A comparison of insulin lispro Mix25 and human insulin 30/70 in the treatment of type 2 diabetes during Ramadan

OBJECTIVE: To compare insulin lispro Mix25 and human insulin 30/70 with regard to their effect on morning and evening postprandial glucose (PPG) control, and on average daily blood-glucose (BG), in patients with Type 2 diabetes who wish to fast during Ramadan. METHOD: Insulin lispro Mix25 and human insulin 30/70 were compared in an open-label, multicenter, randomised, crossover study involving 151 patients. Each treatment period had a duration of 14 days during which the patients self-monitored their BG before and 2 h after the main meals on any 3 days within the last 5 days of each treatment period. RESULTS: The 2 h PPG excursion following the main evening meal after sunset was significantly lower with insulin lispro Mix25 (3.4+/-2.9 mmol/l) compared with human insulin 30/70 (4.0+/-3.2 mmol/l, P=0.007). The evening pre-meal fasting BG values were also lower with insulin lispro Mix25 (7.1+/-2.2 mmol/l) versus human insulin 30/70 (7.5+/-2.6 mmol/l, P=0.034). The average daily BG concentration was 9.5+/-2.4 mmol/l during treatment with insulin lispro Mix25 versus 10.1+/-2.5 mmol/l with human insulin 30/70 given in identical doses (P=0.004). CONCLUSION: When compared with human insulin 30/70, treatment of insulin-requiring Type 2 patients with insulin lispro Mix25 during Ramadan resulted in better average daily glycaemia, and better BG control before and after the evening meal. Insulin lispro Mix25 should be considered as a therapeutic option during Ramadan.     

Prandial insulin substitution with insulin lispro or insulin lispro mid mixture vs. basal therapy with insulin glargine: a randomized controlled trial in patients with type 2 diabetes beginning insulin therapy

PURPOSE: To compare the effects of prandial insulin therapy focusing on postprandial glucose control vs. basal insulin therapy focusing on fasting glucose control in patients with type 2 diabetes. METHODS: This was an open-label, randomized, parallel, three-arm multicenter trial in patients with type 2 diabetes starting insulin treatment. Patients (n=159) were randomly assigned to 24-week treatment with 3x daily insulin lispro, 3x daily lispro mid mixture (MidMix; 50% lispro, 50% protaminated lispro), or 1x daily insulin glargine; oral antihyperglycemic agents were discontinued. Primary end point was the postprandial glucose excursion 2 h after breakfast at the end of study. Secondary outcomes included HbA1c, self-monitored blood glucose profiles, hypoglycemic episodes, body weight, and patient satisfaction. RESULTS: At the end of study, glucose excursions 2 h after breakfast were significantly lower with lispro and MidMix than with glargine (P<.001 for each vs. glargine): lispro, -0.6+/-2.0 mmol/l; MidMix, +0.8+/-2.4 mmol/l; glargine, +2.5+/-2.4 mmol/l. Fasting glucose decreases were significantly greater with glargine (-2.6+/-2.4 mmol/l) than with lispro or MidMix (-0.9+/-2.2 mmol/l; +0.9+/-1.8 mmol/l). Nevertheless, HbA1c decreased by 1.1% (lispro) and 1.2% (MidMix), vs. 0.3% with glargine. Hypoglycemic episodes were rare with 1-1.5 self-reported episodes per 100 patient-days. CONCLUSIONS: In patients with type 2 diabetes starting insulin, 3x daily prandial treatment with a rapid-acting analog focusing on postprandial glucose values enabled better control of postprandial and circadian blood glucose profiles than once-daily glargine, in spite suboptimal fasting glucose levels, which targets fasting glucose values. These results support studies suggesting that control of postprandial hyperglycemia plays a key role in achieving HbA1c targets.     

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.     

Therapy after single oral agent failure: adding a second oral agent or an insulin mixture?

