Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study.

BACKGROUND: Orforglipron, an oral, non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist, is in development for type 2 diabetes and obesity. We assessed the efficacy and safety of orforglipron versus placebo or dulaglutide in participants with type 2 diabetes. METHODS: In this 26-week, phase 2, double-blind, randomised, multicentre study, participants were recruited from 45 centres (private clinics, hospitals, and research centers) in the USA, Hungary, Poland, and Slovakia. Adult participants aged 18 years or older with type 2 diabetes treated with diet and exercise, with or without metformin, and with a glycated haemoglobin (HbA1c) of 7·0-10·5%, and stable BMI of 23 kg/m2 or more, were randomly assigned (5:5:5:5:5:3:3:3:3) via an interactive web-response system to placebo, dulaglutide 1·5 mg once per week, or orforglipron 3 mg, 12 mg, 24 mg, 36 mg (group 1), 36 mg (group 2), 45 mg (group 1), or 45 mg (group 2) once per day with no food or water restrictions. Two different dose escalation regimens were evaluated for each of the 36 mg and 45 mg cohorts. Participants were masked to the study drug, dulaglutide, and placebo. The primary efficacy outcome The primary efficacy outcome was mean change in HbA1c from baseline with orforglipron versus placebo at week 26. Efficacy was analysed in all randomly assigned participants who received at least one dose of study drug and excluded data after the permanent discontinuation of study drug or initiation of rescue medication. Safety was analysed in all participants who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT05048719) and is completed. FINDINGS: Between Sept 15, 2021, and Sept 30, 2022, 569 participants were screened and 383 were enrolled and randomly assigned to a group. 352 (92%) completed the study and 303 (79%) completed 26 weeks of treatment. At baseline, the mean age was 58·9 years, HbA1c was 8·1%, BMI was 35·2 kg/m2, 226 (59%) were men, and 157 (41%) were women. At week 26, mean change in HbA1c with orforglipron was up to -2·10% (-1·67% placebo adjusted), versus -0·43% with placebo and -1·10% with dulaglutide. HbA1c reduction was statistically superior with orforglipron versus placebo (estimated treatment difference -0·8% to -1·7%). Change in mean bodyweight at week 26 was up to -10·1 kg (95% CI -11·5 to -8·7; 7·9 kg placebo adjusted [-9·9 to -5·9]) with orforglipron versus -2·2 kg (-3·6 to -0·7) for placebo and -3·9 kg (-5·3 to -2·4) for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61·8% to 88·9% in orforglipron-treated participants, compared with 61·8% with placebo and 56·0% with dulaglutide. The majority were gastrointestinal events (44·1% to 70·4% with orforglipron, 18·2% with placebo, and 34·0% with dulaglutide) of mild to moderate severity. Three participants receiving orforglipron and one participant receiving dulaglutide had clinically significant (<54 mg/dL [<3 mmol/L]) hypoglycaemia and no participants had severe hypoglycaemia. One death occurred in the placebo group and was not related to study treatment. INTERPRETATION: In this phase 2 trial the novel, oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12 mg or greater showed significant reductions in HbA1c and bodyweight compared with placebo or dulaglutide. The adverse event profile was similar to other GLP-1 receptor agonists in similar stage of development. Orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes. FUNDING: Eli Lilly and Company.

Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity.

BACKGROUND: Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity. METHODS: In this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point). RESULTS: A total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from -8.6% to -12.6% across the orforglipron dose cohorts and was -2.0% in the placebo group. At week 36, the mean change ranged from -9.4% to -14.7% with orforglipron and was -2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class. CONCLUSIONS: Daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists. (Funded by Eli Lilly; GZGI ClinicalTrials.gov number, NCT05051579.).

Once-Weekly Basal Insulin Fc Demonstrated Similar Glycemic Control to Once-Daily Insulin Degludec in Insulin-Naive Patients With Type 2 Diabetes: A Phase 2 Randomized Control Trial.

