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FIGURE 6 A study comparing once daily insulin glargine titrated to achieve fasting glucose control versus exenatide, a GLP-1 mimetic that is injectable twice daily. The average glycemia response is similar in this study with HbA1c reduced by 1.1% from 8.2% to 7.1% in both groups. A striking difference in the preprandial versus the postprandial effects of the two medications is evident.

FIGURE 6 A study comparing once daily insulin glargine titrated to achieve fasting glucose control versus exenatide, a GLP-1 mimetic that is injectable twice daily. The average glycemia response is similar in this study with HbA1c reduced by 1.1% from 8.2% to 7.1% in both groups. A striking difference in the preprandial versus the postprandial effects of the two medications is evident.

glargine and 21 for NPH) and HbA1c values achieved (8.3% and 8.2%) were similar with the two insulins, but the rates of hypoglycemia were significantly less for the group using glargine (33% vs. 51% for all symptomatic hypoglycemia), despite similar average insulin doses. Nocturnal hypoglycemia occurred in less than half as many subjects using glargine (13% vs. 28%). Moreover, glucose control was better in the afternoon and evening with glargine, presumably because of its longer duration of action than NPH. The Treat to Target Trial (49) also compared insulin glargine versus NPH insulin at bedtime. Subjects in this study averaged a baseline HbA1c of 8.6%. Both NPH and glargine study groups were instructed to initiate doses of 10 units of insulin at bedtime and each week the dose was raised between 0 and 8 units based upon how close to goal (< 5.5mmol/L; 100mg/dL). This forced weekly titration of dose based upon fasting glucose concentration with patient self-adjustment according to pattern of therapy response is a key concept in reaching the targeted goal of HbA1c < 7% in about 60% of patients in this study on both NPH and glargine insulin. Subjects in this study did not need to achieve the targeted FPG because hypoglycemia would have been too frequent. Hypoglycemia overnight was more common with NPH insulin as might be expected based upon the differences in kinetics of NPH versus glargine with the former having a greater peak effect usually within the first 4 to 8 hours after s.c. administration.

FIGURE 7 The relative contribution of fasting plasma glucose (FPG; show in the open bars) and the postprandial plasma glucose (PPG; shown in the shaded bars) to overall hyperglycemia. An area under the curve analysis suggests that as HbA1c approaches the ADA goal for minimum desirable glycemic control, the PPG makes a greater contribution to overall hyperglycemia. Conversely, as the HbA1c rises far from goal, the contribution of FPG to overall hyperglycemia is greater. For patients with poor hyperglycemia a focus on the fasting glucose thus becomes an important priority. As patient approaches targeted glycemic goals, greater attention should be directed to postprandial glycemia.

FIGURE 7 The relative contribution of fasting plasma glucose (FPG; show in the open bars) and the postprandial plasma glucose (PPG; shown in the shaded bars) to overall hyperglycemia. An area under the curve analysis suggests that as HbA1c approaches the ADA goal for minimum desirable glycemic control, the PPG makes a greater contribution to overall hyperglycemia. Conversely, as the HbA1c rises far from goal, the contribution of FPG to overall hyperglycemia is greater. For patients with poor hyperglycemia a focus on the fasting glucose thus becomes an important priority. As patient approaches targeted glycemic goals, greater attention should be directed to postprandial glycemia.

Insulin Detemir

Insulin detemir is a new formulation of intermediate to long-acting insulin with a duration of effect in type 1 diabetes single dose studies that is dose dependent. Based upon a common dosage of 0.4 units/kg an average duration of action of about 20 hours is predicted. With higher doses a longer duration approaching 24 hours is achieved (50). In one study (51), twice daily insulin therapy with NPH versus detemir in type 2 diabetes subjects inadequately controlled (HbA1c 8.5% and 8.6% for NPH and detemir, respectively) on therapy (mostly metformin plus secretagogues with some use of glucosidase inhibitors and about 30% of subjects not on oral agents when insulin was used). A total of 475 subjects were randomized to participate in a 24-week study comparing twice daily administration of these two insulins at breakfast and bedtime. Starting with 10 units per injection subjects were instructed to titrate doses every 3 days based upon pre-dinner and pre-breakfast self-monitored glucose averages from 2 up to 10 units per injection. At 24 weeks subjects with insulin detemir decreased HbA1c by 1.8% to an average value of 6.8% while subjects on NPH decreased the HbA1c by 1.9% to an average value of 6.6%. Most subjects (about 70%) achieved HbA1c less than 7% but more subjects on detemir achieved the goal without hypoglycemia. Overall hypoglycemia was significantly less on detemir, which by non-inferiority analysis was comparable in overall glycemic lowering efficacy to NPH. Doses of insulin were a bit higher than might have been expected (36.1 units am and 29.5 units pm for detemir; and 25.3 units am and 19.7pm for NPH given that the average BMI of these patients was a little over 29. Detemir can be administered once in the evening or twice daily. Its desirable features include a lower rate of hypoglycemia, somewhat greater consistency in glycemic response from day to day, and possibly a reduced tendency for weight gain.

Use of Dry Powder Inhaled Insulin

Recently the approval of the first orally inhaled insulin for delivery by pulmonary capillaries to the body has begun to permit patients to choose insulin without concerns about injections. While injection delivery will not represent a barrier for many patients, inhaled insulin may encourage the earlier use of insulin for some reluctant patients and providers. In monotherapy studies with very poorly controlled patients (HbA1c 9.5-9.6%), it can lower HbA1c greater than 2% (52). In studies comparing the addition of inhaled insulin to an oral regimen versus substituting inhaled insulin for dual therapy in poorly controlled subjects, change in HbA1c was -1.67% versus -1.18%, respectively (53). Use of inhaled insulin has substantial meal effects and it is intended for use primarily at meal times. Importantly, however, it also appears to have a significant ability to contribute to fasting glucose lowering, perhaps as a result of a longer duration of action than rapid acting analogs. Thus, one may need to anticipate some caution for avoiding overnight and between-meal hypoglycemia in well controlled patients. It seems unlikely that inhaled insulin will fully replace basal insulin treatment, but, like basal insulin, it may form a bridge from oral agents (with or without incretin mimetics) to more complex insulin regimens.

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