Factors associated with nocturnal hypoglycaemia among patients with type 2 diabetes new to insulin therapy: experience with insulin lispro.

AIM: To identify factors associated with nocturnal hypoglycaemia in patients with type 2 diabetes who were new (< 2 months therapy) to insulin therapy. METHODS: A randomised, multicentre, 12-month parallel open-label study compared the clinical safety and efficacy of insulin lispro with regular human insulin. A cohort of North American patients completed a health-related quality of life (HRQOL) questionnaire which included questions related to the Health Beliefs Model (HBM). Measurements of hypoglycaemia rate and short-and long-term glucose control assessed clinical safety and efficacy. Three hundred and sixty-five type 2 diabetic patients were enrolled in the study, and 195 North American patients completed the HRQOL questionnaire. RESULTS: After adjustment for demographic and psychological factors, the study population demonstrated lower nocturnal hypoglycaemia risk with insulin lispro. Higher nocturnal hypoglycaemia risk was associated with reduced body mass index (b.m.i.), lower age, and basal ultralente insulin therapy. The associated hypoglycaemia risk was lower with increased alcohol consumption. Patients who completed the HRQOL survey demonstrated higher risk for nocturnal hypoglycaemia if they: (1) had more troublesome hyperglycaemia symptoms in the week before starting insulin; (2) were more confident in their ability to control their diabetes; or (3) thought that diabetes control did not offer a clear health benefit. Nocturnal hypoglycaemia risk was inversely associated with fear of hypoglycaemia. CONCLUSIONS: Type 2 diabetic patients new to insulin therapy demonstrated lower risk of nocturnal hypoglycaemia with insulin lispro. Practitioners should consider patient characteristics and psychological factors that may predispose type 2 diabetes patients to nocturnal hypoglycaemia when initiating insulin therapy.

Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Multicenter Insulin Lispro Study Group.

BACKGROUND: Insulin lispro is an insulin analog that was recently developed particularly for a mealtime therapy. It has a fast absorption rate and short duration of action. The efficacy of insulin lispro in the clinical therapy of patients with non-insulin-dependent diabetes mellitus (NIDDM) has not been tested. OBJECTIVES: To compare insulin lispro and human regular insulin in the mealtime treatment of patients with NIDDM. METHODS: A 6-month, randomized, multinational (16 countries), multicenter (80 sites) clinical trial with an open-label, crossover design was performed in 722 patients with NIDDM. Insulin lispro was injected immediately before and human regular insulin 30 to 45 minutes before the meal. RESULTS: Throughout the study, the postprandial rise in serum glucose levels was significantly lower during insulin lispro than human regular insulin treatment. At end point the rise (mean +/- SEM) in serum glucose levels was 30% lower at 1 hour (2.6 +/- 0.1 mmol/L [46.8 +/- 1.8 mg/ dL] for lispro vs 3.7 +/- 0.1 mmol/L [66.6 +/- 1.8 mg/dL] for human regular insulin) and 53% lower 2 hours after the test meal (1.4 +/- 0.1 mmol/L [25.2 +/- 1.8 mg/dL] for lispro vs 3.0 +/- 0.1 mmol/L [54.0 +/- 1.8 mg/dL] for human regular insulin) with insulin lispro compared with human regular insulin therapy (P < .001 for both intervals). During insulin lispro therapy the rate of hypoglycemia overall (P = .01) and overnight (P < .001) was lower and the number of asymptomatic hypoglycemic episodes was smaller (P = .03) than during human regular insulin therapy. Associated with a similar 13% increase (P < .001) in the total daily insulin dose, the glycosylated hemoglobin level decreased (P < .001) equally in both treatment groups. Serum lipid and lipoprotein levels remained unchanged. There were no differences in the adverse events between the 2 treatment groups. CONCLUSIONS: Compared with human regular insulin therapy, mealtime therapy with insulin lispro reduced postprandial hyperglycemia and may decrease the rate of mild hypoglycemic episodes in patients with NIDDM.

Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Multicenter Insulin Lispro Study Group.

