Continuous glucose monitoring-guided insulin adjustment in children and adolescents on near-physiological insulin regimens: a randomized controlled trial

OBJECTIVE: This randomized controlled trial assesses the effect on glycemic control of continuous glucose monitoring system (CGMS)-guided insulin therapy adjustment in young people with type 1 diabetes on intensive diabetes treatment regimens with continuous subcutaneous insulin infusion (CSII) or glargine. RESEARCH DESIGN AND METHODS: Pediatric subjects were recruited if they had an HbA(1c) (A1C) <10% and had been on CSII or glargine for at least 3 months. Thirty-six subjects were randomized to insulin adjustment on the basis of 72 h of CGMS every 3 weeks or intermittent self-monitoring of blood glucose (SMBG) for 3 months. A1C and fructosamine were measured at baseline and 6 and 12 weeks. Follow-up A1C was measured at 6 months. Mean baseline A1C was 8.2% (n = 19) in the CGMS group and 7.9% (n = 17) in the control group. RESULTS: There was a significant improvement in A1C from baseline values in both groups, but there was no difference in the degree of improvement in A1C at 12 weeks between the CGMS (-0.4% [95% CI -0.7 to -0.1]) and the control group (-0.4% [-0.8 to 0.2]). In the CGMS group, improved A1C was at the cost of increased duration of hypoglycemia. CONCLUSIONS: CGMS is no more useful than intermittent fingerstick SMBG and frequent review in improving diabetes control in reasonably well-controlled patients on near-physiological insulin regimens when used in an outpatient clinic setting.     

Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial

OBJECTIVE: This study was conducted to compare the efficacy and safety profiles of exenatide and insulin glargine therapy in patients with type 2 diabetes who had not achieved glucose control with metformin or sulfonylurea monotherapy. METHODS: This multinational, randomized, open-label, crossover noninferiority study compared the efficacy of exenatide 10 pg BID and insulin glargine QD (titrated targeting a fasting serum glucose (FSG) level < or =5.6 mmol/L) in patients with type 2 diabetes treated with a single oral antidiabetic agent. The study included two 16-week treatment periods. The primary a priori outcome variable was the change in glycosylated hemoglobin (HbA(lc)). Secondary outcomes included the proportion of patients achieving the American Diabetes Association (ADA) target HbA(lc) of < or =7% and the European Association for the Study of Diabetes target of < or =6.5%, the change in FSG, end-point values and change in the 7-point self-monitored glucose profile, and change in body weight. Adverse events were assessed based on standard laboratory tests and patient reports. RESULTS: One hundred thirty-eight patients were randomized to study treatment (52.9% female, 47.1% male; 79.7% white; mean [SEM] age, 54.9 [0.8] years; duration of diabetes, 7.4 [0.4] years; body mass index, 31.1 [0.4] kg/m(2); weight, 84.8 [1.4] kg) while continuing to receive metformin (55.1%) or a sulfonylurea (44.9%). The population had a baseline least squares (LS) mean (SEM) HbA(lc) of 8.95% (0.09%) and an LS mean FSG concentration of 12.0 (0.3) mmol/L. Both exenatide and titrated insulin glargine therapy were associated with similar significant changes from baseline in HbA(1c) (both, -1.36% [0.09%]; P < 0.001); the difference between groups was not statistically significant. The LS mean HbA(1c) at end point was above the ADA target with both treatments (exenatide, 7.57% [0.09%]; insulin glargine, 7.58% [0.09%]). Similar proportions of patients achieved an HbA(1c) < or =7% (37.5% and 39.8%, respectively; P = NS) or < or =6.5% (21.5% and 13.6%). Patients lost weight during exenatide treatment, whereas they gained weight during insulin glargine treatment; the between-group difference in weight change was statistically significant (LS mean difference, -2.2 [0.3] kg; 95% CI, -2.8 to-1.7; P < 0.001). Both exenatide and insulin glargine were associated with significant reductions from baseline in FSG (-2.9 [0.2] and -4.1 [0.2] mmol/L, respectively; both, P < 0.001), although the reduction was significantly greater with insulin glargine compared with exenatide (LS mean difference, 1.2 [0.3] mmol/L; 95% CI, 0.7 to 1.7; P < 0.001). Compared with insulin glargine, exenatide was associated with significantly lower 2-hour postprandial glucose (PPG) excursions (P < 0.016) and total daily mean glucose excursion (P < 0.001). The proportions of patients reporting nausea during exenatide and insulin glargine treatment were 42.6% and 3.1%, respectively; the proportions reporting vomiting were 9.6% and 3.1%. The incidence of hypoglycemia in the 2 groups was 14.7% and 25.2% (P = NS). CONCLUSIONS: In this open-label, crossover study, treatment with exenatide or insulin glargine for 16 weeks was associated with similar significant improvements from baseline in HbA(1c), independent of treatment order. The improvements in HbA(1c) from baseline did not differ significantly between treatment groups. Exenatide therapy was associated with significant reductions in body weight and PPG excursions compared with insulin glargine, whereas insulin glargine was associated with a significantly greater reduction in FSG compared with exenatide. These findings provide additional information to guide treatment decisions in patients with type 2 diabetes who are potential candidates for either therapy.     