OBJECTIVE: Basal insulin Fc (BIF) (insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once-weekly basal insulin administration. This phase 2 study assessed the safety and efficacy of BIF versus degludec in insulin-naive patients with type 2 diabetes (T2D) previously treated with oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS: During this randomized, parallel, open-label study, 278 insulin-naive patients with T2D were randomly assigned (1:1) to receive BIF once weekly or degludec once daily over the 26-week treatment period. Both groups were titrated to fasting glucose of 80-100 mg/dL (4.4 to <5.6 mmol/L). The primary end point was HbA1c change from baseline to week 26 (noninferiority margin 0.4%). Secondary end points included fasting blood glucose (FBG), six-point glucose profiles, and rate of hypoglycemia. RESULTS: After 26 weeks of treatment, BIF demonstrated a noninferior HbA1c change from baseline versus degludec, with a treatment difference of 0.06% (90% CI -0.11, 0.24; P = 0.56). Both BIF and degludec treatment led to significant reductions in FBG from baseline. At week 26, the between-treatment difference for BIF versus degludec was 4.7 mg/dL (90% CI 0.1, 9.3; P = 0.09). The rate of level 2 hypoglycemia was low and not significantly different between treatment groups (BIF 0.22 events/patient/year, degludec 0.15 events/patient/year; P = 0.64); there was no severe hypoglycemia. The occurrence of treatment-emergent adverse events was also similar between BIF and degludec. CONCLUSIONS: Once-weekly BIF achieved excellent glycemic control similar to degludec, with no concerning hypoglycemia or other safety findings.

Novel Once-Weekly Basal Insulin Fc Achieved Similar Glycemic Control With a Safety Profile Comparable to Insulin Degludec in Patients With Type 1 Diabetes.

OBJECTIVE: Basal Insulin Fc (BIF; insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once-weekly basal insulin administration. This phase 2 study assessed safety and efficacy of BIF versus degludec in 265 patients with type 1 diabetes (T1D) using multiple daily injections. RESEARCH DESIGN AND METHODS: During this randomized, parallel, open-label study, patients with T1D were randomized (1:1) to receive BIF once weekly or degludec once daily over the 26-week treatment period. Both groups were titrated to a fasting glucose level of 80-100 mg/dL. The primary end point was HbA1c change from baseline to week 26 (noninferiority margin, 0.4%). Secondary end points included percent time in range (TIR) (70-180 mg/dL), continuous glucose monitoring (CGM) fasting glucose (FG) level, and rate of hypoglycemia. RESULTS: After 26 weeks, patients receiving BIF had noninferior HbA1c change from baseline versus those receiving degludec, with a statistically significant treatment difference of 0.17% (90% CI 0.01, 0.32; P = 0.07) favoring the comparator. Percent TIR was similar for patients in the BIF (56.1%) and degludec (58.9%; P = 0.112) groups at week 26. FG values were significantly higher for patients receiving BIF (158.8 mg/dL) versus degludec (143.2 mg/dL; P = 0.003). Rates of CGM-derived hypoglycemia were not statistically significantly different for BIF and degludec over 24 h for level 1 (P = 0.960) or level 2 (P = 0.517) hypoglycemia during the treatment period. Occurrence of serious adverse events was similar between the BIF and degludec groups. CONCLUSIONS: Once-weekly BIF demonstrated noninferior glycemic control to once-daily degludec (treatment difference: 0.17% favoring degludec) and no difference in hypoglycemia or other safety findings in patients with T1D.

Safety and efficacy of once-weekly basal insulin Fc in people with type 2 diabetes previously treated with basal insulin: a multicentre, open-label, randomised, phase 2 study.