AIM: to compare the glycemic response to an insulin lispro mixture (25% insulin lispro and 75% NPL) twice daily plus metformin (Mix25+M) with glibenclamide plus metformin (G+M), in patients with type 2 diabetes inadequately controlled with a single oral agent. METHODS: 597 patients treated in a randomized, open-label, 16-week parallel study. Variables evaluated: hemoglobin A1C (A1C), patient symptoms, hypoglycemia rate (episodes/patient/30 days), and incidence (% patients experiencing > or =1 episode). For a subset of patients (N=120), fasting, 1-h, and 2-h postprandial plasma glucose (FPG, 1-h ppPG, 2-h ppPG) in response to a standardized test meal (STM) and self-monitored blood glucose (BG) profiles were measured. RESULTS: improved A1C at endpoint for both groups, and A1C changes from baseline to endpoint were not significantly different between treatments (Mix25+M, -1.87+/-1.35% vs. G+M, -1.98+/-1.28%; p=0.288). Among patients completing STM; endpoint 2-h ppPG was significantly lower with Mix25+M (9.05+/-3.32 mmol/l vs. 12.31+/-3.65 mmol/l; p<0.001), as was 2-h ppPG excursion (2-h ppPGex)(0.38+/-3.23 mmol/l vs. 2.88+/-1.98 mmol/l; p<0.001). Percentage of patients achieving postprandial BG targets (<10 mmol/l) at endpoint was significantly greater with Mix25+M (80% vs. 48%; p<0.001). Although, overall hypoglycemia rates were similar, percentage of patients experiencing and rate of nocturnal hypoglycemia was less with Mix25+M (1% vs. 5%; p<0.01, and 0.01 vs. 0.08 episodes/pt/30 d; p=0.007). Patients reported less polyuria with Mix25+M (p<0.001). CONCLUSION: in patients with type 2 diabetes failing on metformin or a sulfonylurea, Mix25+M provided similar overall glycemic control, lower ppPG, reduced nocturnal hypoglycemia, and fewer hyperglycemic symptoms compared to G+M.     

Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with Type 2 diabetes.

AIMS: To compare the glycaemic control of an insulin lispro mixture (25% insulin lispro and 75% NPL) twice daily in combination with metformin to that of once-daily insulin glargine plus metformin in patients with Type 2 diabetes inadequately controlled with intermediate insulin, or insulin plus oral agent(s) combination therapy. RESEARCH DESIGN AND METHODS: Ninety-seven patients were randomized in a multicentre, open-label, 32-week crossover study. Primary variables evaluated: haemoglobin A1c (A1c), 2-h post-prandial blood glucose (BG), hypoglycaemia rate (episodes/patient/30 days), incidence (% patients experiencing > or = 1 episode) of overall and nocturnal hypoglycaemia. RESULTS: At endpoint, A1c was lower with the insulin lispro mixture plus metformin compared with glargine plus metformin (7.54% +/- 0.87% vs. 8.14% +/- 1.03%, P < 0.001). Change in A1c from baseline to endpoint was greater with the insulin lispro mixture plus metformin (-1.00% vs. -0.42%; P < 0.001). Two-hour post-prandial BG was lower after morning, midday, and evening meals (P < 0.001) during treatment with the insulin lispro mixture plus metformin. The fasting BG values were lower with glargine plus metformin (P = 0.007). Despite lower BG at 03.00 hours (P < 0.01), patients treated with the insulin lispro mixture plus metformin had a lower rate of nocturnal hypoglycaemia (0.14 +/- 0.49 vs. 0.34 +/- 0.85 episodes/patient/30 days; P = 0.002), although the overall hypoglycaemia rate was not different between treatments (0.61 +/- 1.41 vs. 0.44 +/- 1.07 episodes/patient/30 days; P = 0.477). CONCLUSION: In patients with Type 2 diabetes and inadequate glucose control while on insulin or insulin and oral agent(s) combination therapy, treatment with a twice-daily insulin lispro mixture plus metformin, which targets both post-prandial and pre-meal BG, provided clinically significant improvements in A1c, significantly reduced post-prandial BG after each meal, and reduced nocturnal hypoglycaemia as compared with once-daily glargine plus metformin, a treatment that targets fasting BG.     