An increased dose of insulin detemir improves glycaemic control and reduces body weight of Japanese patients with diabetes

Aims: The aim of study was to evaluate the safety and efficacy of insulin detemir as a basal insulin switching from neutral protamine Hagedorn insulin (NPH) and insulin glargine in patients with diabetes on an intensive insulin therapy regimen. Methods: This 6‐month multicentre, prospective, treat‐to‐target [glycosylated haemoglobin (HbA_1c) less than 6.5%] trial included 92 people with diabetes (61 type 1, 29 type 2 and two unknown diabetes types). Detemir was administered first with fixed dose and injection times and then adapted to optimal dose after 3 months. Results: Mean HbA_1c (%) of all the subjects at months 4 to 6 of the study was improved compared with month 0 (7.34 ± 0.87, 7.28 ± 0.88, 7.25 ± 0.93 vs. 7.55 ± 1.18; p < 0.05 paired t‐test). However, significant improvement was seen only among the patients who had previously used NPH as a basal insulin. Twice‐daily injection of basal insulin increased among people in the type 1 previously injected insulin glargine. Total insulin dose increased in the type 1 glargine group. The mean body weight change in the highest quartile body mass index (BMI) group was from 70.7 to 69.3 kg over the 6 months. Quality of life (QoL) relating to the patients’ glycaemic control tended to improve without a change in frequency of hypoglycaemia. Conclusions: The results suggest that insulin detemir has a greater effect on glycaemic control in subjects with poor glycaemic control using NPH; can reduce or maintain body weight in obese patients; and obtains perceptive stability for patients with unstable glycaemic control.     

Effects of exercise on the absorption of insulin glargine in patients with type 1 diabetes

OBJECTIVE: To study the effects of exercise on the absorption of the basal long-acting insulin analog insulin glargine (Lantus), administered subcutaneously in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 13 patients (12 men, 1 woman) with type 1 diabetes on a basal-bolus insulin regimen were studied. (125)I-labeled insulin glargine at the usual basal insulin dose was injected subcutaneously into the thigh on the evening (2100) before the study day on two occasions 1 week apart. Patients were randomly assigned to 30 min intense exercise (65% peak oxygen uptake [Vo(2peak)]) on one of these visits. The decay of radioactive insulin glargine was compared on the two occasions using a thallium-activated Nal gamma counter. Blood samples were collected at regular intervals on the study days to assess plasma glucose and insulin profiles. RESULTS: No significant difference was found in the (125)I-labeled insulin glargine decay rate on the two occasions (exercise vs. no exercise; repeated-measures ANOVA, P = 0.548). As expected, a significant fall in plasma glucose was observed over the exercise period (area under curve above fasting [DeltaAUC] glucose: -0.39 +/- 0.11 vs. -1.30 +/- 0.16 mmol . l(-1) . h(-1); nonexercise vs. exercise; P = 0.001), but insulin levels did not differ significantly on the two occasions (DeltaAUC insulin: -2.1 +/- 3.9 vs. 1.5 +/- 6.2 pmol . l(-1) . h(-1); nonexercise versus exercise; P = 0.507). CONCLUSIONS: An intense 30-min period of exercise does not increase the absorption rate of the subcutaneously injected basal long-acting insulin analog insulin glargine in patients with type 1 diabetes.     

Insulin glargine: a systematic review of a long-acting insulin analogue

BACKGROUND: Insulin glargine is the first long-acting basal insulin analogue indicated for subcutaneous administration once daily at bedtime in adults with type 1 or type 2 diabetes mellitus and pediatric patients aged > or = 6 years with type 1 diabetes. It differs in structure from native human insulin by 3 amino acids, a structural modification that provides a delayed onset of action and a constant, peakless effect that has a duration of at least 24 hours. OBJECTIVE: The goal of this article was to help determine the current place in therapy of insulin glargine by reviewing all available efficacy and tolerability data published since its introduction onto the market. METHODS: Relevant English-language articles were identified through searches of MEDLINE, PubMed, and EMBASE from 1966 to October 2002 and PREMEDLINE for November 2002. The search terms used were insulin, analogs, analogues, diabetes mellitus, glargine, HOE901, HOE-901, efficacy, safety, comparative study, treatment outcome, and case report. The reference lists of the identified articles were searched for additional relevant publications. Pharmacokinetic and pharmacodynamic data were reviewed and summarized. All large clinical trials (> or = 100 patients) evaluating the efficacy and tolerability of insulin glargine in patients with type 1 or type 2 diabetes were included in the review. Studies were compared in terms of their designs, primary and secondary efficacy parameters (glycosylated hemoglobin [HbA(1c)], fasting plasma glucose [FPG] and/or fasting blood glucose [FBG] level, incidence of hypoglycemia), and tolerability assessments. RESULTS: Fourteen trials met the criteria for inclusion in this review, 7 of them published only in abstract form. All were multicenter, randomized, open-label, parallel-group trials conducted in Europe or the United States, and ranged in duration from 4 to 52 weeks. They compared insulin glargine with neutral protamine Hagedorn (NPH) insulin given once or twice daily in >5000 patients with type 1 or type 2 diabetes, or in insulin-naive patients with type 2 diabetes that was poorly controlled by oral antidiabetic agents. Insulin doses were individually titrated to achieve a target FBG level < or =120 mg/dL (6.7 mmol/L). The studies were typically statistically underpowered to detect a significant difference in HbA(1c) between treatment groups; only 3 trials were of an adequate size to have 90% statistical power to detect a mean 0.5% difference in HbA(1c). Furthermore, analysis of the data from these trials was associated with a number of methodologic problems relating to inconsistencies in reporting. Given these limitations, the available data suggest that insulin glargine treatment produces statistically significant reductions in FPG or FBG levels at end point both compared with baseline and compared with NPH insulin (P < 0.001) without achieving overall significant improvements in HbA(1c) values. However, a recent abstract of a small 52-week trial in patients with type 1 diabetes reported a 0.4% additional decrease in HbA(1c) with insulin glargine treatment compared with NPH insulin. Patients have reported greater treatment satisfaction with insulin glargine compared with NPH insulin. The findings varied regarding weight gain, overall incidence of hypoglycemia, and incidence of nocturnal hypoglycemia. Currently, the cost of insulin glargine is twice that of NPH insulin on a per-unit basis. CONCLUSIONS: As a basal insulin replacement, insulin glargine administered once daily demonstrates a steady time-action profile over 24 hours without a pronounced peak. Based on the evidence from published clinical trials, insulin glargine appears to have equal clinical efficacy to NPH insulin, produces similar reductions in HbA(1c), and is associated with lower FPG and FBG levels and a consistent and significant reduction in the incidence of nocturnal hypoglycemia in patients with type 2 diabetes.     