BACKGROUND: The burden of daily basal insulins often causes hesitancy and delays in the initiation of insulin therapy. Basal insulin Fc (BIF, insulin efsitora alfa), designed for once-weekly administration, is a fusion protein combining a novel single-chain insulin variant with a human immunoglobulin G (IgG) Fc domain. In this study, we explored the safety and efficacy of BIF in people with type 2 diabetes who had been previously treated with basal insulin. METHODS: For this phase 2, 44-site (clinical research centres and hospitals), randomised, open-label, comparator-controlled, 32-week study in the USA, Puerto Rico, and Mexico, we enrolled participants with type 2 diabetes. Eligible participants had to be adults (aged ≥18 years) and to have been treated with basal insulin and up to three oral antidiabetic medicines. Participants were randomly assigned (1:1:1) to subcutaneous administration of BIF (BIF treatment group 1 [BIF-A1] or 2 [BIF-A2]) or insulin degludec. Randomisation was stratified by country, baseline HbA1c values (<8·5% or ≥8·5%; <69·4 or ≥69·4 mmol/mol), use of sulfonylureas (yes or no), and baseline BMI (<30 or ≥30 kg/m2). The randomisation scheme was performed using an interactive web-response system, which ensured balance between treatment groups. Different fasting glucose targets for the BIF-A1 (≤7·8 mmol/L or ≤140 mg/dL; titrated every 2 weeks), BIF-A2 (≤6·7 mmol/L or ≤120 mg/dL; titrated every 4 weeks), and degludec (≤5·6 mmol/L or ≤100 mg/dL) groups were selected. Patients randomly assigned to BIF received a one-time loading dose ranging from 1·5-3 times their calculated weekly dose. The first weekly dose was administered 1 week after the loading dose. We used interstitial fasting glucose measurements from the Dexcom G6 continuous glucose monitoring system to titrate the basal insulin. The primary measure of glycaemic control was change in HbA1c from baseline to week 32 for BIF. BIF was also compared with degludec (with a non-inferiority margin of 0·40%). The efficacy analysis set consisted of data from all randomised study participants who received at least one dose of the study medication and participants were analysed according to the treatment they were assigned. The safety population was the same as the efficacy analysis set. The completed trial is registered at ClinicalTrials.gov (NCT03736785). FINDINGS: Between Nov 15, 2018 and Feb 18, 2020, 399 participants were enrolled and randomised to BIF-A1 (n=135), BIF-A2 (n=132), or degludec (n=132); 202 (51%) were female and 197 (49%) were male. 379 were analysed for the primary outcome (BIF-A1: n=130; BIF-A2: n=125; degludec: n=124). Mean HbA1c change from baseline to week 32, the primary outcome, was -0·6% (SE 0·1%) for BIF-A1 and BIF-A2. Degludec achieved a change from baseline of -0·7% (0·1%). The pooled BIF analysis achieved non-inferiority versus degludec for the treatment difference in HbA1c (0·1% [90% CI -0·1 to 0·3]). The hypoglycaemia (≤3·9 mmol/L or ≤70 mg/dL) event rates (hypoglycaemia events per patient per year) in the BIF groups were 25% lower than those in the degludec group (treatment ratio BIF-A1 vs degludec was 0·75 [0·61-0·93]; and BIF-A2 vs degludec was 0·74 [0·58-0·94]). BIF was well tolerated; treatment-emergent adverse events were similar across groups. INTERPRETATION: Weekly BIF achieved a similar efficacy compared with degludec despite higher fasting glucose targets in the BIF groups. Higher fasting glucose targets and lower glucose variability might have contributed to lower hypoglycaemia rates for BIF compared with degludec. These findings support continued development of BIF as a once-weekly insulin treatment for people with diabetes. FUNDING: Eli Lilly and Company.

Evaluation of Insulin Lispro Pharmacokinetics and Pharmacodynamics Over 10 Days of Continuous Insulin Infusion in People With Type 1 Diabetes.

BACKGROUND: We evaluated the effect of meloxicam on insulin lispro pharmacokinetics and glucose pharmacodynamics over 10 days of continuous subcutaneous insulin infusion (CSII) at one infusion site in people with type 1 diabetes (T1D). METHOD: This phase 1, randomized, double-blind, single-center, two-way crossover study enrolled adults with T1D for ≥1 year on stable CSII for ≥3 months. Participants randomly received U100 insulin lispro and LY900027 (U100 insulin lispro + 0.25 mg/mL meloxicam). Primary end points were area under the insulin lispro curve from 0 to 5 hours (AUCIns.0-5h) after bolus administration prior to a mixed-meal tolerance test (MMTT) and maximum observed concentration of insulin lispro (CIns.max) on days 5, 7, and 10, versus day 3 (baseline). RESULTS: A total of 20 participants were randomized. Insulin absorption was accelerated for insulin lispro and LY900027 from days 1 to 7. The AUCIns.0-5h was significantly lower on day 10 versus day 3 for LY900027 (-19%) and insulin lispro (-14%); the AUCIns.0-5h did not differ significantly between treatments. The CIns.max increased with LY900027 and insulin lispro (by ~14%-23% and ~16%-51%) on days 5, 7, and 10 versus day 3. The CIns.max of LY900027 was ~14%-23% lower than insulin lispro CIns.max on days 7 and 10 (P ≤ .0805). Accelerated insulin absorption and a modest loss of total insulin exposure led to a loss of MMTT glycemic control at later time points. CONCLUSIONS: The pharmacokinetics of insulin changed over catheter wear time even when an anti-inflammatory agent was present. Postprandial glycemic control was adversely affected by the accelerated insulin absorption and decreased insulin exposure.

