Daniel C. Howey

[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 < 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. Although the addition of zinc retarded the absorption of LYSPRO slightly (Cmax, 550 vs. 698 pM, B vs. A), zinc-containing LYSPRO retained its distinct profile (Tmax 53 vs. 42 min, B vs. A). LYSPRO displays faster pharmacodynamic action than human Regular insulin when injected subcutaneously

In vivo evaluation of an electroenzymatic glucose sensor implanted in subcutaneous tissue

Cleanroom processing techniques have been used to mass-produce flexible, electroenzymatic glucose sensors designed for implantation in subcutaneous tissue. In vitro characterization studies have shown the sensors performance to be acceptable. Initial in vivo studies were conducted with the sensor implanted in the subcutaneous tissue of rabbits. Sensors implanted in the subcutaneous tissue of normal human subjects showed an excellent correlation between glucose concentrations measured by the sensor and capillary finger sticks measured with a commercial analyzer.

Biosynthetic human proinsulin. Review of chemistry, in vitro and in vivo receptor binding, animal and human pharmacology studies, and clinical trial experience.

Objective To describe the rationale for the preclinical and clinical developmental course of human proinsulin (HPI), the second product after human insulin for the treatment of diabetes mellitus to be manufactured by DNA technology. Research Design and Methods The relevant and available published and unpublished preclinical and clinical information generated on pork proinsulin and human proinsulin has been integrated to demonstrate how certain clinically attractive features of pork proinsulin (a soluble intermediate-acting and possibly hepatospecific insulin agonist) led to the development of HPI. Results Clinical pharmacology studies demonstrated that HPI was definitely, although marginally, hepatospecific. More striking was the finding that the intrasubject/patient coefficient of variation of response to HPI was significantly less than that observed with NPH insulin. However, the fact that unique efficacy in controlled multicenter studies was not demonstrated suggested that these pharmacological features were not translated into clinical benefit. In one multicenter new patient study there were six myocardial infarctions, including two deaths, in patients treated for ≥1 yr with HPI and none in the control group. Conclusions To obtain an independent review of the risks and benefits of HPI, in February 1988, Lilly convened a consultant group that examined all relevant information on HPI available. These experts shared our concerns about the safety of HPI in light of the failure to demonstrate unique efficacy. Accordingly, clinical trials with HPI were suspended in February 1988. Experience with HPI demonstrates the challenge associated with the development of new drugs in general and insulin agonists in particular.

A Randomized, Controlled Study of Once-Daily LY2605541, a Novel Long-Acting Basal Insulin, Versus Insulin Glargine in Basal Insulin–Treated Patients With Type 2 Diabetes

OBJECTIVE To evaluate whether LY2605541 results in lower fasting blood glucose (FBG) versus insulin glargine (GL). RESEARCH DESIGN AND METHODS This 12-week, randomized, open-label, Phase 2 study enrolled patients with type 2 diabetes (hemoglobin A1c [A1C] ≤ 10.5%), taking metformin and/or sulfonylurea with GL or NPH insulin once daily. Patients converted to morning insulin administration during lead-in were randomized 2:1 from GL (n = 248) or NPH insulin (n = 39) to LY2605541 (n = 195) or GL (n = 95) once daily in the morning. RESULTS At 12 weeks, FBG (mean ± SE) was similar with LY2605541 and GL (118.2 ± 2.0 mg/dL [6.6 ± 0.1 mmol/L] vs. 116.9 ± 2.7 mg/dL [6.5 ± 0.2 mmol/L], P = 0.433) as was A1C (7.0 ± 0.1 vs. 7.2 ± 0.1%, P = 0.279). Intraday blood glucose variability was reduced with LY2605541 (34.4 vs. 39.1 mg/dL [1.9 vs. 2.2 mmol/L], P = 0.031). LY2605541 patients had weight loss (−0.6 ± 0.2 kg, P = 0.007), whereas GL patients gained weight (0.3 ± 0.2 kg, P = 0.662; treatment difference: −0.8 kg, P = 0.001). The incidence and rate of both total hypoglycemia and nocturnal hypoglycemia were comparable between LY2605541 and GL, although, LY2605541 had a 48% reduction in nocturnal hypoglycemia after adjusting for baseline hypoglycemia (P = 0.021). Adverse events were similar across treatments. Alanine aminotransferase and aspartate aminotransferase remained within normal range but were significantly higher with LY2605541 (P ≤ 0.001). CONCLUSIONS In patients with type 2 diabetes, LY2605541 and GL had comparable glucose control and total hypoglycemia rates, but LY2605541 showed reduced intraday variability, lower nocturnal hypoglycemia, and weight loss relative to GL.