Basal insulin glargine (HOE 901) versus NPH insulin in patients with type 1 diabetes on multiple daily insulin regimens. U.S. Insulin Glargine (HOE 901) Type 1 Diabetes Investigator Group

OBJECTIVE: Insulin glargine (HOE 901, 21(A)-Gly-30(B)a-L-Arg-30(B)b-L-Arg human insulin) is a novel recombinant analog of human insulin with a shift in the isoelectric point producing a retarded absorption rate and an increased duration of action that closely mimics normal basal insulin secretion. It recently received approval from the Food and Drug Administration. The aim of this study was to evaluate 2 formulations of insulin glargine for safety and efficacy in the treatment of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: In a 4-week trial, 256 patients with type 1 diabetes received either NPH insulin or insulin glargine containing 30 microg/ml zinc (insulin glargine[30]) or 80 microg/ml zinc (insulin glargine[80]). Insulin glargine was given subcutaneously once daily at bedtime. NPH insulin was given either once daily (at bedtime) or twice daily (before breakfast and at bedtime), according to the patient's prestudy regimen. The initial doses of insulin glargine and NPH were based on the previous NPH total daily dose. RESULTS: At study end point, insulin glargine-pooled groups had significantly lower fasting plasma glucose (FPG) levels than the NPH insulin group, with adjusted mean FPG levels reduced by 2.2 mmol/l (P = 0.0001). Insulin glargine was superior to NPH insulin in reducing FPG levels in patients who had previously received NPH insulin twice daily but not in patients who had previously received NPH once daily. FPG levels were more stable in patients using insulin glargine than in patients using NPH insulin. A subset of patients (n = 71) underwent hourly overnight plasma glucose measurements. Insulin glargine patients exhibited lower FPG levels after 5:00 A.M.; the difference was significant by 8:00 A.M. The adjusted mean FPG for insulin glargine[30] was 7.8 mmol/l; for insulin glargine[80], 7.3 mmol/l; and for NPH, 10.7 mmol/l. Both formulations of insulin glargine were well tolerated, similar to NPH insulin. CONCLUSIONS: Basal insulin glargine administered once daily for 4 weeks as part of a basal-bolus multiple daily insulin regimen was safe and more effective in lowering fasting plasma glucose levels than NPH in patients with type 1 diabetes.     

Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy

OBJECTIVE: This study aimed to assess glycemic response to a mixture of 75% insulin lispro protamine suspension and 25% insulin lispro (Mix 75/25) BID plus metformin versus insulin glargine QD plus metformin in patients with type 2 diabetes mellitus (DM). METHODS: Adults new to insulin therapy were enrolled in a multicenter, randomized, prospective, open-label, crossover study with 16 weeks on each treatment. Variables included glycosylated hemoglobin (HbA(1c)), hypoglycemia rate, fasting blood glucose (FBG), 2-hour postprandial blood glucose (ppBG), and rise in blood glucose after meals. RESULTS: One hundred five patients (mean age, 55 years) were randomized. There was no difference in baseline mean values for either treatment sequence group for body mass index, duration of DM, or HbA(1c). Ninety-five patients completed the study and 67 were included in the efficacy analysis. Mix 75/25 was associated with lower mean (SD) HbA(1c) at end point (7.4% [1.1%] vs 7.8% [1.1%]; P = 0.002). More patients using Mix 75/25 achieved target HbA(1c) < or =7.0% (42% [30/71] vs 18% [13/71]; P < 0.001). With Mix 75/25, the mean (SD) 2-hour ppBG was similar after lunch but lower after breakfast (156.4 [43.6] vs 171.1 [44.9] mg/dL; P = 0.012) and dinner (164.8 [42.5] mg/dL vs 193.8 [51.0] mg/dL; P < 0.001), although FBG was higher (139.3 [36.6] mg/dL vs 123.9 [34.9] mg/dL; P < 0.001). Rise in ppBG was lower with Mix 75/25 after breakfast (16.9 [47.0] mg/dL vs 47.4 [34.8] mg/dL; P < 0.001) and dinner (14.2 [44.1] mg/dL vs 45.9 [41.3] mg/dL; P < 0.001). Gain in mean (SD) body weight was greater with Mix 75/25 than insulin glargine (2.3 [4.0] kg vs 1.6 [4.0] kg; P = 0.006). For all randomized patients, mean (SD) hypoglycemia rates were lower with insulin glargine (0.68 [1.38] vs 0.39 [1.24] episodes/patient per 30 days; P = 0.041), although nocturnal hypoglycemia was similar. CONCLUSION: In this study population, Mix 75/25 plus metformin was associated with lower HbA(1c) than insulin glargine plus metformin, smaller rise in ppBG after breakfast and dinner, and higher proportion of patients achieving HbA(1c) < or =7.0%, with a slight increase in overall (but not nocturnal) hypoglycemia.     