Ultra-rapid lispro shows faster pharmacokinetics and reduces postprandial glucose excursions versus Humalog® in patients with type 2 diabetes mellitus in a randomized, controlled crossover meal test early phase study.

AIMS: To compare the pharmacokinetics (PK), glucodynamics (GD) and tolerability following single and multiple daily subcutaneous doses of ultra rapid lispro (URLi) and Humalog® in patients with type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: This was a two-part, randomized, double-blind Phase 1b study. Part A used a six-period crossover design to assess PK and GD response to a solid mixed meal tolerance test (MMTT) following a single dose of URLi or Humalog administered 15 minutes before, immediately before, or 15 minutes after the start of the meal. Part B evaluated URLi or Humalog during 2 weeks of multiple daily dosing with a parallel design. The PK and GD were assessed following MMTTs at the beginning and end of the 2 weeks when insulins were administered immediately before the start of the meal. RESULTS: URLi increased the insulin exposure within the first 30 minutes postdose by 2.2-fold and reduced the time to the early half-maximal drug concentration by 22.6% compared with Humalog. Overall, URLi resulted in better postprandial glucose lowering when dosed before, immediately before, or after a meal. In comparing the same meal-to-dose timing between the insulins, the postprandial glucose excursion over 5 hours was significantly reduced by 29%-105% for all three dose timings (-15, 0 and +15 minutes) with URLi. The PK and GD were sustained after daily subcutaneous dosing for 2 weeks in patients with T2D. URLi had more hypoglycaemic events during the MMTTs; few events occurred for both treatments during the 2 weeks of outpatient dosing. CONCLUSIONS: URLi demonstrated accelerated insulin lispro absorption and greater postprandial glucose reduction at different meal-to-dose timings compared with Humalog and was well tolerated in patients with T2D.

Ultra rapid lispro (URLi) shows accelerated pharmacokinetics and greater reduction in postprandial glucose versus Humalog® in patients with type 1 diabetes mellitus in a randomized, double-blind meal test early-phase study.

AIM: To compare the pharmacokinetics (PK), glucodynamics (GD), and tolerability following single and multiple daily subcutaneous (SC) doses of ultra rapid lispro (URLi) and Humalog® in patients with type 1 diabetes mellitus (T1D). MATERIALS AND METHODS: This was a two-part, randomized, double-blind, Phase 1b study. Part A used a six-period crossover design to assess PK and GD response to a solid mixed meal tolerance test (MMTT) following a single dose of URLi or Humalog administered 15 min before, immediately before, and 15 min after the start of the meal. Part B evaluated URLi or Humalog during 2 weeks of multiple daily dosing with a parallel design. The PK and GD were assessed following MMTTs at the beginning and end of the 2-week period when insulins were administered immediately before the start of the meal. RESULTS: URLi increased the insulin exposure within the first 30 min postdose by 2.2-fold and reduced the time to early half-maximal drug concentration by 37% compared with Humalog. Overall, URLi resulted in better postprandial glucose lowering when dosed before, immediately before, or after a meal compared with Humalog. Comparing the same meal-to-dose timing between the insulins, postprandial glucose excursion over 5 hours was reduced by 40%-44% for all three dose timings (-15, 0, and +15 min) with URLi, achieving statistical significance for the 0- and +15-min timings. The PK and GD profiles were sustained after daily SC dosing for 2 weeks in patients with T1D. The number of documented hypoglycaemic events was similar between URLi and Humalog during the postprandial period of the MMTTs and the outpatient period. CONCLUSIONS: URLi showed accelerated insulin lispro absorption and greater postprandial glucose reduction at different meal-to-dose timings compared with Humalog and was well tolerated in patients with T1D.

Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist.

LY2409021 is a glucagon receptor antagonist that was associated with hepatic steatosis and elevated aminotransferases in phase 2 diabetes studies. We investigated the relationship between selected genetic variants and hepatic steatosis and elevated alanine aminotransferases (ALTs) associated with LY2409021. Patients participated in a 6-week placebo-controlled trial (I1R-MC-GLDI [GLDI], n = 246) and a 52-week placebo- and active comparator-controlled trial (I1R-MC-GLDJ [GLDJ], n = 158). GLDJ had endpoints at 6 months, including measures of hepatic fat fraction (HFF) by magnetic resonance imaging. The five genes tested were patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 and rs738491), transmembrane 6 superfamily member 2 (TM6SF2) (rs58542926), peroxisome proliferative activated receptor gamma coactivator 1 alpha (PPARGC1A) (rs4361373, rs3774921, rs2970849), adenylate cyclase 3 (ADCY3) (rs713586), and insulin-like growth factor 1 (IGF-1) (rs1520220). In GLDI, PNPLA3 I148M (P = 0.001) and TM6SF2 E167K (P = 0.001) were significantly associated with an increase in ALT at 6 weeks for LY2409021 but not for placebo. In GLDJ, PNPLA3 I148M showed the same effect (P = 0.007) on ALT at 6 months but the placebo or sitagliptin did not. In GLDJ, both PNPLA3 and TM6SF2 risk-allele carriers showed increases in HFF that were numerically greater but not statistically significant. The carriers of PNPLA3 and/or TM6SF2 risk alleles showed significantly increased ALT (GLDI, +13.28 U/L in carriers versus +4.84 U/L in noncarriers, P = 4 × 10-5; GLDJ, +14.6 U/L in carriers versus +1.7 in noncarriers, P = 0.0018) and HFF (GLDJ, +5.35% in carriers versus 2.38% in noncarriers, P = 0.048). Elevation of transaminase and HFF were also noted in the noncarriers but at a significantly lower degree. Conclusion: The carriers of PNPLA3 and/or TM6SF2 variant alleles are at risk for hepatic steatosis and elevated ALT levels caused by LY2409021, a glucagon receptor antagonist. More studies are needed to investigate if our observations are generalizable to hepatic steatosis caused by other medications. (Hepatology Communications 2018;2:561-570).

Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes.

AIMS: To evaluate whether treatment with LY2409021, a novel, selective glucagon receptor antagonist, is associated with changes in hepatic fat and other safety variables related to the benefit-risk profile for chronic use in patients with type 2 diabetes (T2D). METHODS: Safety and efficacy were assessed in patients with T2D taking metformin and sulphonylurea who were randomized to LY2409021 20 mg (n = 65), placebo (n = 68), or sitagliptin 100 mg (n = 41). Key endpoints included change from baseline to month 6 in hepatic fat fraction (HFF), assessed by magnetic resonance imaging; hepatic aminotransferases; blood pressure; lipid profile; fasting plasma glucose; and glycated haemoglobin (HbA1c). RESULTS: A significant increase in HFF was seen with LY2409021 vs sitagliptin (least squares [LS] mean difference 3.72%; P < .001) and placebo (4.44%; P < .001), accompanied by significant elevations in alanine aminotransferase levels with LY2409021 vs sitagliptin (6.8 U/L; P = .039) and vs placebo (10.7 U/L; P < .001). No patients had concomitant elevations in bilirubin levels. LY2409021 treatment showed significant HbA1c reductions vs placebo (LS mean difference -0.77%; P < .001) but not sitagliptin (-0.20%; P = .383). Similar results were observed for fasting plasma glucose. LY2409021 was also associated with significant increases in systolic blood pressure vs sitagliptin (4.9 mm Hg; P = .030) and vs placebo (4.3 mm Hg; P = .029), as well as significant increases in body weight and total cholesterol. All effects of LY2409021 were reversible. CONCLUSION: In this cohort of patients with T2D, chronic glucagon receptor antagonism with LY2409021 was associated with glucose-lowering but also demonstrated increases in hepatic fat, hepatic aminotransferases, and other adverse effects.

