Insulin Lispro Mixture Research Articles

Association between mild and severe hypoglycemia in people with type 2 diabetes initiating insulin

AimsPrimary objective: Identify risk factors associated with severe hypoglycemia (SH) and investigate the association between mild hypoglycemia and SH in people with type 2 diabetes starting insulin. Secondary objectives: Investigate the association of demographics and clinical factors with SH incidence. MethodsIntegrated trial database data were obtained for 3 randomized controlled trials that included insulin-naïve people with type 2 diabetes initiating basal (insulin glargine) versus biphasic (insulin lispro mixture) insulin. Standard definitions were used for SH; mild hypoglycemia was defined as all non-SH. Cox regression identified risk factors associated with SH and the correlation between SH and mild hypoglycemia. ResultsData were pooled (N=2931). During 24–48weeks' treatment, 2127 (72.6%) participants experienced ≥1 mild hypoglycemic event but no SH (mean mild hypoglycemia rate=2.33/month). 56 participants (1.9%) experienced ≥1 SH event plus mild hypoglycemia (mean mild hypoglycemia rate=3.95/month); 748 participants (25.5%) had no hypoglycemia. Among factors tested, only mild hypoglycemia rate/month was associated with SH. SH risk was higher (HR=4.24; 95%CI=2.57–6.99;p<0.0001) for participants experiencing multiple mild hypoglycemic events/month compared with those experiencing ≤1 mild hypoglycemic event/month. ConclusionsMild hypoglycemia may predict the first SH event, which is important because SH is a strong and consistent risk factor for morbidity/mortality.

A review of insulin lispro for the treatment of patients with type 2 diabetes mellitus

A critical aspect of the treatment of most patients with type 2 diabetes mellitus (T2DM) is the initiation (and subsequent intensification) of insulin therapy when lifestyle interventions and oral anti-hyperglycaemic drugs fail to maintain or improve glycaemic control. There are several insulin treatment options available, including basal insulin, basal-bolus insulin and premixed insulin. Each of these options has advantages and disadvantages. The insulin lispro premixed insulin analogues, mix 25 (25% insulin lisproand 75% insulin lispro protamine suspension) and mix 50 (50% insulin lispro and 50% insulin lispro protamine suspension), which include intermediate- and rapid-acting components, were recently added to Russia’s national drug reimbursement program, increasing the treatment options for patients with T2DM. The aim of this review is to provide Russian physicians with current information on the efficacy and safety of insulin lispro, with a focus on insulin lispro mixtures, for the treatment of T2DM.

The Risk of Severe Hypoglycemia in Patients with Type 2 Diabetes Mellitus Starting Insulin Therapy with Premixed Insulin Analogues Taken Twice Daily: An Observational Study in Turkish Patients

Abs tract Purpose: To assess the risk of severe hypoglycemia in Turkish patients with type 2 diabetes mellitus (T2DM) starting insulin therapy with premixed insulin analogues alone or in combination with oral antihyperglycemic medications. Material and Method: Data from a subset of Turkish patients who participated in a 1-year, multinational, multicenter, prospective observational study were evaluated. Insulin treatment was initiated using commonly prescribed premixed regimens: insulin lispro mixture 25/75 (25% insulin lispro, 75% insulin lispro protamine suspension) or biphasic insulin aspart 30/70 (30% insulin aspart, 70% insulin aspart protamine suspension) twice daily. Results: Of the 154 patients treated, 61 (39.6%) were male with a mean age of 56 years and a T2DM duration of 8.9 years. Twelve patients (7.8%) experienced ≥1 episode of severe hypoglycemia, but all recovered. The severe hypoglycemic rate was 0.14 episodes/patient-year. The mean glycated hemoglobin decreased by 2.7% (10.4% to 7.8%) and fasting plasma glucose by 115.9 mg/dL (265.3 mg/dL to 157.6 mg/dL) (p<0.0001). Self-monitored blood glucose (2-hour post morning meal) decreased by 163.3 mg/dL (327.0 mg/dL to 216.2 mg/dL; p<0.0001). Self-monitored blood glucose level was low, particularly at the 2-hour post evening meal. Body mass index increased by 1.4 kg/m, and total daily insulin dose by 4.2 IU. Discussion: In Turkish patients with T2DM, initiation of premixed insulin analogues during routine clinical care significantly improves glycemic control during the first year of treatment, but comes with a risk for severe hypoglycemia. Improvements in physician and patient education within the Turkish population regarding hypoglycemia management may be of benefit. Turk Jem 2013; 17: 83-8