Glycemic control with insulin glargine as part of an ethnically diverse, community-based diabetes management program

OBJECTIVE: To evaluate the contribution of long-acting basal insulin therapy (insulin glargine) to glycemic control in a predominantly Hispanic population participating in a community-based diabetes management program, Project Dulce. RESEARCH DESIGN AND METHODS: This retrospective analysis included 3122 adult patients with diabetes from 17 community clinics in San Diego County, California who participated in Project Dulce between July 2000 and March 2003. A subset of 180 patients received insulin glargine because of ongoing, inadequate glycemic control (ie, elevated HbA1c). Glycemic control was evaluated by mean adjusted HbA1c during follow-up clinical visits using hierarchical linear modeling, with values determined separately before and after initiation of insulin glargine. RESULTS: At baseline, the mean number of individuals with hypoglycemia, presence of diabetic complications, and duration of diabetes were greater in the glargine group that in the reference group. HbA1c at baseline was 8.79 and 9.44 (P = 0.019) in the reference and glargine groups, respectively. Mean adjusted HbA1c in the glargine group was 8.80 at baseline, 7.89 before initiation of insulin glargine (P < 0.001 vs baseline), and 7.34 after adding insulin glargine (P < 0.001 vs pre-glargine). In the reference group, mean adjusted HbA1c decreased from 8.81 at baseline to 7.40 during follow-up (P < 0.001 vs baseline). CONCLUSIONS: A comprehensive program of diabetes care in Project Dulce improved HbA1c significantly in a predominantly Hispanic population. Adding long-acting basal insulin therapy with insulin glargine produced significant incremental improvement in HbA1c.     

Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites

OBJECTIVE: To determine the subcutaneous absorption rates and the appearance in plasma of 3 formulations of the long-acting human insulin analog insulin glargine (HOE 901) differing only in zinc content (15, 30, and 80 microg/ml). RESEARCH DESIGN AND METHODS: We conducted 2 studies. Study 1 compared the subcutaneous abdominal injection of 0.15 U/kg of 125I-labeled insulin glargine[15], insulin glargine[80], NPH insulin, and placebo. In study 2, 0.2 U/kg of insulin glargine[30] was injected into the arm, leg, and abdominal regions. Both studies had a randomized crossover design; each enrolled 12 healthy men, aged 18-50 years. RESULTS: In study 1, the time in hours for 25% of the administered radioactivity to disappear after bolus subcutaneous injection (T75%) for NPH insulin indicated a significantly faster absorption rate compared with the 2 insulin glargine formulations (3.2 vs. 8.8 and 11.0 h, respectively P < 0.0001). Mean residual radioactivity with NPH insulin was also significantly lower at 24 h (21.9 vs. 43.8 and 52.2%, P < 0.0001). The calculated plasma exogenous insulin concentrations after NPH insulin were substantially higher than those with insulin glargine, reaching a peak within the first 6 h after administration before declining. Insulin glargine, however, did not exhibit a distinct peak. Weighted average plasma glucose concentration between 0 and 6 h was significantly lower after NPH compared with insulin glargine (P < 0.001). In study 2, there were no significant differences in the absorption characteristics of insulin glargine between the 3 injection sites (T75% = 11.9, 15.3, and 13.2 h for arm, leg, and abdomen, respectively) or in residual radioactivity at 24 h. CONCLUSIONS: Subcutaneous absorption of insulin glargine is delayed compared with NPH insulin. There is little or no difference in the absorption rate of insulin glargine between the main subcutaneous injection sites.     

Dose-response relationship of an oral insulin spray in six patients with type 1 diabetes: a single-center, randomized, single-blind, 5-way crossover study