Better glycaemic control with BioChaperone glargine lispro co-formulation than with insulin lispro Mix25 or separate glargine and lispro administrations after a test meal in people with type 2 diabetes

Because of its physico-chemical properties, insulin glargine is usually not mixable with rapid insulins. BioChaperone BC147 is a polyanionic amphiphilic polymer, solubilizing insulin glargine at neutral pH, and thus enabling stable glargine formulation with fast-acting insulin lispro (BioChaperone glargine lispro co-formulation [BC Combo]). We investigated pharmacokinetic (PK) endpoints and postprandial glucose (PPG) control after administration of BC Combo (75% insulin glargine, 25% insulin lispro), insulin lispro Mix25 (LMix) and separate injections of insulins glargine (75% total dose) and lispro (25% total dose [G + L]) immediately before ingestion of a mixed meal in people with type 2 diabetes mellitus (T2DM), using a randomized, double-blind, double-dummy crossover study design. Participants received individualized bolus doses (mean 0.62 U/kg) of BC Combo, LMix or G + L, together with a solid mixed meal (610 kcal, 50% carbohydrate, 30% fat, 20% protein). Insulin dosages were kept constant for each study day. Thirty-nine participants with T2DM (mean ± SD age and glycated haemoglobin 60.8 ± 7.5 years and 64 ± 6 mmol/mol, respectively) were randomized. BC Combo improved the predefined primary endpoint, early PPG control, compared to LMix (incremental area under the blood glucose concentration–time curve from 0 to 2 hours after the meal [ΔAUC_BG,0–2h] reduction of 18%; P = 0.0009) and G + L (ΔAUC_BG,0–2h reduction of 10%; P = 0.0450). The number of mealtime hypoglycaemic episodes per participant was lower with BC Combo (22 episodes in 14 participants) compared to LMix (43 episodes in 20 participants; P = 0.0028), but not significantly different from G + L (28 episodes in 19 participants; P = 0.2523). BC Combo demonstrated superior early PPG control with fewer hypoglycaemic episodes compared to LMix and superior early PPG control compared to separate G + L administrations.     

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.     

Basal-bolus insulin therapy in Type 1 diabetes: comparative study of pre-meal administration of a fixed mixture of insulin lispro (50%) and neutral protamine lispro (50%) with human soluble insulin.

AIMS: To ascertain whether pre-meal administration of 50% insulin lispro and 50% neutral protamine lispro (NPL), given as a fixed mixture (Humalog Mix50, human soluble (regular) insulin as a basal-bolus regimen in people with Type 1 diabetes. Both regimens included bedtime human isophane (NPH) insulin. METHODS: This was a multinational, multicentre, randomized, open-label, two-period crossover comparison of two insulin treatments for two 12-week periods in 109 patients with Type 1 diabetes. The protocol provided preliminary evaluations of dose requirements and recommendations for insulin dose adjustment when switching regimens on the basis of blood glucose (BG) values. Eight-point BG profiles, frequency of hypoglycaemia, HbA1c, insulin dose, time of injection, and frequency of snacking were assessed during each treatment. RESULTS: Total daily insulin dose was similar for both treatments, but the total pre-meal doses were higher (P < 0.001) and the bedtime dose of isophane was lower (P < 0.001) with Mix50. The pre-meal dose before breakfast and lunch, although statistically different (P = 0.006 and P < 0.001, respectively), was of similar magnitude, but the pre-evening meal dose was higher with Mix50 (P < 0.001). Median (interquartile range) time of insulin injection before meals was: Mix50 4.2 (25th percentile = 1.0; 75th percentile = 6.3) min, human soluble insulin 24.6 (25th percentile = 16.6; 75th percentile = 30.0) min. Pre-meal and bedtime BG concentrations did not differ between treatments. The BG 2 h after the evening meal was lower with Mix50 (8.40 +/- 2.95 mmol/l vs. 9.60 +/- 3.47 mmol/l) (P = 0.049). BG after breakfast and lunch, mean HbA1c, frequency of hypoglycaemia, frequency of snacks, and body weight were not different. CONCLUSION: The use of Mix50 in a basal-bolus regimen achieved similar control of pre-meal BG to human soluble insulin, and overall glycaemic control and hypoglycaemia risk were equivalent. This suggests that Mix50 can provide an adequate supply of insulin to control BG between meals while providing the convenience of injecting immediately before meals.     

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.     