Better Glycemic Control and Weight Loss With the Novel Long-Acting Basal Insulin LY2605541 Compared With Insulin Glargine in Type 1 Diabetes: A randomized, crossover study

OBJECTIVE To compare effects of LY2605541 versus insulin glargine on daily mean blood glucose as part of a basal-bolus regimen for type 1 diabetes. RESEARCH DESIGN AND METHODS In this randomized, Phase 2, open-label, 2 × 2 crossover study, 137 patients received once-daily basal insulin (LY2605541 or glargine) plus mealtime insulin for 8 weeks, followed by crossover treatment for 8 weeks. Daily mean blood glucose was obtained from 8-point self-monitored blood glucose profiles. The noninferiority margin was 10.8 mg/dL. RESULTS LY2605541 met noninferiority and superiority criteria compared with insulin glargine in daily mean blood glucose (144.2 vs. 151.7 mg/dL, least squares mean difference = −9.9 mg/dL [90% CI −14.6 to −5.2], P < 0.001). Fasting blood glucose variability and A1C were reduced with LY2605541 compared with insulin glargine (both P < 0.001). Mealtime insulin dose decreased with LY2605541 and increased with insulin glargine. Mean weight decreased 1.2 kg with LY2605541 and increased 0.7 kg with insulin glargine (P < 0.001). The total hypoglycemia rate was higher for LY2605541 (P = 0.04) and the nocturnal hypoglycemia rate was lower (P = 0.01), compared with insulin glargine. Adverse events (including severe hypoglycemia) were similar, although more gastrointestinal-related events occurred with LY2605541 (15% vs. 4%, P < 0.001). Mean changes (all within normal range) were higher for alanine aminotransferase, aspartate aminotransferase, triglycerides, and LDL-cholesterol and lower for HDL-cholesterol with LY2605541 compared with insulin glargine (all P < 0.02). CONCLUSIONS In type 1 diabetes, compared with insulin glargine, LY2605541, a novel, long-acting basal insulin, demonstrated greater improvements in glycemic control, increased total hypoglycemia, and reduced nocturnal hypoglycemia, as well as reduced weight and lowered mealtime insulin doses.

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

[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.

Steady-state pharmacokinetics and glucodynamics of the novel, long-acting basal insulin LY2605541 dosed once-daily in patients with type 2 diabetes mellitus.

To assess the pharmacokinetics (PK) and glucodynamics (GD) of LY2605541 in patients with type 2 diabetes mellitus.

Establishment of Time-Action Profiles for Regular and NPH Insulin Using Pharmacodynamic Modeling

OBJECTIVE To provide distinct definitions and quantify the establishment of onset, peak, and duration of action for insulins. RESEARCH DESIGN AND METHODS We administered single subcutaneous doses of 10 U regular insulin to 10 volunteer subjects and 25 U NPH insulin to 6 healthy male volunteer subjects on separate occasions. Each dose was given after an overnight fast during a glucose clamp to maintain an euglycemic state. We measured serum insulin concentrations and glucose infusion rates (GIR) from frequent blood sampling after each treatment. Serum insulin concentrations were related to GIR values at each collection time and a counter-clockwise hysteresis resulted. An effect compartment model was used to simultaneously describe the pharmacokinetics and pharmacodynamics of each insulin and to resolve the hysteresis. RESULTS From the resulting relationship, GIR could then be predicted, with onset and duration of action reflecting the time when effect compartment concentrations initially exceeded then declined below a 10% maximum possible effect (Emax) level. Ninety-five percent confidence intervals were constructed allowing a predictive range of values. For regular insulin, a mean onset of 0.75 h, peak of 2 h, and duration of 6 h was estimated. Mean values were also produced with NPH, with an onset of 3 h, peak of 6–7 h, and a duration of 13 h estimated. CONCLUSIONS This method estimates the onset, peak, and duration of insulin action. Although these estimates were from single doses, we believe they can provide good estimations of insulin activity.