OBJECTIVE: This study evaluated the pharmacokinetic and pharmacodynamic properties and dose-response effects of an oral insulin spray formulation compared with those of subcutaneously injected regular insulin and placebo in patients with type 1 diabetes mellitus. METHODS: This was a single-center, randomized, single-blind, open-label, 5-way crossover study in which patients with type 1 diabetes received 5, 10, and 20 puffs of the oral insulin spray; regular insulin 0.1 U/kg SC; and placebo spray. The pharmacokinetic parameters of interest were the maximum serum insulin concentration (Ins-C(max)); the incremental insulin AUC from 0 to 120 minutes (Ins-AUC(0-120)), from 0 to 240 minutes, and from 0 to 360 minutes; and the time to maximum serum insulin concentration (Ins-T(max)). The pharmacodynamic parameters of interest were the maximum glucose infusion rate (GIR(max)); the incremental glucose AUC from 0 to 120 minutes (GIR-AUC(0-120)), from 0 to 240 minutes, and from 0 to 360 minutes; the time to maximum GIR (GIR-T(max)); the time to early half-maximal GIR (early T50%); and the time to late half-maximal GIR (late T50%). Pharmacokinetic and pharmacodynamic parameters were assessed using the euglycemic clamp technique. RESULTS: The study enrolled 6 white men with type 1 diabetes (mean [SD] age, 37.5 [16.2] years, mean weight, 82.7 [17.0] kg). Ins-T(max) was shorter for 5, 10, and 20 puffs of oral insulin spray than for SC insulin (26.7 [13.7], 29.2 [7.4], 23.3 [5.2], and 142.5 [73.2] min, respectively; P < 0.05). There was no effect of dose on Ins-T(max). The Ins-AUC(0-120) for 5, 10, and 20 puffs of oral insulin spray (304.8 [277.9], 689.2 [353.0], and 1808.8 [1252.6] microU/mL per min, respectively; P < 0.05) and the corresponding Ins-Ca(max) (12.9 [8.7], 26.7 [14.5], and 47.6 [40.1] microU/mL; P < 0.05) suggested a dose-response relationship. Five, 10, and 20 puffs of oral insulin spray had an earlier onset of action than SC insulin (early T50%: 23.3 [15.1], 28.3 [12.3], 31.2 [111.8], and 87.0 [39.6] min, respectively; P < 0.05), an earlier maximal effect (GIR-T(max): 40.0 [23.7], 45.8 [22.7], 44.2 [5.8], and 145.0 [43.7] min; P < 0.05), and a shorter duration of action (late T50%: 56.5 [31.0], 70.2 [12.9], 75.5 [6.0], and 290.8 [84.0] min; P < 0.05). Dose-dependent increases in maximal metabolic effect were observed with 5, 10, and 20 puffs: the GIR(max) was 0.9 (0.5), 2.0 (1.3), and 3.9 (2.5) mg/kg per minute, respectively (P < 0.05), and the GIR-AUC(0-120) was 39.6 (34.9), 76.8 (67.4), and 189.1 (163.0) mg/kg per minute (P < 0.05). CONCLUSIONS: In this study in patients with type 1 diabetes, oral insulin spray had a faster onset and shorter duration of action than subcutaneously injected regular insulin. A dose-response relationship was noted in the metabolic effect and absorption of oral insulin spray.     

Use of glargine in pregnant women with type 1 diabetes mellitus: a case-control study

BACKGROUND: Insulin glargine is a once-daily basal insulin analog with prolonged duration of action and absence of an evident peak. Glargine is associated with reduced frequency of hypoglycemic episodes (mostly nocturnal) as well as effective glycemic control. Maintenance of good metabolic control before conception and throughout pregnancy is essential to lower the risk of fetal malformations. Glargine might be a valuable alternative in the management of pregnancies complicated by diabetes mellitus. However, because its clinical utility has not been established, the use of glargine is not currently recommended during pregnancy. OBJECTIVE: The aim of this study was to retrospectively evaluate (years 2004-2007) the effectiveness and safety of insulin glargine compared with neutral protamine Hagedorn (NPH) in women affected by type 1 diabetes mellitus (T1DM) during pregnancy. METHODS: The study comprised pregnant women affected by T1DM who were followed up in the Diabetes and Pregnancy Outpatient Clinic at the University of Palermo, Palermo, Italy, within 8 +/- 3.4 weeks subsequent to a positive pregnancy test. All patients with T1DM were treated with conventional basal-bolus insulin therapy (aspart or lispro analogs at the 3 main meals plus glargine or NPH at bedtime). Healthy pregnant women were used as controls for fetal and neonatal parameters. Patients were consecutively enrolled. In all women, metabolic status was determined daily by mean glycemic values (2-hour postprandial blood glucose) and glycosylated hemoglobin (HbA1c) values (at 3-month intervals). Fetal measurements (<50th and >90th centiles of the head circumference, abdomen circumference, and femoral length) were evaluated by ultrasound at second and third trimesters. Weight and femoral length were assessed at birth, and neonates were classified according to the fetal growth curve for the Italian population (<10th centile = small for gestational age; and >90th centile = large for gestational age (LGA). RESULTS: A total of 73 pregnant women (30 with T1DM and 43 healthy [control]) were included in the study. Of the 30 diabetic pregnant women included in the study, 15 (mean [SD] age, 27.4 [5.2] years; mean pregravidic weight, 59.7 [11.7] kg) maintained their preconception therapy with glargine, and 15 (mean age, 30.1 [2.4] years; mean pregravidic weight, 60.7 [8.7] kg) with NPH. No significant difference was observed between the glargine-treated group and the NPH-treated group with regard to pregravidic hypertension, third-trimester preeclampsia, maternal complications and/or their progression during pregnancy (diabetic retinopathy, micro- or macroalbuminuria) and episodes of mild hypoglycemia, severe hypoglycemia, and ketosis. There were no significant between group differences in insulin requirements (IU/kg of body weight) and glycemic profile, with the exception of better fasting and 2 hours after breakfast glycemic values in the glargine group during the first (P = 0.008 and P < 0.001, respectively) and the second (P = 0.015 and P = 0.016) trimesters, confirmed by the lower HbA1c levels in the first trimester (P = 0.037). The frequency of femoral length <50th centile at both second and third trimesters was 4/15 (26.7%) in the glargine-treated group (P = 0.033 and P = 0.013, respectively, vs control), 3/15 (20.0%) and 1/15 (6.7%), respectively, in the NPH-treated group (both, P = NS vs control), and 2/43 (4.7%) and 1/43 (2.3%), respectively, in the control group. The prevalence of LGA was 7/15 (46.7%) in the glargine group (P < 0.001 vs control), 4/15 (27.6%) in the NPH group (P = 0.033 vs control), and 2/43 (4.7%) in the control group. CONCLUSIONS: Although our retrospective study involved only a small number of participants, no significant difference was found in glycemic control between glargine and NPH treatments. Use of glargine was associated with a significantly higher frequency of femoral length <50th centile. Further larger prospective studies are necessary to assess the safety profile of glargine in T1DM during pregnancy.     