The relationship between self‐monitored blood glucose values and glycated haemoglobin in insulin‐treated patients with Type 2 diabetes

Self-monitoring of blood glucose (SMBG) is an important self-management tool for insulin-treated patients with Type 2 diabetes mellitus (T2DM). Its value in estimating glycaemic control in insulin-treated T2DM patients remains unclear. The relationship between glycated haemoglobin (HbA(1c)) and SMBG measures in T2DM patients treated with premixed insulin lispro mixtures or basal insulin glargine was examined. HbA(1c) and plasma equivalent glucose (PGe) data derived from SMBG profiles were pooled from five randomized clinical trials of patients with T2DM on one or more oral glucose-lowering medication +/- 0-2 insulin injections per day switching to insulin lispro mixtures (N = 317) or glargine (N = 306). Patients generated seven-point SMBG profiles three times in a 2-week period prior to each HbA(1c) measurement. Pearson's correlation coefficients (r) were calculated for PGe values and HbA(1c). Receiver-operating characteristic (ROC) curves determined the ability of sets of PGe to estimate HbA(1c) (< or > 7.0%). Mean +/- standard deviation age was 57.5 +/- 9.5 years, body mass index 31.3 +/- 5.6 kg/m(2), 52.5% were male and HbA(1c) overall was 7.4 +/- 1.0% at end-point. Among individual SMBG measures, r for HbA(1c) ranged from 0.34 to 0.49. For means of two or more PGe measures, r for HbA(1c) ranged from 0.51 to 0.59. Correlations were similar for either regimen. ROC curves were consistent with the correlation data. These data provide patients and clinicians information on the relationship between HbA(1c) and SMBG measurements in patients with T2DM, and support the value of frequent blood glucose measurements for assessing overall glycaemic control.

Pre-Mixed Rapid-Acting Insulin 50/50 Analogue Twice Daily is Useful Not Only for Controlling Post-Prandial Blood Glucose, but Also for Stabilizing the Diurnal Variation of Blood Glucose Levels: Switching from Pre-Mixed Insulin 70/30 or 75/25 to Pre-Mixed Insulin 50/50

This study assessed the clinical effects of switching from twice-daily rapid-acting insulin 70/30 or 75/25 to twice-daily rapid-acting insulin lispro mixture 50/50 (Mix 50/50) in order to stabilize the diurnal variation of blood glucose levels in patients who showed poor control of blood glucose levels on their original medication. The patients were hospitalized for the switch. The initial dose (units of insulin) of Mix 50/50 that patients were switched to was the same as that of the insulin preparations that they were receiving previously. Mix 50/50 significantly suppressed blood glucose elevation from the time before breakfast to the period between breakfast and lunch and also from the time before supper to the period between supper and bedtime, thereby stabilizing the diurnal variation of blood glucose levels. None of the patients experienced any episodes of hypoglycaemia. In conclusion, switching to twice-daily Mix 50/50 insulin injections controlled post-prandial blood glucose levels and stabilized diurnal blood glucose variations in patients with type 2 diabetes mellitus who had poor glucose control on insulin 70/30 or 75/25.

Continuous glucose monitoring with Humalog Mix 25 versus Humalog Mix 50, twice daily: A comparative pilot study -Results from the Jikei-EValuation of insulin Lispro mixture on pharmacodynamics and glycemic VariancE (J-EVOLVE) study

ObjectiveTo evaluate glycemic variability associated with two different premixed insulin analogue formulations when used in a twice-daily regimen.Patients and MethodsSubjects comprised type 2 diabetic patients aged 20-79 years, treated with twice daily premixed insulin or insulin analogue formulations. All subjects were hospitalized for 6 days and randomized to receive either Humalog Mix 25 (Mix 25) or Humalog Mix 50 (Mix 50). They were then crossed over to the other arm between day 3 and day 4 of the study. Continuous glucose monitoring (CGM) was performed on all subjects to examine the differences in glycemic variability.ResultsEleven type 2 diabetic patients were enrolled. No significant difference was found in 24-hour mean glucose values and their SDs, pre-meal glucose values, increases from pre-meal to peak glucose values, or time to peak glucose levels between either group. However, the mean glucose values observed during 0-8 hrs were significantly lower with Mix 25 compared to Mix 50 (128 vs. 147 mg/dL; p = 0.024).ConclusionsThe twice-daily Mix 25 regimen provided superior overnight glycemic control compared to the Mix 50 regimen in Japanese patients with type 2 diabetes. However, both twice-daily regimens with either Mix 25 or Mix 50 provided inadequate post-lunch glycemic control.Trial RegistrationCurrent Controlled Trials UMIN000001327