Efficacy and safety of insulin glulisine in Japanese patients with type 1 diabetes mellitus

Aim: The rapid‐acting insulin analogue insulin glulisine (glulisine) was compared with insulin lispro (lispro) for efficacy and safety in Japanese patients with type 1 diabetes mellitus (T1DM), using insulin glargine (glargine) as basal insulin. Methods: This was an open, randomized, parallel‐group, comparative non‐inferiority study. The primary efficacy measure was change in adjusted mean haemoglobin A1c (HbA1c) from baseline to endpoint. Safety and treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) were also assessed. Patients were treated for 28 weeks with either glulisine or lispro administered 0–15 min before a meal. Doses were titrated to obtain 2‐h postprandial plasma glucose (2h‐PPG) of 7.11–9.55 mmol/l (128–172 mg/dl). All patients were concomitantly treated with glargine at bedtime, titrated to obtain a fasting (prebreakfast) plasma glucose level of 5.27–7.11 mmol/l (95–128 mg/dl). Results: Baseline mean HbA1c values were similar for the glulisine (n = 132) and lispro (n = 135) groups (7.44 and 7.50% respectively). From baseline to endpoint, adjusted mean HbA1c increased by 0.10% in the glulisine group and by 0.04% in the lispro group. Non‐inferiority of glulisine compared with lispro was shown. There were no significant differences between glulisine and lispro in adjusted mean 2h‐PPG [glulisine, 9.06 mmol/l (163 mg/dl) vs. lispro, 8.13 mmol/l (146 mg/dl); p = 0.065] and change in adjusted mean daily rapid‐acting insulin dose (glulisine, 0.26 U vs. lispro, 0.26 U; p = 0.994) at study endpoint. There was a significant difference for change in adjusted mean daily basal insulin dose from baseline to study endpoint (glulisine, –0.54 U vs. lispro, 0.26 U; p = 0.013). The most common serious adverse events were hypoglycaemia‐related events (hypoglycaemia, hypoglycaemic seizure and hypoglycaemic coma) with no difference observed between the two groups [glulisine, 6.8% (9/132) vs. lispro, 4.4% (6/135); p = 0.437]. No noteworthy differences were observed for change in insulin antibodies from baseline to endpoint. Assessment of treatment satisfaction score and perceived frequency of hyperglycaemia and hypoglycaemia by DTSQ showed no changes from baseline in either group. Conclusions: Glulisine was as effective as lispro with respect to change in HbA1c and was well tolerated when used in combination with glargine in Japanese patients with T1DM.     

A comparison of intensive mixture therapy with basal insulin therapy in insulin-naïve patients with type 2 diabetes receiving oral antidiabetes agents

Aim: In patients with type 2 diabetes, insulin therapy is commonly initiated with either a single dose of basal insulin or twice‐daily premixed (basal plus prandial) insulin despite no widely accepted recommendation. We compared the glycaemic control, as measured by a change in HbA1c, of intensive mixture therapy (IMT), a basal plus prandial regimen using insulin lispro mixture 50/50 (50% lispro and 50% NPL) before breakfast and lunch and insulin lispro mixture 25/75 (25% lispro and 75% NPL) before dinner, vs. once‐daily insulin glargine therapy, while continuing patients on oral antidiabetes medications. Methods: Following inadequate glycaemic control (HbA1c 1.2–2.0 times the upper limit of normal) and at least 2 months of two or more oral antidiabetes agent therapy, 60 insulin‐naïve patients with type 2 diabetes were randomized to one of the insulin regimens for 4 months with crossover to the alternative regimen for an additional 4 months. Glycaemic goals were preprandial blood glucose <120 mg/dl (6.7 mmol/l) and 2‐h postprandial blood glucose <180 mg/dl (10.0 mmol/l). The insulin dose was optimized by investigators without forced titration. Results: Mean prestudy (baseline) HbA1c for all patients was 9.21 ± 1.33% (±s.d.). IMT compared to glargine resulted in both a lower endpoint in HbA1c (7.08 ± 0.11% vs. 7.34 ± 0.11%; p = 0.003) and a greater change in HbA1c from pretherapy (?1.01 ± 0.10% vs. ?0.75 ± 0.10%; p = 0.0068). Forty‐four per cent of patients receiving IMT and 31% of patients receiving insulin glargine achieved HbA1c ≤ 7%. Two‐hour postprandial glucose values (for all three meals) and predinner glucose values were significantly less with IMT than with insulin glargine (p = 0.0034, 0.0001, 0.0066 and 0.0205). Overall hypoglycaemia throughout the complete treatment period was infrequent (IMT vs. Glargine: 3.98 ± 4.74 vs. 2.57 ± 3.22 episodes/patient/30 days, p = 0.0013), and no severe hypoglycaemia was observed during the study with either therapy. There was no difference in nocturnal hypoglycaemia between the two therapies. The mean insulin dose at the end of therapy was greater for IMT than for once‐daily insulin glargine (0.353 ± 0.256 vs. 0.276 ± 0.207 IU/kg, p = 0.0107). Conclusions: In combination with oral antidiabetes agents, multiple daily injections of a basal plus prandial insulin IMT regimen (using premixed insulin lispro formulations) resulted in greater improvements and a lower endpoint in HbA1c compared with a basal‐only insulin regimen. IMT also resulted in improved postprandial blood glucose control at each meal and enabled administration of a greater daily dose of insulin, which most likely contributed to these lower HbA1c measures. This greater reduction in HbA1c with IMT is accompanied by a small increased occurrence of mild hypoglycaemia but without any severe hypoglycaemia. Greater consideration should be given to initiating insulin as a basal plus prandial regimen rather than a basal‐only regimen.     

