Refining basal insulin therapy: what have we learned in the age of analogues?

BACKGROUND: The basal insulin analogues glargine and detemir have been subject to a series of trials comparing their clinical profiles to the conventional preparation, neutral protamine Hagedorn (NPH). Careful review of these trials provides opportunities to learn clinically useful lessons about these insulins. METHODS: MedLine-indexed trials comparing glargine or detemir to NPH were scrutinized for control, tolerability and dose data. Separate considerations were made for types 1 and 2 diabetes, and for basal-bolus and basal plus oral glucose-lowering drugs (OGLD) therapy. Attention was paid to dosing schedules and 24-h glycaemic profiles. RESULTS: Collectively, the trials demonstrated an improved balance between glycaemic control and tolerability for both analogues compared to NPH, regardless of regimen and diabetes type. Neither once-daily glargine nor detemir reliably provides 24-h basal insulin replacement in all patients with type 1 diabetes; a waning of effect frequently obliges twice-daily administration. When added to OGLDs in type 2 diabetes, goal-titrated once-daily basal insulin generally lowered HbA(1c) by approximately 1.5%, whereas twice-daily administration tended to increase insulin dose disproportionately to improvement in control. Hence, adding bolus insulin may be a preferable intensification method to dividing the basal dose. Varying injection time or dividing the basal insulin dose predictably affects the pattern of hypoglycaemia and bolus dose requirements. Morning administration tends to require higher dosing than evening administration. CONCLUSIONS: Scrutiny of trials involving glargine and detemir has increased our understanding of how best to dose basal insulins. An individualized approach is still necessary however, and several questions remain that require further research.     

Cost-effectiveness of basal insulin from a US health system perspective: Comparative analyses of detemir, glargine, and NPH

The purpose of this study was to compare in clinical and economic terms the long-acting insulin analogue detemir with intermediate-acting Neutral Protamine Hagedorn (NPH) insulin and with long-acting insulin glargine. Investigators used the validated Center for Outcomes Research (CORE) Diabetes Model to project clinical and cost outcomes over a 35-year base case time horizon; outcome data were extracted directly from randomized, controlled trials designed to compare detemir with NPH and with insulin glargine. Modeled patient characteristics were derived from corresponding trials, and simulations incorporated published quality-of-life utilities with cost data obtained from a Medicare perspective. Detemir, when compared with NPH, increased quality-adjusted life expectancy by 0.698 quality-adjusted life-years (QALYs). Lifetime direct medical costs were increased by $10,451 per patient, although indirect costs were reduced by $4688. On the basis of direct costs, the cost per QALY gained with detemir was $14,974. In comparison with glargine, detemir increased quality-adjusted life expectancy by 0.063 QALYs, reduced direct medical costs by $2072 per patient, and decreased indirect costs by $3103 (dominant). Reductions in diabetes-related comorbidities were also associated with detemir in both instances, most notably in the complications of retinopathy and nephropathy. Relative reductions in rates of complications were greatest in the comparison of detemir with NPH. Results were most sensitive to variation in hemoglobin A_1c (HbA_1c) levels. However, variation among any of the key assumptions, including HbA_1c, did not alter the relative results. Detemir represents an attractive clinical and economic intervention in the US health care setting compared with both NPH insulin and insulin glargine.     

Once-daily insulin detemir is comparable to once-daily insulin glargine in providing glycaemic control over 24 h in patients with type 2 diabetes: a double-blind, randomized, crossover study

Once-daily dosing with insulin detemir and insulin glargine were compared in a double-blind, randomised, crossover study in type 2 diabetes subjects previously treated with other antihyperglycaemic medications. Blood glucose was measured through continuous glucose monitoring (CGM). Insulin dose was adjusted daily during the titration phase to achieve target blood glucose values of (70-120 mg/dL) during the basal period, defined as 2400–0600 hours. The last meal of the day started at 1800 h and basal insulin was injected at 2000 h. The CGM data for a 24-h period on the second consecutive day after achieving target blood glucose levels were compared between treatments. Twenty-nine subjects completed the study. Over a 24-h measurement period, once-daily dosing with insulin detemir provided glycaemic control very similar to that of once-daily insulin glargine in patients with type 2 diabetes after both had been titrated to the same glucose target. Insulin detemir- and insulin glargine-treated subjects had similar mean 24-h glucose values (133 ± 21 mg/dL compared with 126±20 mg/dL respectively, p = 0.385) and similar glucose values during the basal period (105 ± 23 mg/dL compared with 98 ± 19 mg/dL, respectively p = 0.204).Target basal glycaemic control was achieved in all subjects in a mean of 3.8 days for detemir and 3.5 days for glargine (p = 0.360). The mean dose of detemir was similar to that of glargine (26.3 and 26.6 units/day, respectively, p = 0.837). In this study, once-daily dosing of insulin detemir provided 24-h glycaemic control similar to that of insulin glargine in patients with type 2 diabetes.     