Insulin lispro, an insulin analog recently developed particularly for mealtime therapy, has a fast absorption rate and a short duration of action. We compared insulin lispro and regular human insulin in the mealtime treatment of 1,008 patients with IDDM. The study was a 6-month randomized multinational (17 countries) and multicenter (102 investigators) clinical trial performed with an open-label crossover design. Insulin lispro was injected immediately before the meal, and regular human insulin was injected 30-45 min before the meal. Throughout the study, the postprandial rise in serum glucose was significantly lower during insulin lispro therapy. At the endpoint, the postprandial rise in serum glucose was reduced at 1 h by 1.3 mmol/l and at 2 h by 2.0 mmol/l in patients treated with insulin lispro (P < 0.001). The rate of hypoglycemia was 12% less with insulin lispro (6.4 +/- 0.2 vs. 7.2 +/- 0.3 episodes/30 days, P < 0.001), independent of basal insulin regimen or HbA1c level. The reduction was observed equally in episodes with and without symptoms. When the total number of episodes for each patient was analyzed according to the time of occurrence, the number of hypoglycemic episodes was less with insulin lispro than with regular human insulin therapy during three of four quarters of the day (P < 0.001). The largest relative improvement was observed at night. In conclusion, insulin lispro improves postprandial control, reduces hypoglycemic episodes, and improves patient convenience, compared with regular human insulin, in IDDM patients.

Improved mealtime treatment of diabetes mellitus using an insulin analogue. Multicenter Insulin Lispro Study Group.

The absorption of regular human insulin from subcutaneous injection sites is delayed due to the self-association of insulin to multimeric forms. The insulin analogue insulin lispro has a weak self-association and a fast absorption rate. We examined the safety and efficacy of insulin lispro in the premeal treatment of patients with diabetes mellitus. A 12-month study was performed in 336 patients with insulin-dependent diabetes mellitus (IDDM) and 295 patients with non-insulin-dependent diabetes mellitus (NIDDM). The patients were randomized to inject either regular human insulin 30 to 45 minutes before eating, or insulin lispro immediately before each meal, in addition to basal insulin. The postprandial rise in serum glucose was lower in patients receiving insulin lispro than in those receiving regular human insulin therapy. At end point the increment was significantly lower at 1 hour (35%) and at 2 hours (64%) after the meal in IDDM patients; in NIDDM patients, the increment was nonsignificantly lower at 1 hour (19%) and significantly lower at 2 hours (48%). IDDM patients receiving insulin lispro achieved significantly lower glycated hemoglobin (HbA1c) levels in patients receiving regular human insulin (8.1% vs 8.3%). In NIDDM patients, HbA1c levels decreased equally in both treatment groups. Due to its fast absorption rate, insulin lispro improves postprandial control in diabetes. Insulin lispro can be considered one step toward optimal insulin therapy and improved patient convenience.

Effects of meperidine on the pancreatic and biliary sphincter.

BACKGROUND: Opioids are traditionally avoided during sphincter of Oddi manometry because of indirect evidence suggesting that these agents cause sphincter of Oddi spasm. This study was undertaken to determine the direct effects of meperidine on the biliary and pancreatic sphincter. METHODS: Forty-seven patients were prospectively evaluated by sphincter of Oddi manometry in the conventional retrograde fashion. Manometry was initially performed with intravenous diazepam sedation alone. The manometry was repeated 3 to 5 minutes after meperidine was administered. RESULTS: The basal sphincter pressure of the biliary sphincter, pancreatic sphincter, and the combined sphincter group were not significantly altered by meperidine. Concordance (normal versus abnormal) between the basal sphincter pressure before and after meperidine was seen in 44 of 47 patients (94%). Meperidine produced a significant increase in the pancreatic, biliary, and combined sphincter phasic frequency and a significant decrease in the phasic duration. The pancreatic and combined sphincter phasic pressures were significantly reduced following meperidine administration. Seventeen manometry tracings (36%) were believed to be qualitatively better after meperidine, while only four (8.5%; p < .001) were qualitatively better with diazepam alone. CONCLUSION: Meperidine can be used for additional analgesia during sphincter of Oddi manometry if the basal sphincter pressure is the parameter used to determine therapy.