The Relationship between Self-Monitored Blood Glucose Values and Glycated haemoglobin in Insulin-treated Patients with Type 2 Diabetes

Diabet. Med. 27, 589–592 (2010) Abstract Aims Self-monitoring of blood glucose (SMBG) is an important self-management tool for insulin-treated patients with Type 2 diabetes mellitus (T2DM). Its value in estimating glycaemic control in insulin-treated T2DM patients remains unclear. The relationship between glycated haemoglobin (HbA1c) and SMBG measures in T2DM patients treated with premixed insulin lispro mixtures or basal insulin glargine was examined. Methods HbA1c and plasma equivalent glucose (PGe) data derived from SMBG profiles were pooled from five randomized clinical trials of patients with T2DM on one or more oral glucose-lowering medication ± 0–2 insulin injections per day switching to insulin lispro mixtures (N = 317) or glargine (N = 306). Patients generated seven-point SMBG profiles three times in a 2-week period prior to each HbA1c measurement. Pearson’s correlation coefficients (r) were calculated for PGe values and HbA1c. Receiver–operating characteristic (ROC) curves determined the ability of sets of PGe to estimate HbA1c (< or > 7.0%). Results Mean ± standard deviation age was 57.5 ± 9.5 years, body mass index 31.3 ± 5.6 kg/m2, 52.5% were male and HbA1c overall was 7.4 ± 1.0% at end-point. Among individual SMBG measures, r for HbA1c ranged from 0.34 to 0.49. For means of two or more PGe measures, r for HbA1c ranged from 0.51 to 0.59. Correlations were similar for either regimen. ROC curves were consistent with the correlation data. Conclusions These data provide patients and clinicians information on the relationship between HbA1c and SMBG measurements in patients with T2DM, and support the value of frequent blood glucose measurements for assessing overall glycaemic control.

Impact of Prandial Plus Basal vs Basal Insulin on Glycemic Variability in Type 2 Diabetic Patients

To determine whether metformin-treated patients with type 2 diabetes given an analogue mixture of basal and rapid-acting insulins (insulin lispro protamine suspension plus insulin lispro) would have less glycemic variability than patients given basal insulin glargine. Two post hoc analyses were used to compare 7-point blood glucose profiles from 3 published studies comparing basal plus prandial premixed insulin lispro mixtures with insulin glargine in metformin-treated patients with type 2 diabetes. Glycemic variability indices used included standard deviation of mean daily blood glucose, coefficient of variation, M-value, mean amplitude of glycemic excursion, and J-index. Patients on the twice-daily insulin lispro mix 75/25 (75% insulin lispro protamine suspension/25% insulin lispro) plus metformin regimen had significantly lower standard deviation, M-value, and J-index than patients on the insulin glargine plus metformin regimen, but not lower coefficient of variation or mean amplitude of glycemic excursion. Patients on the 3 times daily insulin lispro mix 50/50 (50% insulin lispro protamine suspension/50% insulin insulin lispro) plus metformin regimen had significantly lower values for all 5 indices than patients on the insulin glargine plus metformin regimen. Use of basal plus prandial insulin lispro mixtures at 2 or 3 meals was associated with lower glycemic variability in metformin-treated patients with type 2 diabetes.

