An exploratory study of the effect of using high-mix biphasic insulin aspart in people with type 2 diabetes.

OBJECTIVE: To compare blood glucose control when using biphasic insulin aspart (BIAsp) three times a day (using 70/30 high-mix before breakfast and lunch), with biphasic human insulin (BHI, 30/70) twice daily in adults with type 2 diabetes already treated with insulin. RESEARCH DESIGN AND METHODS: In a 60-day, open-label, crossover study, people with insulin-treated type 2 diabetes [n = 38, baseline haemoglobin A1c 8.3 +/- 0.9 (s.d.) %] were randomized to BIAsp three times a day before meals, as BIAsp 70 (70% insulin aspart and 30% protamine-complexed insulin aspart) before breakfast and lunch and BIAsp 30 (30/70 free and protamine-complexed insulin aspart) before dinner, or to human premix insulin (BHI) 30/70 twice a day before meals. A 24-h in-patient plasma glucose profile was performed at the end of each 30-day treatment period. The total daily insulin dose of BIAsp regimen was 110% of BHI and the doses were not changed during the study. RESULTS: There was no difference between BIAsp and BHI in geometric weighted average serum glucose over 24 h [7.3 vs. 7.7 mmol/l, BIAsp/BHI ratio 0.95 (95% CI 0.88-1.02), not significant (NS)], but daytime geometric weighted average glucose concentration was significantly lower with the BIAsp regimen than with BHI [8.3 vs. 9.2 mmol/l, BIAsp/BHI ratio 0.90 (0.84-0.98), p = 0.014]. The mealtime serum glucose excursion was also lower with BIAsp than with BHI with statistically significant differences at lunchtime [difference -4.9 (-7.0 to -2.7) mmol/l, p = 0.000); the difference in glucose excursions above 7.0 mmol/l was also significant [-5.8 (-8.3 to -3.2) mmol/l, p = 0.000). The proportion of participants experiencing confirmed hypoglycaemic episodes was similar between regimens (42 vs. 43%, NS). CONCLUSIONS: An insulin regimen using high-mix BIAsp (BIAsp 70) before breakfast and lunch and BIAsp 30 before dinner can achieve lower blood glucose levels during the day through reduced mealtime glucose excursions in particular at lunchtime than a twice-daily premix regimen.

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.

Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart.

AIM: To compare blood glucose control when using insulin glargine twice daily at breakfast- and dinner-times with insulin glargine once daily at dinner time, in unselected people with Type 1 diabetes using insulin aspart at meal-times. METHODS: In this 8-week, two-way, cross-over study, 20 people with Type 1 diabetes were randomized to insulin glargine injection once daily at dinner-time or twice daily at breakfast- and dinner-times, both plus meal-time insulin aspart. Each 4-week treatment period concluded with a 24-h inpatient metabolic profile. RESULTS: Insulin doses, HbA1c, fructosamine concentration and pre-breakfast self-monitored blood glucose (SMBG) concentration did not differ between treatment periods. SMBG concentrations after breakfast, after lunch and before dinner were lower with twice-daily compared with once-daily dinner-time glargine [9.3 +/- 0.5 (+/- se) vs. 6.7 +/- 0.5 mmol/l, P = 0.003; 10.2 +/- 0.9 vs. 7.0 +/- 0.9 mmol/l, P = 0.024; 9.6 +/- 0.5 vs. 6.6 +/- 0.5 mmol/l, P = 0.001]. Mean 24-h SMBG concentration was lower with twice-daily glargine (7.1 +/- 0.5 vs. 8.8 +/- 0.5 mmol/l, P = 0.031). Within-day variability of SMBG concentration was lower with twice-daily glargine (sd 3.2 +/- 0.2 vs. 4.0 +/- 0.3 mmol/l, P = 0.044). Plasma free insulin concentration was higher in the afternoon with twice-daily glargine (21.9 +/- 1.4 vs. 16.1 +/- 1.3 mU/l, P = 0.009), but lower overnight (12.1 +/- 1.7 vs. 17.8 +/- 1.7 mU/l, P = 0.030), compared with once-daily injection. Plasma glucose concentration overnight was higher with twice-daily compared with once-daily glargine (mean 9.0 +/- 0.4 vs. 6.6 +/- 0.4 mmol/l, P = 0.001). CONCLUSIONS: Blood glucose concentration rises in the late afternoon in association with falling plasma insulin levels towards the end of the 24-h period after insulin glargine injection in some people with Type 1 diabetes using once-daily glargine at dinner-time plus a rapid-acting insulin analogue at meal-times. This is prevented by twice-daily injection of insulin glargine.

Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with Type 1 diabetes.

AIMS: To compare blood glucose control using insulin glargine + insulin lispro with that on NPH insulin + unmodified human insulin in adults with Type 1 diabetes managed with a multiple injection regimen. METHODS: In this 32-week, five-centre, two-way cross-over study, people with Type 1 diabetes (n = 56, baseline HbA1c 8.0 +/- 0.8%) were randomized to evening insulin glargine + mealtime insulin lispro or to NPH insulin (once- or twice-daily) + mealtime unmodified human insulin. Each 16-week period concluded with a 24-h inpatient plasma glucose profile. RESULTS: HbA1c was lower with glargine + lispro than with NPH + human insulin [7.5 vs. 8.0%, difference -0.5 (95% CI -0.7, -0.3) %, P < 0.001]. This was confirmed by an 8% lower 24-h plasma glucose area under the curve (AUC) (187 vs. 203 mmol l(-1) h(-1), P = 0.037), a 24% reduction in plasma glucose AUC > 7.0 mmol/l1 (47 vs. 62 mmol l(-1) h(-1), P = 0.017) and a 15% lower post-prandial plasma glucose AUC (75 vs. 88 mmol l(-1) h(-1), P = 0.002). There was no reduction in night-time plasma glucose AUC or increase in plasma glucose area < 3.5 mmol/l. Monthly rate of nocturnal hypoglycaemia was reduced by 44% with glargine + lispro (0.66 vs. 1.18 episodes/month, P < 0.001). CONCLUSIONS: Compared with NPH insulin + unmodified human insulin, the combination of insulin glargine with a rapid-acting insulin analogue as multiple-injection therapy for Type 1 diabetes improves overall glycaemic control as assessed by HbA1c and 24-h plasma glucose monitoring to a clinically significant degree, together with a reduction in nocturnal hypoglycaemia.

Optimal timing of injection of once-daily insulin glargine in people with Type 1 diabetes using insulin lispro at meal-times.

AIMS: To compare blood glucose control when insulin glargine is given at lunch-time, dinner-time, and bed-time in people with Type 1 diabetes using insulin lispro at meal-times. METHODS: In this 16-week, three-way, cross-over study, 23 people with Type 1 diabetes were randomized to insulin glargine injection at lunch-time (L) [mean 12.37 +/- 00.34 (+/- sd) h], dinner-time (D) (18.12 +/- 00.40 h), or bed-time (B) (22.29 +/- 00.40 h), each plus meal-time insulin lispro. Each 4-week treatment period concluded with a 24-h inpatient metabolic profile. RESULTS: Insulin doses, HbA(1c), and fructosamine concentration did not differ between treatment periods. Pre-breakfast self-monitored blood glucose (SMBG) concentration was higher with injection of glargine at lunch-time than at other times [L: 9.2 +/- 0.3 (+/- se) vs. D: 8.2 +/- 0.3 or B: 8.0 +/- 0.3 mmol/l, P = 0.016], as probably was pre-lunch SMBG (L: 8.6 +/- 0.7 vs. D: 6.4 +/- 0.7 or B: 6.4 +/- 0.8 mmol/l, P = 0.051). Pre-dinner SMBG level was higher with dinner-time glargine than other injection times (D: 9.4 +/- 0.9 vs. L: 4.9 +/- 0.9 or B: 7.4 +/- 1.1 mmol/l, P = 0.007). For 22.00 to 02.00 h, mean inpatient plasma glucose concentration was higher with injection of glargine at bed-time than other times (B: 9.1 +/- 0.6 vs. L: 7.8 +/- 0.6 or D: 6.7 +/- 0.6 mmol/l, P = 0.023). Plasma free insulin concentration was lower at the end of the afternoon with dinner-time glargine than other injection times (D: 11.5 +/- 1.4 vs. L: 20.2 +/- 1.3 or B: 16.5 +/- 1.3 mU/l, P < 0.001). Frequency of hypoglycaemia was not different, but timing of hypoglycaemia differed between treatment periods. CONCLUSIONS: Blood glucose levels rise around the time of injection of insulin glargine whether given at lunch-time, dinner-time or bed-time. Bed-time injection leads to hyperglycaemia in the early part of the night which is improved by giving insulin glargine at lunch-time or dinner-time.