[Lys(B28), Pro(B29)]-human insulin: effect of injection time on postprandial glycemia.

BACKGROUND: [Lys(B28), Pro(B29)]-human insulin (lispro) is an insulin analogue with a reduced capacity for self-association and faster absorption from subcutaneous injection sites. We hypothesized that administration of lispro closer to a meal would result in better glucose control than that achieved with regular insulin. METHODS: This trial used a randomized crossover design that consisted of a period of metabolic stabilization lasting 9 days followed by an evaluation period lasting 5 days. The patients received weight-maintenance diets, and insulin doses were adjusted as needed. Calorie intake, insulin dose, and activities were kept constant once the evaluation period began. During the evaluation period, we varied the time between insulin injection and mealtime and assessed glucose control. RESULTS: During the evaluation period, the lowest mean glucose concentrations were 117.9 mg/dl for lispro and 119.8 mg/dl (p = 0.817) for regular insulin. To obtain these, we gave lispro, on average, 22.5 minutes before meals and regular insulin 63.8 minutes before meals (p = 0.006). A similar pattern was evident throughout the glucose control parameters. The exception was mean amplitude of glucose excursion, which was lower after lispro (59 versus 75 mg/dl; p = 0.007) compared with regular insulin. CONCLUSIONS: We achieved equal or slightly better glucose control, as reflected by mean amplitude of glucose excursion, with insulin lispro given much closer to meal time than that achieved with regular insulin. As a result of these findings, we propose that a rapidly absorbed analogue of insulin is capable of achieving better control of postprandial glucose at a more convenient injection time.

Comparative pharmacokinetics and glucodynamics of two human insulin mixtures. 70/30 and 50/50 insulin mixtures.

OBJECTIVE: To compare and contrast the pharmacokinetics and glucodynamics of two insulin mixtures, one of 50% NPH human insulin and 50% Regular human insulin (50/50) and one of 70% NPH human insulin and 30% Regular human insulin (70/30), in healthy male volunteers after subcutaneous administrations of 0.3 U/kg. RESEARCH DESIGN AND METHODS: We administered single doses of 50/50 and 70/30 insulins to 18 volunteers in a randomized crossover fashion. All subjects received 0.3 U/kg of each mixture separated by at least 7 days. Each dose was given after an overnight fast and during a glucose clamp to maintain a euglycemic state. We measured serum insulin and C-peptide concentrations through frequent blood sampling after each treatment. Pharmacokinetic measurements were calculated from insulin data corrected for C-peptide, including maximum insulin concentration (Cmax), time to maximum insulin concentration (tmax), terminal rate constant (beta), area under the curve from 0 to infinity (AUCinfinity0), and mean residence time (MRT). Pharmacodynamic measurements were summarized from C-peptide concentrations (minimum C-peptide concentration [Cmin], time to minimum C-peptide concentration [tmin], area between the C-peptide baseline and the C-peptide suppression curve [AOCc], absolute maximal difference from baseline [Sdiff] and glucose clamp measurements. The glucose clamp measurements included maximum infusion rates (Rmax) and time to Rmax (TRmax) from glucose infusion rate (GIR) documentation, as well as cumulative glucose infused during the first 4 h ((0)4Gtot) and total glucose infused (Gtot) during the study. RESULTS: For the pharmacokinetic assessment, statistically greater values of insulin Cmax and beta were found for the 50/50 mixture, whereas the 70/30 mixture had a greater MRT. Statistical differences were also detected in glucodynamics, with greater values of Rmax and (0)4Gtot found with the 50/50 mixture. Notably, differences were not detected for insulin AUCinfinity0 and Gtot values. CONCLUSIONS: Higher insulin concentrations and a greater initial response were present with the 50/50 mixture, but the two mixtures had equivalent bioavailability and cumulative effects. These results support use of the 50/50 mixture in situations where greater initial glucose control is required.

[Lys(B28), Pro(B29)]-human insulin. A rapidly absorbed analogue of human insulin.