Better long-term glycaemic control with the basal insulin glargine as compared with NPH in patients with Type 1 diabetes mellitus given meal-time lispro insulin.

BACKGROUND: Glargine is a long-acting insulin analogue potentially more suitable than NPH insulin in intensive treatment of Type 1 diabetes mellitus (T1 DM), but no study has proven superiority. The aim of this study was to test superiority of glargine on long-term blood glucose (BG) as well as on responses to hypoglycaemia vs. NPH. METHODS: One hundred and twenty-one patients with T1 DM on intensive therapy on four times/day NPH and lispro insulin at each meal, were randomized to either continuation of NPH four times/day (n = 60), or once daily glargine at dinner-time (n = 61) for 1 year. Lispro insulin at meal-time was continued in both groups. In 11 patients from each group, responses to stepped hyperinsulinaemic-hypoglycaemia were measured before and after 1 year's treatment. RESULTS: Mean daily BG was lower with glargine [7.6 +/- 0.11 mmol/l (137 +/- 2 mg/dl)] vs. NPH [8.1 +/- 0.22 mmol/l (146 +/- 4 mg/dl)] (P < 0.05). HbA(1c) at 4 months did not change with NPH, but decreased with glargine (from 7.1 +/- 0.1 to 6.7 +/- 0.1%), and remained lower than NPH at 12 months (6.6 +/- 0.1%, P < 0.05 vs. NPH). Frequency of mild hypoglycaemia [self-assisted episodes, blood glucose < or = 4.0 mmol/l (72 mg/dl)] was lower with glargine vs. NPH (7.2 +/- 0.5 and 13.2 +/- 0.6 episodes/patient-month, P < 0.05). After 1 year, NPH treatment resulted in no change of responses to hypoglycaemia, whereas with glargine plasma glucose, thresholds and maximal responses of plasma adrenaline and symptoms to hypoglycaemia improved (P < 0.05). CONCLUSIONS: The simpler glargine regimen decreases the percentage of HbA(1c) and frequency of hypoglycaemia and improves responses to hypoglycaemia more than NPH. Thus, glargine appears more suitable than NPH as basal insulin for intensive treatment of T1 DM.     

The DURABLE Trial Study Design: Comparing the Safety, Efficacy, and Durability of Insulin Glargine to Insulin Lispro Mix 75/25 Added to Oral Antihyperglycemic Agents in Patients with Type 2 Diabetes

Background

While studies have compared the safety and efficacy of starter insulin regimens in type 2 diabetes, none have evaluated regimen durability (length of time a patient can maintain glycemic control) or the safety and efficacy of subsequent intensification regimens in a large, multinational cohort.