The efficacy and safety of lanreotide Autogel in patients with acromegaly previously treated with octreotide LAR.

OBJECTIVE: Lanreotide Autogel is a sustained-release aqueous gel formulation supplied in a prefilled syringe, with injection volume <0.5 ml. The aim of this study was to establish the efficacy and safety of Autogel in patients with acromegaly previously treated with octreotide LAR. DESIGN: A 28-week, open, multicentre study. PATIENTS: Twelve patients with acromegaly, treated with 20 mg octreotide LAR for >4 months, with serum GH levels <10.0 mU/l. METHODS: Autogel (90 mg) was given every 28 days during weeks 0-12. At week 16 the dose was titrated based on GH levels at weeks 8 and 12. If GH levels were <2.0, 2.0-5.0, or >5.0 mU/l, Autogel was reduced to 60 mg, maintained at 90 mg, or increased to 120 mg respectively, for the next three injections. GH and IGF-I levels were reassessed at weeks 24 and 28. RESULTS: Ten patients completed the study. Five remained on 90 mg Autogel throughout the study; in two patients the dose was reduced to 60 mg from week 16; in three patients it was increased to 120 mg. Mean GH levels were: baseline, 3.0+/-1.7 mU/l; week 12, 3.5+/-1.8 mU/l; week 28, 3.3+/-1.6 mU/l (NS). Mean IGF-I levels were: baseline, 212+/-70 microg/l; week 12, 185+/-91 microg/l; week 28: 154+/-61 microg/l (P=0.027). Six patients at baseline and eight at week 28 had normalised GH and IGF-I levels. Three patients reported adverse events: musculoskeletal pain (n=2) and injection-site symptoms (n=1). CONCLUSIONS: Lanreotide Autogel is effective and well tolerated in patients with acromegaly. This study in a small group of patients with well-controlled acromegaly suggests that the majority of patients switched from 20 mg LAR to 90 mg Autogel will have equivalent or better disease control.

Insulin glargine: the first clinically useful extended-action insulin analogue.

Insulin glargine is a new extended-action insulin analogue, created by recombinant DNA modification of human insulin. Extension of the C-terminal of the B-chain with two arginine residues and the substitution of glycine for asparagine at position A-21 increases the isoelectric point, resulting in precipitation of the insulin at the injection site and a protracted absorption. Pharmacodynamic studies have demonstrated a prolonged metabolic profile without a pronounced peak and with a duration of action of 20 - 30 h. In clinical studies in people with Type 1 and Type 2 diabetes, insulin glargine has demonstrated improved pre-breakfast blood glucose control and a reduction in the frequency of hypoglycaemia, especially nocturnal hypoglycaemia, in comparison with neutral protamine hagedorn (NPH) insulin. In addition, 24h glycaemic control in Type 2 diabetes and treatment satisfaction may also be improved. However, whilst appearing achievable, insulin glargine has not yet demonstrated the ability to improve HbA(1c), though this may relate to inexperience in the use of the new compound. In order to fully exploit its metabolic advantages, it appears vital that the dose of insulin glargine should be titrated to achieve aggressive pre-breakfast blood glucose targets beyond those achievable with NPH in the absence of nocturnal hypoglycaemia. Insulin glargine appears to be a promising new addition to the insulin family and with increased experience in its use, especially in combination with rapid-acting insulin analogues, its full benefits may be realised. The use of insulin glargine with a rapid-acting insulin analogue brings us the closest we have ever been to providing the physiological insulin replacement that has long been awaited.