A Comparative Evaluation of two Types of Dacron Vascular Prostheses

The function of two types of Dacron vascular prostheses was evaluated in dogs using the abdominal aorta, inferior vena cava and iliac artery as host vessels. The transplants used were woven and knitted DeBakey prostheses and knitted Cooley prostheses. It is concluded that the function of a prosthesis with a diameter less than 5 mm is unsatisfactory. The same is true of a prosthesis implanted on the venous side, even in a large vein, such as the inferior caval vein, with a high flow. There is no significant difference between the function of DeBakey and Denton Cooley prostheses.     

In Type 1 diabetic patients with good glycaemic control,blood glucose variability is lower during continuous subcutaneous insulin infusion than during multiple daily injections with insulin glargine

Aims The superiority of continuous subcutaneous insulin infusion (CSII) over multiple daily injections (MDI) with glargine is uncertain. In this randomized cross‐over study, we compared CSII and MDI with glargine in patients with Type 1 diabetes well controlled with CSII. The primary end‐point was glucose variability. Methods Thirty‐nine patients [38.1 ± 9.3 years old (mean ± sd ), diabetes duration 16.6 ± 8.2 years, glycated haemoglobin (HbA_1c) 7.6 ± 0.8%], already on CSII for at least 6 months, were randomly assigned to CSII with lispro or MDI with lispro and glargine. After 4 months they were switched to the alternative treatment. During the last month of each treatment blood glucose variability was analysed using glucose standard deviation, mean amplitude of glycaemic excursions (MAGE), lability index and average daily risk range (ADRR). As secondary end‐points we analysed blood glucose profile, HbA_1c, number of episodes of hypo‐ and hyperglycaemia, lipid profile, free fatty acids (FFA), growth hormone and treatment satisfaction. Results During CSII, glucose variability was 5–12% lower than during MDI with glargine. The difference was significant only before breakfast considering glucose standard deviation (P = 0.011), significant overall using MAGE (P = 0.016) and lability index (P = 0.005) and not significant using ADRR. Although HbA_1c was similar during both treatments, during CSII blood glucose levels were significantly lower, hyperglycaemic episodes were fewer, daily insulin dose was less, FFA were lower and treatment satisfaction was greater than during MDI with glargine. The frequency of hypoglycaemic episodes was similar during both treatments. Conclusions During CSII, glucose variability is lower, glycaemic control better and treatment satisfaction higher than during MDI with glargine.     

Insulin glargine in combination with nateglinide in people with Type 2 diabetes: a randomized placebo-controlled trial.

OBJECTIVE: To determine the effect of adding nateglinide to therapy with insulin glargine in adults with Type 2 diabetes previously treated with insulin and with poor blood glucose control. RESEARCH DESIGN AND METHODS: In this 16-week, double-blind, placebo-controlled study, people with Type 2 diabetes [n = 55, HbA(1c) 8.2 +/- 1.0 (+/- sd)%, duration of diabetes 12.8 +/- 6.0 years, duration of insulin treatment 6.0 +/- 4.0 years] were transferred to single bedtime injection of insulin glargine for a titration period of 4 weeks, and then randomized to nateglinide or matching placebo before meals in addition to insulin glargine. Metformin was continued if taken. Doses of insulin and oral medication were titrated to protocol for the treatment period of 12 weeks. RESULTS: Baseline-adjusted self-monitored capillary blood glucose concentration at 12 weeks was significantly lower with nateglinide + insulin glargine compared with placebo + insulin glargine after breakfast [difference -2.3 (95% confidence interval -4.4, -0.2) mmol/l, P = 0.030], before lunch [-2.5 (-4.6, -0.3) mmol/l, P = 0.029], and after lunch [-2.3 (-4.3, -0.4) mmol/l, P = 0.021], but not at other times. Baseline-adjusted HbA(1c) was not lower with nateglinide + insulin glargine as compared with placebo + insulin glargine [7.8 +/- 1.4 vs. 8.3 +/- 1.0%, difference -0.43 (-0.98, 0.12)%]. CONCLUSIONS: Addition of nateglinide before meals to once-daily insulin glargine in people with long-standing diabetes already requiring insulin therapy improves blood glucose control in the early part of the day after breakfast and lunch, but does not provide good control of blood glucose levels overall.     