[Lys(B28, Pro(B29)]-human insulin (LYSPRO) is an insulin analogue in which the natural amino acid sequence of the B-chain at positions 28 and 29 is inverted. These changes result in an insulin molecule with a greatly reduced capacity for self-association in solution. These clinical studies were designed to compare LYSPRO with human Regular insulin after subcutaneous injection in humans. We wanted to evaluate the effect of adding zinc to LYSPRO on its pharmacokinetics and pharmacodynamics. In addition, we compared the pharmacokinetics and pharmacodynamics of LYSPRO and human Regular insulin after subcutaneous injection to those of human Regular insulin given intravenously. Thus, we compared four treatments: solutions of zinc-free LYSPRO given subcutaneously (A), zinc-containing LYSPRO given subcutaneously (B), human Regular insulin given subcutaneously (C), and human Regular insulin given intravenously (D). We gave a 10-U dose of each treatment to 10 healthy (nondiabetic) men during glucose clamps. Serum insulin concentrations peaked more than two times higher (maximum serum insulin level [Cmax], 698 vs. 308 pM, A vs. C) and in less than half the time (time to Cmax [Tmax], 42 vs. 101 min, A vs. C) after subcutaneous injection of zinc-free LYSPRO. At the same time, the glucose infusion rate peaked in about half the time (time to maximum glucose infusion rate [TRmax], 99 vs. 179 min, A vs. C) and was slightly but not significantly higher (maximum glucose infusion rate [Rmax], 3.1 vs. 2.2 mmol/min, A vs. C) than that of human Regular insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Picenadol in a large multicenter dental pain study.

STUDY OBJECTIVE: To estimate the analgesic dose of picenadol hydrochloride equal to codeine 60 mg in a dental pain model. DESIGN: Randomized, double-blind, parallel, dose-response study. SETTING: Four university-based dental clinics. PATIENTS: Four hundred eight adult patients with moderate or severe pain after extraction of one or more impacted molar teeth plus bone removal. INTERVENTIONS: Patients received orally administered single doses of picenadol 15 and 30 mg, codeine phosphate 30 and 90 mg, or placebo. METHODS: Single oral doses of picenadol 15 and 30 mg, an opioid agonist-antagonist, were compared with codeine 30 and 90 mg and placebo in 408 patients with moderate or severe pain from third molar extraction in a randomized, double-blind, parallel study. Assessments were performed for pain intensity, pain relief, and adverse events for up to 6 hours after drug administration. MAIN RESULTS: Picenadol 30 mg and codeine 90 mg were more effective than placebo based on sum of pain intensity differences, total pain relief, peak pain relief, and duration of analgesia (p < 0.05). Compared with placebo, the frequency of adverse events was highest for patients receiving codeine 90 mg (p < 0.05). No patients discontinued due to adverse events, and all such events resolved spontaneously. CONCLUSIONS: Picenadol 22 mg was estimated to be equianalgesic to codeine 60 mg, and picenadol 30 mg was safe in this dental pain model.

Intramuscular picenadol in patients with postoperative pain.

1. The analgesic efficacy and safety of a single 50 mg intramuscular dose of rac-picenadol, a centrally acting agonist-antagonist opioid analgesic, were compared with pethidine (meperidine) 100 mg and placebo in 60 patients with moderate to severe postoperative pain using hourly pain intensity and relief measurements for up to 6 h following injection of the study medications. 2. Both picenadol and pethidine were statistically significantly (P < 0.05) more effective than placebo in reducing pain intensity and in increasing total relief. Patients receiving picenadol and pethidine had higher frequency of somnolence than patients receiving placebo. In addition, patients receiving picenadol 50 mg experienced a higher incidence of confusion (30%), speech disorders (30%), and tremors (25%) than the patients receiving either pethidine or placebo. 3. These results were compared with those of a similar study which investigated the effects of a 25 mg intramuscular dose of picenadol vs pethidine and placebo. This comparison suggests that 25 mg of picenadol is a more acceptable dosage since both 25 and 50 mg were effective dosages.