A 16-week comparison of the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin lispro in patients with type 1 diabetes

OBJECTIVE: To determine the safety and efficacy of the long-acting insulin analog, insulin glargine, as a component of basal bolus therapy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes receiving basal-bolus insulin treatment with NPH human insulin and insulin lispro were randomized to receive insulin glargine (HOE 901), a long-acting basal insulin analog, once a day (n = 310) or NPH human insulin (n = 309) as basal treatment with continued bolus insulin lispro for 16 weeks in an open-label study NPH insulin patients maintained their prior schedule of administration once or twice a day, whereas insulin glargine patients received basal insulin once a day at bedtime. RESULTS: Compared with all NPH insulin patients, insulin glargine patients had significant decreases in fasting blood glucose measured at home (means +/- SEM, -42.0 +/- 4.7 vs. -12.4 +/- 4.7 mg/dl [-2.33 +/- 0.26 vs. -0.69 +/- 0.26 mmol/l]; P = 0.0001). These differences were evident early and persisted throughout the study More patients in the insulin glargine group (29.6%) than in the NPH group (16.8%) reached a target fasting blood glucose of 119 mg/dl (< 6.6 mmol/l). However, there were no differences between the groups with respect to change in GHb. Insulin glargine treatment was also associated with a significant decrease in the variability of fasting blood glucose values (P = 0.0124). No differences in the occurrence of symptomatic hypoglycemia, including nocturnal hypoglycemia, were observed. Overall, adverse events were similar in the two treatment groups with the exception of injection site pain, which was more common in the insulin glargine group (6.1%) than in the NPH group (0.3%). Weight gain was 0.12 kg in insulin glargine patients and 0.54 kg in NPH insulin patients (P = 0.034). CONCLUSIONS: Basal insulin therapy with insulin glargine once a day appears to be as safe and at least as effective as using NPH insulin once or twice a day in maintaining glycemic control in patients with type 1 diabetes receiving basal-bolus insulin treatment with insulin lispro.     

Insulin therapy in type 2 diabetes: role of the long-acting insulin glargine analogue

Insulin glargine is a long‐acting insulin analogue, with a longer duration of action and a flatter time‐action profile compared with NPH insulin. These properties can be predicted to result in higher glucose levels during the night and lower glucose levels after dinner following bedtime injection of insulin glargine compared with an equal dose of NPH insulin injected at bedtime. In two large‐scale clinical trials involving either insulin‐naïve (426 patients treated for 1 year) or previously insulin‐treated (518 patients treated for 28 weeks) patients with type 2 diabetes, comparing addition of once‐daily insulin glargine or NPH insulin to oral agents, these predictions were proven to be correct. Nocturnal hypoglycaemia was reduced by 58% in insulin‐naive patients and by 22% in previously insulin‐treated patients, and dinner‐time glucose control was significantly better with insulin glargine than with NPH insulin once daily in the study in insulin‐naive patients. The ‘treat‐to‐target study’ (756 insulin‐naive patients treated for 24 weeks) showed that good glycaemic control can be achieved with aggressive titration of the insulin dose with either once‐daily insulin glargine or NPH insulin combined with oral agents (mean endpoint HbA_1c was 6·96% with insulin glargine and 6·97% with NPH insulin); however, this was achieved with less variability and nocturnal hypoglycaemia with insulin glargine. These data support use of insulin glargine instead of NPH insulin for basal insulin replacement in patients with type 2 diabetes.     

Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes

OBJECTIVE: Insulin glargine (21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin) is a biosynthetic insulin analog with a prolonged duration of action compared with NPH human insulin. This study compared insulin glargine with NPH human insulin in subjects with type 1 diabetes who had been previously treated with multiple daily injections of NPH insulin and regular insulin. RESEARCH DESIGN AND METHODS: This study was a multicenter randomized parallel-group study in which subjects were randomized to receive premeal regular insulin and either insulin glargine (at bedtime) or NPH insulin (at bedtime for patients on once-daily therapy and at bedtime and in the morning for patients on twice-daily therapy) for up to 28 weeks. Dose titration of both basal insulins was based on capillary fasting whole blood glucose (FBG) levels; the goal was a premeal blood glucose concentration of 4.4-6.7 mmol/l. RESULTS: A total of 534 well-controlled type 1 diabetic subjects (mean GHb 7.7%, mean fasting plasma glucose [FPG] 11.8 mmo/l) were treated. A small decrease in GHb levels was noted with both insulin glargine (-0.16%) and NPH insulin (-0.21%; P > 0.05). Significant reductions in median FPG levels from baseline (-1.67 vs. -0.33 mmol/l with NPH insulin, P = 0.0145) and a trend for a reduction in capillary FBG levels were achieved with insulin glargine. After the 1-month titration phase, significantly fewer subjects receiving insulin glargine experienced symptomatic hypoglycemia (39.9 vs. 49.2%, P = 0.0219) or nocturnal hypoglycemia (18.2 vs. 27.1%, P = 0.0116) with a blood glucose level <2.0 mmol/l compared with subjects receiving NPH insulin. CONCLUSIONS: Lower FPG levels with fewer episodes of hypoglycemia were achieved with insulin glargine compared with once- or twice-daily NPH insulin as part of a basal-bolus regimen in patients with type 1 diabetes.     