Relationship between HbA1c and hypoglycaemia in patients with type 2 diabetes treated with different insulin regimens in combination with metformin

To examine the relationship between glycaemic control and hypoglycaemia in patients with type 2 diabetes treated with metformin (Met) and either insulin lispro mixtures, given twice or thrice daily (LM + Met), or insulin glargine, given once daily (G + Met). Data from three randomized clinical trials were pooled to compare effects of LM + Met with G + Met. The LM + Met group achieved lower mean HbA(1c) (mean+/-SE, 7.2+/-0.1 vs. 7.7+/-0.1%, p<0.0001) and all meals combined post-prandial blood glucose (BG) (8.9+/-0.1 vs. 10.2+/-0.1 mmol/L, p<0.0001) compared with the G + Met group, but had higher fasting blood glucose (8.1+/-0.1 vs. 6.8+/-0.1 mmol/L, p<0.0001) and insulin requirement (0.7+/-0.01 vs. 0.6+/-0.01 U/kg, p<0.0001). Over the entire study period, daytime hypoglycaemia was higher for the LM + Met group (10.3 vs. 3.5 episodes/patient/year, p<0.0001) than for the G + Met group; however, nocturnal hypoglycaemia was lower (3.4 vs. 6.6 episodes/patient/year, p=0.003). At endpoint, daytime hypoglycaemia was higher for the LM + Met group (6.2 vs. 1.4 episodes/patient/year, p<0.0001); however, nocturnal hypoglycaemia was similar in both groups (1.9 vs. 3.0 episodes/patient/year). An inverse relationship was observed between all confirmed hypoglycaemia and HbA(1c) at endpoint; for every 1% reduction in HbA(1c), the increase (in slope) was 1.4 episodes/patient/year (p=0.04). Patients with confirmed hypoglycaemia had lower HbA(1c) than patients without hypoglycaemia (7.39 vs. 7.64%, respectively; decrement=0.26%, p=0.026). These studies demonstrated an inverse relationship between HbA(1c) and 24-h and daytime hypoglycaemia. Lispro insulin mixtures provided lower HbA(1c) and post-prandial blood glucose values than glargine, but caused more daytime hypoglycaemia. Frequency of nocturnal hypoglycaemia was similar and severe hypoglycaemia was rare with both insulin regimens.

Effects of Blood Glucose Rate of Changes on Perceived Mood and Cognitive Symptoms in Insulin-Treated Type 2 Diabetes

Studies indicate that diabetes affects mood, cognitive function, and motor performance (1–5). As cognitive dysfunction and depressive mood symptoms have been reported with hyperglycemia (5–7), we hypothesized that the impact of insulin on blood glucose parameters would affect mood and cognitive symptoms. Consistent with our past post hoc findings (7), we specifically hypothesized that rapid pre- to postmeal blood glucose rate of change (BGRATE) correlates with negative mood and cognitive postmeal symptoms but not with energy or positive mood. We report the results of correlation analyses of BGRATE with symptoms from a pilot investigation designed to evaluate whether improvements in glycemic control seen with basal plus prandial insulin analog regimens compared with basal insulin analog in patients with type 2 diabetes (8–10) would lead to measurable mood and cognitive differences. A single-center, open-label, crossover, randomized, controlled clinical trial enrolled 60 adults with type 2 diabetes, A1C 7–10%, and prestudy use of metformin (with or without oral antihyperglycemic medications or once daily insulin). Pregnant or breast-feeding women and patients with a previous diagnosis of depression or treated with centrally acting medications (e.g., antidepressants or anxiolytics) were excluded. Patients were randomly assigned to treatment with Humalog Mix 75/25 (insulin lispro mixture [75% lispro protamine suspension/25% …

A single-center, randomized, double-blind, three-way crossover study examining postchallenge glucose responses to human insulin 70/30 and insulin lispro fixed mixtures 75/25 and 50/50 in patients with type 2 diabetes mellitus