Methods

The DURABLE (Assessing the DURAbility of Basal vs Lispro Mix 75/25 Insulin Efficacy) trial will compare the ability of glargine once daily vs lispro mix 75/25 (75% insulin lispro protamine suspension, 25% lispro) twice daily added to oral antihyperglycemic agents to achieve and maintain hemoglobin A1c (HbA1c) goals. This randomized, open label, parallel study will enroll over 2000 insulin-naïve patients with type 2 diabetes from 11 countries, ages 30 to 80, with HbA1c >7.0% on at least two oral antihyperglycemic agents. At the completion of the 6-month initiation phase, safety and efficacy of the two regimens will be compared. Patients who achieve an HbA1c ≤7.0% at 6 months will continue into the 24-month maintenance phase to evaluate durability.In a substudy, patients not achieving HbA1c ≤7.0% at 6 months may be randomized to one of two intensification comparisons: patients previously on glargine will receive lispro mix 75/25 twice daily or basal/bolus therapy (glargine + thrice-daily mealtime lispro) and patients previously on lispro mix 75/25 will receive lispro mix 50/50 (50% insulin lispro protamine suspension, 50% lispro) thrice daily or basal/bolus therapy.

Results

Upon completion, this trial will provide new information about starter insulin durability, defined as the length of time patients can maintain HbA1c control (HbA1c ≤7.0%, or >7.0% but with an increase of <0.4% from the most recent HbA1c ≤7.0%). Additionally, the study will provide comparative data on HbA1c, blood glucose profiles, 1,5-anhydroglucitol, hypoglycemic episodes, weight change, and insulin dose for starter insulin regimens following 6 and 24 months of treatment, as well as intensified insulin via the 6-month substudy.

Conclusion

This trial aims to broaden clinicians'' understanding of the ability of starter insulin and insulin intensification regimens to achieve and maintain glycemic control in patients with type 2 diabetes.     

A randomized trial of adding insulin glargine vs. avoidance of insulin in people with Type 2 diabetes on either no oral glucose-lowering agents or submaximal doses of metformin and/or sulphonylureas. The Canadian INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) Study.

AIMS: Insulin is generally withheld until people with Type 2 diabetes are unresponsive to other therapies. However, its potential advantages suggest that it could be added earlier to achieve glycaemic goals; this possibility was tested in a clinical trial. METHODS: Consenting adults aged 18-80 years with Type 2 diabetes for at least 6 months, HbA1c of 7.5-11%, and on 0, 1 or 2 oral agents, were randomized to one of two therapeutic approaches for 24 weeks: evening insulin glargine plus self-titration by 1 unit/day if the fasting plasma glucose (FPG) was > 5.5 mmol/l; or conventional therapy with physician adjustment of oral glucose-lowering agents if capillary FPG levels were > 5.5 mmol/l. The primary outcome was the first achievement of two consecutive HbA1c levels 相似文献   

谷赖胰岛素或赖脯胰岛素联合甘精胰岛素对糖尿病的有效性及安全性

目的 比较谷赖胰岛素和赖脯胰岛素联合甘精胰岛素对糖尿病的有效性、安全性.方法 本研究为多中心、随机、对照研究,包括4周的导人期和12周的治疗期.2007年2月至2008年6月共人选糖尿病患者484例（1型34例,2型450例）,患者糖化血红蛋白（HbA1c）为6.5％～11.0％,之前已接受连续3个月的胰岛素治疗.按3：1随机给予谷赖胰岛素（363例）或赖脯胰岛素（121例）每日3次联合甘精胰岛素每日1次治疗,比较两组治疗12周后HbA1c、血糖变化及低血糖发生情况和治疗满意度.组间数据比较采用ANOVA方法.结果 治疗12周后,谷赖胰岛素和赖脯胰岛素组HbA1c分别由8.7％±1.2％降至7.9％±1.0％及由8.8％±1.2％降至7.9％±1.0％（组内治疗前后比较,t=- 12.55、-8.88,均P＜0.05）.两组空腹血糖（FPG）分别由（8.6±2.8）mmol/L降至（7.7±2.5）mmol/L及由（8.6±2.5） mmol/L降至（7.8±2.2）mmol/L（组内治疗前后比较,t=-6.55、-2.98,均P＜0.05）.谷赖胰岛素组标准餐后2h血糖（2 h PPG）由（10.6±3.8） mmol/L降至（ 10.2±3.7） mmol/L（t=-2.07,P＜0.05）;赖脯胰岛素组2 h PPG治疗前后差异无统计学意义[由（ 10.9±4.0）mmol/L降至（10.4±3.5） mmol/L,t=-1.37,P＞0.05].治疗12周期间,谷赖胰岛素组和赖脯胰岛素组低血糖事件发生率分别为33.9％ （123/363）和34.7％ （42/121）.治疗前后谷赖胰岛素组和赖脯胰岛素组治疗满意度总评分分别由29±5升至31±5及由29±5升至31±4（组内治疗前后比较,t =6.81、4.21,均P＜0.05）.结论 谷赖胰岛素和赖脯胰岛素联合甘精胰岛素治疗糖尿病的临床疗效、安全性及治疗满意度相似.     