预混胰岛素转为基础胰岛素联合口服降糖药物治疗2型糖尿病的临床实践分析

目的探讨预混胰岛素治疗的2型糖尿病患者转为基础胰岛素联合口服降糖药的有效性与安全性。方法选取2010年2月-2011年8月就诊的36例使用预混胰岛素2次／d,稳定剂量治疗12周以上,糖化血红蛋白≤10％的门诊2型糖尿病患者。将治疗药物转为基础胰岛素加口服降糖药物,随访治疗24周,观察分析患者的体质量,空腹、餐后血糖,糖化血红蛋白,低血糖事件及胰岛素剂量变化。结果36例患者完成研究。甘精胰岛素治疗后患者的体质量较治疗前下降[（63．77±10．34）、（62．31±9．98）kg,P=0．002],胰岛素总量较前有明显下降[（23．56±6．15）、（10．28±4．04）U／d,P=0．000]。预混胰岛素治疗糖化血红蛋白≤7％的亚组,经甘精胰岛素治疗后糖化血红蛋白有进一步的下降[（6．70±0．81）％、（6．34±0．55）％,P=0．007],胰岛素的剂量为（0．16±0．06）u／（kg·d）,低血糖事件与非达标组相比差异无统计学意义（33．33％、55．56％,P=0．267）。与预混胰岛素相比,会增加1～2种口服药的联合使用,使用最多的为二甲双胍（17／36）。结论糖化血红蛋白≤7％的预混胰岛素治疗患者,换用甘精胰岛素联合口服降糖药物治疗,在获得良好的血糖控制的同时,也具有良好的安全性和其他综合疗效。     

Comparison of pharmacokinetic and pharmacodynamic properties of single-dose oral insulin spray and subcutaneous insulin injection in healthy subjects using the euglycemic clamp technique

BACKGROUND: Oral insulin spray is a new, noninjectable method of insulin delivery. This system delivers an aerosol of uniform-sized droplets containing regular human insulin at a high velocity into the oropharyngeal cavity for local transmucosal absorption. OBJECTIVE: The purpose of this study was to compare the pharmacokinetic and pharmacodynamic properties of single-dose oral insulin spray and SC insulin injection in healthy subjects. METHODS: Healthy male volunteers aged 21 to 25 years participated in this open-label study conducted at the Diabetes Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel. Subjects presented at 2 visits separated by 7 to 14 days. At both visits, the euglycemic clamp technique was used to maintain a constant blood glucose level. At one visit, subjects received regular human insulin 0.1 U/kg by SC injection. At the other visit, subjects received 15 puffs (150 U) of oral insulin spray. The pharmacokinetic (insulin absorption) and pharmacodynamic (glucose uptake) properties of the drugs were evaluated using blood analyses over the subsequent 360 minutes. RESULTS: Six volunteers were enrolled (mean [SD] age, 22.8 [1.2] years; mean [SD] body mass index, 23.2 [2.2] kg/m(2)). The mean (SD) baseline-corrected C(max) was significantly higher with oral insulin spray compared with SC insulin (54.0 [20.3] vs 30.8 [6.1] microU/mL; P = 0.028). Mean (SD) T(max) was significantly shorter with oral insulin spray compared with SC insulin (23.3 [5.2] vs 83.3 [42.2] minutes; P = 0.027). The mean (SD) time to maximal metabolic effect (maximum glucose infusion rate [GIR(max)]) (44.2 [8.6] vs 100.0 [35.6] minutes) and late time to half-maximal effect (101.0 [41.0] vs 257.2 [27.8] minutes) were shorter with oral insulin spray compared with SC insulin (both, P = 0.028). The baseline-corrected GIR(max) (6.8 [3.3] vs 6.2 [2.3] mg/kg . min) and glucose consumption (396.7 [178.0] vs 432.1 [226.0] mg/kg) during the 120 minutes after study drug administration were comparable between oral and SC insulin, respectively. CONCLUSIONS: In this study in a small, selected population of healthy male subjects under euglycemic conditions, oral insulin spray was associated with a higher C(max), shorter T(max), and faster time to peak glucose uptake compared with SC insulin. The short T(max) and the 120-minute duration of effect of oral insulin spray suggest it may be a promising alternative for fulfilling meal-related insulin requirements in persons with diabetes.     

A randomized clinical trial comparing breakfast,dinner, or bedtime administration of insulin glargine in patients with type 1 diabetes

OBJECTIVE: Insulin glargine (Lantus), a long-acting human insulin analog, provides effective glycemic control when administered at bedtime. This open-label, randomized, parallel group, multicenter study investigated whether insulin glargine is equally effective if administered before breakfast, before dinner, or at bedtime. RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes on basal-bolus therapy (n = 378, 18-68 years, HbA(1c) 5.5-9.8%) were treated with once-daily individually titrated insulin glargine in combination with prandial insulin lispro for 24 weeks. RESULTS: Baseline characteristics were similar in the three groups (overall age 40.9 +/- 11.9 years, diabetes duration 17.3 +/- 11.5 years). Median total daily insulin dose was similar at baseline (0.65, 0.65, and 0.66 IU/kg for breakfast, dinner, and bedtime, respectively) and remained relatively constant over the study period; however, the insulin glargine-to-total insulin dose ratio increased more in the breakfast group than in the dinner and bedtime groups. A similar reduction of adjusted mean HbA(1c) from baseline to end point occurred in all patients (7.6-7.4, 7.6-7.5, and 7.6-7.5% for breakfast, dinner, and bedtime, respectively), and a similar percentage achieved HbA(1c) <7.0% at end point in all groups (29.5, 29.8, and 25.8%, respectively). The 24-h blood glucose profiles in relation to injection time were similar in all groups. The incidences of total symptomatic and severe hypoglycemia did not differ between the three treatment groups; however, nocturnal hypoglycemia occurred in significantly fewer patients in the breakfast group (59.5%) compared with the dinner (71.9%) and bedtime (77.5%) groups (P = 0.005). CONCLUSIONS: These data suggest that insulin glargine, in combination with insulin lispro, is safe and effective when administered before breakfast, before dinner, or at bedtime.     