Objective: The aim of this study was to test the ability of human insulin 70130, insulin lispro mixture 75/25 (75% neutral protamine lispro [NPL], 25% insulin lispro), and insulin lispro mixture 50150 (50% NPL, 50% insulin lispro) to control postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus (DM). Methods: This single-center, randomized, double-blind, 3-way crossover study was conducted at the Diabetes and Glandular Disease Research Center, San Antonio, Texas. We measured serum glucose responses after a standardized breakfast test meal (500 kcal; 50% carbohydrate, 34% fat, 16% protein) in patients with type 2 DM receiving a single preprandial dose of human insulin 70/30, insulin lispro 75/25, or insulin lispro 50/50 by SC injection. All patients previously used insulin for at least 1 month prior to the study. The glucose responses were compared with those of healthy, untreated subjects administered the identical meal. Results: A total of 33 patients were enrolled (23 with type 2 DM and 10 healthy controls). The baseline characteristics of the patients were as follows: sex ratio (M:F), 17:6; mean (SD) age, 61.3 (10.0) years; mean (SD) body weight, 98.5 (13.2) kg; mean (SD) body mass index, 33.0 (3.8) kg/m 2; mean (SD) glycosylated hemoglobin, 8.1% (1.6%); mean (SD) fasting serum glucose (FSG), 158.7 (27.6) mgldL; and 56.5% white, 8.7% black, and 34.8% Hispanic. The mean (SD) doses (U/d) of the fixed-mixture preparations were similar: human insulin 70/30, 44.1 (18.2); insulin lispro 75/25, 44.1 (18.2); and insulin lispro 50/50, 43.8 (17.8). FSG levels obtained before the test meal were not significantly different between treatments. Compared with those in healthy subjects, incremental glucose AUC values for the 4 hours after the meal (AUCglucose 0–4) for patients with type 2 DM were 6.4-fold higher with human insulin 70/30, 4.6-fold higher with insulin lispro 75/25, and 3.0-fold higher with insulin lispro 50/50. Each insulin regimen produced AUC glucose 0–4 and 2-hour PPG values significantly different from all other regimens (all, P < 0.05). Mean (SD) 2-hour PPG values (mg/dL) were lower with mixtures containing insulin lispro than with human insulin 70/30 and decreased as the proportion of insulin lispro within the fixed mixtures increased: human insulin 70/30, 212.6 (47.0); insulin lispro 75/25, 198.0 (67.5); and insulin lispro 50/50, 158.8 (52.3). Conclusions: In this small study in patients with type 2 DM and healthy controls, preprandial administration of a fixed mixture containing rapid-acting or regular insulin and intermediate-acting components was associated with attenuation of the rise in PPG in patients with type 2 DM administered a test meal. Mixtures containing insulin lispro were associated with greater decreases in PPG concentrations compared with human insulin 70/30. Furthermore, greater amounts of rapid-acting insulin contained within the mixture were associated with better PPG control.

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

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. 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. 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 < or = 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). 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.

Comparison of insulin lispro mixture 25/75 with insulin glargine during a 24‐h standardized test‐meal period in patients with Type 2 diabetes

To compare insulin lispro mixture (25% insulin lispro and 75% NPL; Mix 25/75) twice-daily plus oral glucose-lowering medications (metformin and/or sulphonylurea) with once-daily insulin glargine plus oral agents with respect to postprandial glycaemic control and other glucose and lipid parameters in patients with Type 2 diabetes inadequately controlled with insulin and/or oral glucose-lowering agents. This was a randomized, open-label, crossover study. Prestudy oral agents were continued and patients not already on oral agents were treated with metformin. Mix 25/75 and insulin glargine were adjusted over 3 months to attain premeal plasma glucose (PG) < 6.0 mmol/l and were then given during a 24-h in-patient test meal period with frequent PG, serum triglyceride (TG) and free fatty acid (FFA) measurements. Twenty patients (10 F/10 M; mean +/-sd age 54.0 +/- 10.7 years, body mass index 37.0 +/- 8.6 kg/m2, HbA1c 8.4 +/- 1.01%) participated. Mean doses were 23 U before the morning and 37 U before the evening meal for Mix 25/75 and 44 U for insulin glargine. The combined 2-h morning and evening meal postprandial plasma glucose (PPG) was not different between groups (9.2 +/- 2.04 vs. 9.9 +/- 1.66 mmol/l, P = 0.161). Mix 25/75 was associated with a lower mean 2-h PPG for all meals combined (9.0 +/- 1.88 vs. 9.9 +/- 1.80 mmol/l, P < 0.05) and lower mean 24-h PG (6.7 +/- 1.00 vs. 7.5 +/- 1.32 mmol/l, P < 0.01). Eight patients experienced mild hypoglycaemia (PG < 3.5 mmol/l) with Mix 25/75 and 3 with insulin glargine. The endpoint HbA1c was lower with Mix 25/75 (6.9 +/- 0.52% vs. 7.3 +/- 0.81%, P < 0.05). In a 24-h test-meal setting in 20 patients, Mix 25/75 insulin plus oral glucose-lowering agents was associated with lower mean PPG and 24-h PG, more mild hypoglycaemia and similar TG, FFA and fasting PG concentrations. HbA1c was lower with Mix 75/25 plus oral agents, although it may not have reached steady state due to ongoing dose adjustment.

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

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. 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. 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). 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.

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 ≥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 ppPG ex)(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.