Efficacy of conversion from bedtime NPH insulin to morning insulin glargine in type 2 diabetic patients on basal-prandial insulin therapy

In normal subjects, approximately half of the daily insulin requirement constitutes basal insulin. We investigated whether increasing the dose of insulin glargine up to half of the total insulin requirement could lead to better glycemic control in type 2 diabetic patients who were treated on basal-prandial insulin therapy. A total of 62 patients with type 2 diabetes on mealtime rapid-acting insulin analogue and bedtime NPH were randomized to either continuation of bedtime NPH (n=31) or morning glargine (n=31) for 6 months while continuing the aspart/lispro at each meal. The two groups were matched for age, sex, diabetes duration, BMI, HbA(1C), endogenous insulin secretion, and proportion of numbers using aspart/lispro and using oral hypoglycemic agents. The dose of insulin glargine was increased by 2-4 units to meet the target fasting blood glucose, whereas the dose of NPH was principally unchanged as a control group. Mean HbA(1C) at baseline was similar between patients with glargine and NPH (7.2% versus 6.9%). The percentage of glargine dose increased significantly (31% at baseline to 48% at 6 months) without any significant changes in total insulin dose. Mean HbA(1C) at 3 months was 6.6% with glargine and 7.0% with NPH (P<0.0001, adjusted mean change between-treatment difference 0.6% [95% CI 0.3-0.9]), and the values at 6 months were 6.6% and 6.9%, respectively (P=0.007). Frequency of hypoglycemia did not differ between the groups. Increasing the dose of glargine without changing the total daily insulin dose resulted in significantly better glycemic control in type 2 diabetic patients on basal-prandial insulin therapy. Conversion from bedtime NPH to morning glargine appears efficacious with no increase in frequency of hypoglycemia.     

A morning dose of insulin glargine prevents nocturnal ketosis after postprandial interruption of continuous subcutaneous insulin infusion with insulin lispro

AIM: The aim of this crossover trial was to evaluate the potential of partial substitution of basal insulin with glargine, administered once daily in the morning, to protect against nocturnal ketosis after postprandial interruption of continuous subcutaneous insulin infusion (CSII). METHODS: Seven patients with type 1 diabetes received 4 weeks of treatment with insulin lispro, administered by CSII, and 4 weeks of treatment with CSII and a partial basal replacement dose of insulin glargine administered in the morning. On day 28 of each treatment phase, patients were admitted to the research unit where dinner was served and their usual dinner insulin bolus dose given, after which CSII was discontinued at 7 pm. Plasma (p) beta-hydroxybutyrate and p glucose were measured every hour for 12 h thereafter. RESULTS: Plasma beta-hydroxybutyrate at 7 pm was 0.16+/-0.05 and 0.13+/-0.07 mmol/l with and without glargine, respectively, and increased to 0.17+/-0.10 and 0.60+/-0.3 mmol/l within 6 h (P=0.02). Plasma glucose increased without glargine, from 8.6+/-2.9 to 21.1+/-3.0 mmol/l (P=0.003), but did not rise significantly following glargine (13.6+/-4.7 vs. 12.6+/-5.6 mmol/l; P=0.65). CONCLUSIONS: Partial replacement with a morning dose of insulin glargine protects against the development of ketosis for as much as 12 h after postprandial interruption of CSII. This treatment strategy could, therefore, be useful for patients who are prone to ketosis but, for other reasons, are deemed suitable for CSII.     

Efficacy of Humalog injections before an afternoon meal and their acceptance by children and adolescents with type 1 diabetes.