阿卡波糖联合不同胰岛素控制血糖疗效比较

目的:观察阿卡波糖分别与甘精胰岛素及精蛋白胰岛素联合控制血糖之疗效。方法:将58例患者随机分为甘精胰岛素组或人精蛋白(NPH)胰岛素组,于睡前皮下注射胰岛素并联合阿卡波糖治疗3周,观察试验终点时两组间的血糖控制情况、胰岛素用量及低血糖事件。结果:两组的空腹血糖平稳,治疗终点时甘精胰岛素组全天各时点血糖均值低于精蛋白胰岛素组,尤以晚餐后血糖与精蛋白胰岛素组相差最大,早中餐后2h血糖差异无统计学意义。结论:阿卡波糖联合甘精胰岛素或精蛋白胰岛素对控制2型糖尿病患者,24h总体血糖的稳态有效,低血糖发生率低,阿卡波糖联合甘精胰岛素疗效更优。     

甘精胰岛素联合吡格列酮及阿卡波糖治疗初诊2型糖尿病30例

目的:观察甘精胰岛素联合吡格列酮及阿卡波糖治疗初诊2型糖尿病的降糖效果及对胰岛素抵抗和β细胞功能的影响。方法:30例初诊2型糖尿病患者应用甘精胰岛素每日一次注射,联合口服吡格列酮及阿卡波糖4周,4周后停药继续观察半年,分别于治疗前后测身高、体重、三酰甘油、空腹血糖(FPG)、空腹胰岛素(FINS)、空腹C肽(FCP)、糖化血红蛋白(HbA1c)、餐后2h血糖(2hPG)、2h胰岛素(2hINS)、2hC肽(2hCP),计算体重指数、胰岛素抵抗指数(HOMA-IR)、β细胞功能指数(HOMA-b)。结果:治疗4周时血糖基本恢复正常,HbA1c明显下降,空腹及餐后2h胰岛素、C肽以及HOMA-β明显升高,HOMA-IR明显下降,三酰甘油明显改善,体重指数无明显变化。随访半年时,80%患者血糖维持在正常范围,20%血糖升高者多数仅需增敏剂或/及葡萄糖糖苷酶抑制剂即可满意控制血糖。结论:甘精胰岛素联合吡格列酮及阿卡波糖可迅速控制初诊2型糖尿病患者的血糖,恢复β细胞功能,降低胰岛素抵抗,使血糖长期稳定在较好水平。     

Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique

Aims/hypothesis This single-dose, double-blind, randomised, parallel-group study evaluated the reproducibility in systemic exposure and glucodynamic effect of insulin glargine, NPH insulin (NPH) and insulin ultralente (ultralente) using the manually adjusted euglycaemic clamp technique.Methods In total, 36 healthy volunteers received two consecutive s.c. injections (0.4 IU/kg) of glargine, NPH or ultralente with a wash-out period of 7 days between treatments.Results In healthy volunteers, glargine presented well-reproduced flat concentration profiles and no pronounced peaks in activity. NPH, by contrast, showed well-defined peaks in concentration and glucose disposal, while ultralente had highly variable profiles. Within-subject variability (ANOVA) for insulin exposure over 24 h was 15% for glargine and 19% for NPH, compared with 67% for ultralente (p<0.05, glargine and NPH vs ultralente). The 49% within-subject variability in total glucose disposal (glucose infusion rate [GIR]-AUC_{0–24 h}) with ultralente was about twice as large as the 22% with NPH (p<0.05), but was intermediate with glargine at 31% (p=NS). By contrast, variability in the diurnal time-action profile (SD of diurnal day-to-day differences in GIR) for glargine was 30% (p<0.05) and 50% (p<0.05) less than with NPH and ultralente, respectively. No serious adverse events were reported.Conclusions/interpretation Although representing insulins of different profiles, glargine and NPH showed a high and similar reproducibility of total absorption and glucodynamic effect, whereas ultralente proved to have poor reproducibility. However, while NPH yields peaks in concentration and activity, glargine shows flat and non-fluctuating profiles resulting in less variation in day-to-day 24-h activity.