胰岛素强化治疗在ICU危重症高血糖患者中的应用

【目的】观察甘精胰岛素联合门冬胰岛素在ICU危重症高血糖患者中应用的疗效及安全性。【方法】将90例ICU危重症高血糖患者随机分成三组,①中效鱼精蛋白锌胰岛素（NPH）组：加餐前门冬胰岛素;②甘精胰岛素组：给予甘精胰岛素加餐前门冬胰岛素皮下注射;③胰岛素泵（CSⅡ）组：胰岛素泵持续皮下注射,加餐前门冬胰岛素负荷。比较三种治疗方案的降糖效果、达标时间以及发生低血糖的次数。【结果】三种治疗方案均能使血糖达标。NPH组的达标时间为（5．2±1．5）d,而CSⅡ组和甘精胰岛素组血糖达标时间分别为（2．9±0．9）d和（2．8±1．2）d,与NPH组比较差异有显著性（P〈0．05）。NPH组有12人次出现低血糖事件,其中2人次严重低血糖和8人次夜间低血糖事件,CSⅡ组和甘精胰岛素组中低血糖事件以及夜间低血糖事件明显减少,与NPH组比较差异均有显著性（P〈0．01）。【结论】以甘精胰岛素提供基础胰岛素配合餐前门冬胰岛素皮下注射方案治疗伴有高血糖的危重症患者是相对简单、安全、有效的治疗方案。     

甘精胰岛素联合瑞格列奈治疗老年2型糖尿病的疗效观察

目的观察老年2型糖尿病(T2DM)病人甘精胰岛素联合瑞格列奈降糖治疗的效果。方法 60例T2DM患者随机分为甘精组和预混组,甘精组三餐前15 min口服瑞格列奈0.5～1.0 mg,晚10∶00皮下注射甘精胰岛素。预混组于早晚饭前30 min注射预混胰岛素,应用罗康全血糖仪,住院期间监测空腹、三餐后2 h、夜10∶00、夜3∶00指尖血糖,根据血糖调整胰岛素剂量。空腹血糖(FPG)<7.0 mmol/L,餐后2 h血糖(2 hPG)<10.0 mmol/L为达标。观察血糖达标时间、胰岛素用量、低血糖发生次数、发生人数;12周后的FPG、2 hPG、糖化血红蛋白(HbAlc)、体质量指数(BMI)。结果两组血糖控制均达标,预混组和甘精组12周后,FPG2、hPG、HbA1c组间差异无统计学意义(P>0.05),组内与治疗前相比差异有统计学意义(P<0.01)。两组血糖达标时间差异无统计学意义(P>0.05),甘精组BMI较治疗前无明显增加(P>0.05),预混组BMI较治疗前明显增加(P<0.05)。甘精组胰岛素日用量、低血糖发生人数显著低于预混组(P<0.01),差异有统计学意义。结论两种治疗方案对控制血糖都有效,但甘精胰岛素联合瑞格列奈降糖治疗方案能减少注射次数和胰岛素的日用量,减少低血糖风险,不增加体质指数,依从性好。     

Is self-monitoring of blood glucose appropriate for all type 2 diabetic patients? The Fremantle Diabetes Study

OBJECTIVE: We sought to determine whether self-monitoring of blood glucose (SMBG) is associated with better glycemic control in type 2 diabetes. RESEARCH DESIGN AND METHODS: We used cross-sectional and longitudinal data from type 2 diabetic participants in the observational, community-based Fremantle Diabetes Study (FDS) who reported SMBG status at study entry (n = 1,286) and annual reviews over 5 years (n = 531). RESULTS: At study entry, 70% of patients performed SMBG, with a median of four tests per week (interquartile range two to seven). Patients with shorter diabetes duration; who were attending diabetes education, diabetes-related clinics, or medical specialists; who were taking insulin with or without oral hypoglycemic agents (OHAs); and who were self-reporting hypoglycemic events were more likely to use SMBG. Both cross-sectional and longitudinal FDS data showed that HbA(1c) (A1C) was not significantly different between SMBG users and nonusers, either overall or within diabetes treatment groups (diet, OHAs, and insulin with or without OHAs). There was also no independent cross-sectional relationship between A1C and SMBG frequency. The average annual societal cost of using SMBG (in year 2000 Australian dollars [Adollars], excluding glucometers) was 162 Australian dollars per type 2 diabetic patient or 51 million Australian dollars when projected to the Australian diagnosed type 2 diabetic population. CONCLUSIONS: Neither SMBG testing nor its frequency was associated with glycemic benefit in type 2 diabetic patients regardless of treatment. Our data did not include methods of SMBG delivery and application, factors that require further assessment in the evaluation of SMBG utility in non-insulin-treated type 2 diabetes. SMBG may be still of value in the identification and prevention of hypoglycemia and in dose adjustment in insulin-treated patients.