AIMS: To evaluate the acceptability and efficacy of an injection of insulin lispro, before an afternoon meal. METHODS: The subjects, 43 patients with Type 1 diabetes, 16 boys and 27 girls, aged 12.4 +/- 2.4 years, were randomly assigned to the treatment (n = 20) or the untreated control group (n = 23). The treatment was an injection of insulin lispro immediately before the afternoon meal. The control group had no injection. The treatment and the control group consumed identical types of meals for 2 months. The mean before-dinner blood glucose was measured during the last 2 weeks of the study. RESULTS: Injection of insulin lispro resulted in a significant reduction in the before-dinner blood glucose compared with the untreated control group (10.4 +/- 3.8 mmol/l vs. 14.7 +/- 3.9 mmol/l, respectively). The number of days on which the blood glucose was > 10 mmol/l was reduced by half in the insulin lispro group. The difference in HbA1c between baseline and endpoint differed slightly but significantly between the two groups, in boys. Treated patients ate the meal less frequently (11.4 +/- 3.0 times per 15 days) than the control patients (14.4 +/- 0.6 times per 15 days) and injected themselves with insulin 8.9 +/- 3.6 times per 15 days. The HbA1c increased significantly with the number of meals taken without injection. There was no statistically significant difference in the frequency of hypoglycaemia or changes in weight between the two groups. CONCLUSIONS: We conclude that an injection of insulin lispro before the afternoon meal can effectively lower the before-dinner blood glucose, and in boys also lowers the HbA1c. Patients were satisfied with the lower blood glucose before dinner, and did not find the insulin lispro injection difficult. However, compliance with the protocol procedures decreased during a subsequent 6-month period.     

A comparison of mealtime insulin aspart and human insulin in combination with metformin in type 2 diabetes patients

This randomized, open-label, cross-over study compares the efficacy of mealtime rapid-acting analog insulin aspart with human insulin, in combination with metformin. A total of 30 patients with type 2 diabetes, inadequately controlled (HbA(1c)>7.5%) with oral hypoglycemic agents (OHAs), were assigned to human insulin 30 min before meals or aspart immediately before meals, both with metformin 500 mg t.i.d. for 90 days. Patients then switched to the alternate insulin. At 90 and 180 days, blood glucose and lipids were measured at baseline and every 30 min after test meals, for 3h. HbA(1c) and hypoglycemic events were also assessed. After 3 months, HbA(1c) was significantly reduced with aspart, but not human insulin (-0.4+/-0.7% versus +0.1+/-0.7%, p<0.05). During meal tests, blood glucose area under the curve (AUC) was significantly lower with aspart than human insulin (1240+/-476 min/mmol/l versus 1588+/-766 min/mmol/l, p<0.01). AUCs for lipids were similar for both treatments. Neither group experienced serious hypoglycemic events. These results encourage treatment with mealtime insulin aspart plus metformin, in type 2 diabetes patients with postprandial hyperglycemia inadequately controlled by OHAs alone.     

Insulin lispro (Lys(B28), Pro(B29) in the treatment of diabetes during the fasting month of Ramadan. Ramadan Study Group.

AIMS: To compare insulin lispro with soluble human insulin in patients with Type 2 diabetes mellitus fasting during Ramadan, with respect to the rate of hypoglycaemic episodes and postprandial blood glucose values after the main meal after sunset. METHODS: The insulins were compared in an open-label, randomized, cross-over study of 70 outpatients. Hypoglycaemic episodes were recorded by the patients in a self-monitoring diary. Fasting, 1-h and 2-h postprandial blood glucose values were recorded by the patient on three consecutive days at the end of each treatment period. RESULTS: The fasting blood glucose values before sunrise (P>0.4) and after sunset (P>0.6) were similar and did not differ significantly between both treatment groups. The rise in blood glucose after the main meal after sunset was 3.0+/-0.4 mmol/l after 1 h in the insulin lispro treatment group compared to 4.3+/-0.4 mmol/l in the soluble insulin treatment group (P<0.01), and 2.6+/-0.4 mmol/l after 2h with insulin lispro compared to 4.0+/-0.5 mmol/l with soluble insulin (P<0.008). Mean hypoglycaemic episodes per patient over 14 days were 1.3+/-0.1 vs. 2.6+/-0.2, P<0.002, respectively, for insulin lispro and soluble insulin. Most hypoglycaemic episodes occurred during the time period from 6 h after the before sunrise meal until breaking the fast after sunset. CONCLUSIONS: The significantly lower rate of hypoglycaemic episodes combined with better control of postprandial blood glucose suggest insulin lispro may be more suitable prandial insulin for patients treated with Type 2 diabetes who fast during Ramadan.