulfonylurea, metformin, or thiazolidinedione) received insulin glargine or NPH insulin. The insulin dosage, taken at bedtime, was systematically titrated, based on before-breakfast glucose tests performed daily by the patients. Mean A1C levels fell from 8.6% to 6.9% after 24 weeks of therapy ( Figure 3 ). Both insulins performed similarly in terms of glycemic control, with 57% of patients in each group achieving an A1C of ≥7.0%. However, there was a significant difference in the incidence of hypoglycemia. Complete treatment success, defined as reaching target A1C without a single episode of nocturnal hypoglycemia (≤72 mg/dL), was achieved in 33% of the glargine patients and in 27% of the NPH group (P<.05). Overall rates of hypoglycemia, expressed as events per patient per year, were as follows: 14 symptomatic events in glargine patients vs 18 in NPH patients (P<.02), 9 confirmed events of ≤72 mg/dL in glargine patients vs 13 in NPH patients (P<.005), and 3 confirmed events of ≤56 mg/dL in glargine patients vs 5 in NPH patients (P<.003).