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159159 152150 143138 126132 121 127 116123 1 2 3 4 5 6

Years from randomization

FIGURE 6 Proportions of patients requiring early addition of insulin. Proportions of patients (%) allocated to sulfonylurea requiring early addition of insulin each year because FPG increased to > 108mg/dL (6.0mmol/L) despite maximal sulfonylurea doses. Those requiring but refusing additional insulin are indicated separately. The number below each column is the number of patients per year. There were no significant differences between the chlorpropamide and glyburide groups at any time point. Source: From Ref. 61.

159159 152150 143138 126132 121 127 116123 1 2 3 4 5 6

Years from randomization

FIGURE 6 Proportions of patients requiring early addition of insulin. Proportions of patients (%) allocated to sulfonylurea requiring early addition of insulin each year because FPG increased to > 108mg/dL (6.0mmol/L) despite maximal sulfonylurea doses. Those requiring but refusing additional insulin are indicated separately. The number below each column is the number of patients per year. There were no significant differences between the chlorpropamide and glyburide groups at any time point. Source: From Ref. 61.

preprandial home blood glucose levels remained >126mg/dL. Median A1c over 6 years was significantly lower for those allocated to sulfonylurea + insulin (SI) (6.6% [6.0-7.6]) than insulin alone (7.1[6.2-8.0], p = 0.0066). The proportion of patients with A1c < 7% at 6 years was greater in patients taking SI compared with those taking insulin alone (47 vs. 35%, p = 0.011) (Fig. 7). The Glucose Study 2 component of the UKPDS shows that glycemic control can be significantly improved with almost 50% of patients maintaining A1c target of < 7% using insulin plus sulfonylurea therapy and without promoting substantial increases in hypogly-cemia or weight gain despite the limitations of ultralente insulin.

Combining a sulfonylurea with bedtime intermediate or long acting insulin is an effective strategy to improve glucose control and to overcome secondary sulfonylurea failure. The rationale of combination therapy with sulfonylureas and insulin is based on the assumption that, if bedtime insulin (BI) lowers the fasting glucose concentration to normal, then daytime sulfonylureas (DS) will have a more effective meal-mediated insulin release controlling postprandial hyperglycemia throughout the day (143). In addition, the fasting blood glucose concentration is highly correlated with the degree of hepatic glucose production during the early morning hours (144).

Shank et al., studied 30 subjects with type 2 diabetes in whom sulfonylurea therapy had failed by switching them to the various combinations of BI/DS therapy in a double-blind fashion (145). To confirm sulfonylurea failure, subjects were switched to glipizide for (phase I) and then randomly assigned BI/DS, BI alone, and DS alone. During phase II the BI dose was fixed (20U/1.732m3, low dose) then during phase III the BI dose was titrated up to achieve good control or until further dose increases were prevented by hypoglycemic symptoms. During phase IV, which lasted for 6 months, 25 of the original 30 subjects received open-labeled, high-dose BI/DS. Unlike low-dose BI alone or DS alone, low-dose BI/DS (phase II) markedly reduced FPG, mean 24-h glucose, HbA1c from 8.9% - 0.7% to 7.6% - 0.3%, and basal hepatic glucose production. High-dose BI/DS (phase III) further reduced the HbA1c to

FIGURE 7 Proportions (%) of patients achieving HbA1c > 7% at 6 years. Source: From Ref. 61.

7.1% ±0.3%. Subjects who received the same dose of insulin without sulfonylurea had no improvement in glycemic control or weight gain. The study showed that combined BI/DS can achieve good long-term glycemic control for up to 1 year.

Riddle et al., added further proof of concept to the BI/DS regimen with a modified strategy in which 145 patients were randomized to receive either glimepiride or placebo in combination with insulin (70/30 at supper) (Fig. 7) (146). Reduction in mean HbA1c values was comparable in the two treatment groups after 24 weeks (9.7-7.6%, glimepiride plus insulin; 9.9-7.9%, placebo plus insulin). The addition of glimepiride produced a much more rapid decrease in FPG levels compared with placebo and demonstrated a significant insulin-sparing effect, with a 38% reduction of insulin requirements allowing for more patients to use only one injection of insulin 70/30 at supper (Fig. 8).

Starting Insulin Therapy with Bolus Insulin

For patients starting insulin therapy, the need for multiple premeal injections makes mealtime insulin supplementation strategy considerably more complex and less attractive than the once-daily evening dose of basal insulin. While the addition of prandial insulin is scientifically very appealing for the management of diabetes, the successful implementation of the addition of prandial insulin, in a pilot study of patients who were already treated with metformin and a glitizone, demonstrated that adding prandial insulin alone can significantly improve glucose control (147). While patients are slow to accept premeal insulin injections, it is possible they will be more open to the addition of premeal inhaled insulin. Perhaps with the availability of inhaled insulin, non injectable premeal insulin replacement may turn into firstline intervention followed by basal insulin supplementation as required. Although this would require a paradigm shift in the management of type 2 diabetes, the fact that we are not reaching A1c goals suggests that we need to change the ways we have traditionally managed hyperglycemia.

Starting Therapy with Basal/Bolus

Traditionally, twice-daily mixtures of NPH and regular insulin have been widely used for type 2 diabetes for many years. However, most patients using this "split-mixed" regimen rarely achieve reasonably good glycemic control by present standards and often experience late morning or nocturnal hypoglycemia because of excessive levels of insulin at these times as well as intermittent hyperglycemia due to insufficient insulin replacement.

Intensive insulin strategies using the twice daily split-mixed regimen were largely unsuccessful until a study by Henry et al. who studied a group of 14 patients with type 2 diabetes to determine whether tight glycemic control can be obtained using conventional insulin therapy in an outpatient setting by aggressively titrating insulin therapy (25). Patients received conventional subcutaneous NPH and regular insulin before breakfast and supper for 6 months, with dose adjustments based on an algorithm built on frequent blood glucose measurements (4-6 times a day). The total dose of required exogenous insulin was 86 ± 13 U at 1 month and 100 ± 24 U at 6 months. One month after initiating intensive insulin therapy,

Fasting plasma glucose

Insulin dose

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