Clinical pharmacokinetics and pharmacodynamics of insulin lispro mixtures.

Rapid-acting insulin analogues such as insulin lispro and insulin aspart produce a more physiological profile of insulin activity than does conventional regular human insulin because of their unique pharmacokinetics. These insulin analogues are absorbed rapidly from the subcutaneous injection site, resulting in a better matching of the appearance of insulin in the circulation with nutrient absorption from the intestine. In addition, they are shorter-acting than regular human insulin, thus decreasing the risk of late postprandial hypoglycaemia due to inappropriate hyperinsulinaemia. Because self-prepared mixtures of these rapid-acting insulin analogues with longer-acting insulins such as neutral protamine Hagedorn (NPH) insulin have been shown to be clinically useful, and because manufactured fixed-ratio mixtures of regular human insulin and NPH already represent a large proportion of insulin use, manufactured fixed-ratio mixtures of insulin lispro and a sustained-release insulin known as NPL have been developed (insulin lispro mixtures). NPL is a protamine-based insulin lispro formulation with pharmacokinetics and glucodynamics comparable to those of human NPH insulin. NPL was developed for use within insulin lispro mixtures because an exchange between soluble insulin lispro and protamine-bound human insulin within human NPH precludes prolonged storage of mixtures of these insulins. An insulin lispro mixture consisting of 25% insulin lispro and 75% NPL is now commercially available. This preparation is intended primarily as an alternative to human insulin 30/70, which is commonly used within a twice-daily injection regimen. A mixture containing 50% insulin lispro and 50% NPL is also available. The rapid activity of insulin lispro is maintained within insulin lispro mixtures, allowing injection just prior to a meal, a convenience that is not available with commercial mixtures of regular human insulin and human NPH insulin, which should be injected 30 to 45 minutes prior to meals. As with insulin lispro itself, the rapid action of insulin lispro within the insulin lispro mixtures also results in a smaller increase in blood glucose levels after meals than with comparable human insulin mixtures. In addition, data from two studies have shown that when Mix25 is injected prior to the evening meal the incidence of nocturnal hypoglycaemia is decreased in comparison with the same dose of human insulin 30/70. The combined rapid and prolonged insulin activity provided by insulin lispro mixtures has been defined both in healthy subjects without diabetes and in patients with diabetes.

Use of insulin lispro (Humalog®) mixtures in the elderly provides comparable safety to that of human insulin mixtures

Use of insulin lispro (Humalog®) mixtures in the elderly provides comparable safety to that of human insulin mixtures

Improved postprandial blood glucose control and reduced nocturnal hypoglycemia during treatment with two novel insulin lispro-protamine formulations, insulin lispro Mix25 and insulin lispro Mix50

The objective of this 6-month, open-label, randomized, two-period crossover study was to compare glycemic control when patients were treated with (1) 2 manufactured premixed insulin formulations containing insulin lispro and a novel insulin lispro-protamine formulation, neutral protamine lispro (NPL), and (2) 2 manufactured premixed human insulin formulations, human insulin 50/50 and human insulin 30/70. One hundred individuals, 37 with type 1 diabetes mellitus (12 females, 25 males; mean age, 39.4 years; mean body mass index [BMI], 24.8; mean duration of diabetes, 12.9 years) and 63 with type 2 diabetes mellitus (33 females, 30 males; mean age, 59.0 years; mean BMI, 28.4; mean duration of diabetes, 12.6 years), were treated with insulin lispro mixtures. Insulin lispro Mix50 (50% insulin lispro/50% NPL) and human insulin 50/50 (50% regular insulin/50% neutral protamine Hagedorn [NPH] insulin) were administered before breakfast; insulin lispro Mix25 (25% insulin lispro/75% NPL) and human insulin 30/70 (30% regular insulin/70% NPH) were administered before dinner. Blood glucose (BG), hypoglycemic episodes (hypoglycemic signs or symptoms or BG <3.0 mmol/L), insulin dose and timing of dose before meals, and hemoglobin A 1c were measured. Mean doses of insulin lispro and human insulin mixtures were similar overall and for both diabetes subgroups. However, compared with human insulin mixtures, twice-daily administration of insulin lispro mixtures resulted in improved postprandial glycemic control, similar overall glycemic control, and less nocturnal hypoglycemia, as well as offering the convenience of dosing closer to meals.