Potent and Selective PPAR-α Agonist LY518674 Upregulates Both ApoA-I Production and Catabolism in Human Subjects With the Metabolic Syndrome

Objective—The study of PPAR-α activation on apoA-I production in humans has been limited to fibrates, relatively weak PPAR-α agonists that may have other molecular effects. We sought to determine the effect of a potent and highly specific PPAR-α agonist, LY518674, on apoA-I, apoA-II, and apoB-100 kinetics in humans with metabolic syndrome and low levels of HDL cholesterol (C). Methods and Results—Subjects were randomized to receive LY518674 (100 &mgr;g) once daily (n=13) or placebo (n=15) for 8 weeks. Subjects underwent a kinetic study using a deuterated leucine tracer to measure apolipoprotein production and fractional catabolic rates (FCR) at baseline and after treatment. LY518674 significantly reduced VLDL-C (−38%, P=0.002) and triglyceride (−23%, P=0.002) levels whereas LDL-C and HDL-C levels were unchanged. LY518674 significantly reduced VLDL apoB-100 (−12%, P=0.01) levels, attributable to an increased VLDL apoB-100 FCR with no change in VLDL apoB-100 production. IDL and LDL apoB-100 kinetics were unchanged. LY518674 significantly increased the apoA-I production rate by 31% (P<0.0001), but this was accompanied by a 33% increase in the apoA-I FCR (P=0.002), resulting in no change in plasma apoA-I. There was a 71% increase in the apoA-II production rate (P<0.0001) accompanied by a 25% increase in the FCR (P<0.0001), resulting in a significant increase in plasma apoA-II. Conclusions—Activation of PPAR-α with LY518674 (100 &mgr;g) in subjects with metabolic syndrome and low HDL-C increased the VLDL apoB-100 FCR consistent with enhanced lipolysis of plasma triglyceride. Significant increases in the apoA-I and apoA-II production rates were accompanied by increased FCRs resulting in no change in HDL-C levels. These data indicate a major effect of LY518674 on the production and clearance of apoA-I and HDL despite no change in the plasma concentration. The effect of these changes on reverse cholesterol transport remains to be determined.

Single-dose pharmacokinetics and glucodynamics of the novel, long-acting basal insulin LY2605541 in healthy subjects.

LY2605541 is a novel basal insulin analog with a prolonged duration of action. Two Phase I studies assessed LY2605541 pharmacokinetics (PK), glucodynamics (GD), and tolerability in healthy subjects. In Study 1, 33 subjects received single subcutaneous (SC) doses of LY2605541 (0.01–2.22 U/kg) and insulin glargine (0.5–0.8 U/kg) followed by euglycemic clamp for up to 24–36 hours. In Study 2, absolute bioavailability of SC LY2605541 was assessed in 8 subjects by comparing dose normalized area under concentration versus time curve of SC against IV administration. Time‐to‐maximum plasma concentration (medians) and geometric means for half‐life (t1/2) and apparent clearance, respectively, ranged from 18.0 to 42.0 hours, 24.4–45.5 hours, and 1.8–2.8 L/h for SC LY2605541, versus 10.0–12.0 hours, 12.2–14.9 hours, and 51.4–65.2 L/h for SC insulin glargine. LY2605541 glucose infusion rate (GIR) profiles were sustained for ≥36 hours versus glargine GIR profiles, which waned at 24 hours. After IV administration, LY2605541s geometric mean t1/2 was 2.3 hours. LY2605541 intra‐subject variability (CV%) was <18% for PK and <32% for GD parameters. The most common adverse events were related to study procedures and were mild‐moderate in severity. These results established a well‐tolerated baseline dose for LY2605541 with a relatively flat PK profile and low intra‐subject variability.