Treatment with the glucagon receptor antagonist LY2409021 increases ambulatory blood pressure in patients with type 2 diabetes.

AIMS: To assess the effect of LY2409021 on systolic blood pressure (SBP) in patients with type 2 diabetes. MATERIALS AND METHODS: This 6-week, randomized, crossover study evaluated the effects of once-daily administration of LY2409021 20 mg vs those of placebo on SBP, diastolic BP (DBP), and mean arterial pressure (MAP) using 24-hour ambulatory BP monitoring (ABPM) in 270 subjects treated with diet/exercise ± metformin. Other measures included changes in glycemic control, serum lipids, and hepatic safety markers. RESULTS: At 6 weeks of LY2409021 treatment, 24-hour mean SBP was increased, with a least squares mean (LSM) difference of 2.26 mm Hg vs placebo (95% CI: 1.11, 3.40; P < .001). The 24-hour mean DBP and MAP also increased, with LSM differences of 1.37 mm Hg (95% CI: 0.66, 2.08; P < .001) and 1.67 mm Hg (95% CI: 0.86, 2.47; P < .001) vs placebo, respectively. At week 6, LY2409021 treatment reduced glycated hemoglobin (HbA1c) levels, with an LSM difference of -0.49% (-5.4 mmol/mol) (95% CI: -0.56%, -0.42% [-6.1, -4.6 mmol/mol]; P < .001) vs placebo. Mean HbA1c at baseline was 7.3% (56 mmol/mol). Small but significant changes in serum lipid and aminotransferase levels were observed with LY2409021 treatment (all P < .05 vs placebo). CONCLUSIONS: Statistically significant increases in BP, MAP and serum lipid levels were observed with LY2409021 treatment at a dose that lowered HbA1c and glucose levels. These effects may limit the clinical utility of LY2409021 as a chronic treatment for type 2 diabetes.

Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies.

OBJECTIVE: Type 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The efficacy (HbA1c and glucose) and safety (serum aminotransferase) of once-daily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks. RESULTS: LY2409021 produced reductions in HbA1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA1c was -0.83% (10 mg), -0.65% (30 mg), and -0.66% (60 mg) (all P < 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA1c was -0.45% (2.5 mg), -0.78% (10 mg, P < 0.05), -0.92% (20 mg, P < 0.05), and -0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] ≤10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo. CONCLUSIONS: In patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed.

Contribution of insulin deficiency and insulin resistance to the development of type 2 diabetes: nature of early stage diabetes.

At the time of diagnosis of type 2 diabetes (T2D), patients already have varying degrees of beta-cell dysfunction and insulin resistance and the defects continue to deteriorate despite treatment. We examined insulin secretion impairment and insulin resistance in overweight patients with T2D who had metformin failure, with elevated HbA1c at maximal metformin dose. Patients (N = 1,039) were examined at entry to the European Exenatide (EUREXA) clinical trial of add-on exenatide versus sulphonylurea. Mean (±SD) age was 57 ± 10 years, and BMI was 32.4 ± 4.1 kg/m(2). All patients underwent an oral glucose tolerance test; HOMA-IR, HOMA-B, ∆I(30)/∆G(30), disposition index and pro-insulin/insulin ratio were evaluated in relation to stratified HbA1c levels (≤7.3, >7.3-8.2, >8.2%) and duration of diabetes (<3, ≥3-<6, ≥6 years) using non-parametric analysis of variance. Patients overall had a wide range of impaired insulin secretion (HOMA-B: median 50.4, interquartile range 32.8-78.8) and insulin resistance (HOMA-IR: 4.8, 3.0-7.4). With increasing HbA1c levels, there was a statistically significant decrease in HOMA-B (P < 0.001), ∆I(30)/∆G(30) (P = 0.003) and disposition index (P < 0.001), and increase in pro-insulin/insulin (P < 0.001) and HOMA-IR (P < 0.001). With increasing duration since diabetes diagnosis, there was a significant decrease in HOMA-B (P < 0.001), but no significant trend in HOMA-IR, ∆I(30)/∆G(30), disposition index or pro-insulin/insulin. Metformin failure in these patients was associated with beta-cell dysfunction to a greater extent than insulin resistance. Loss of the first-phase insulin release, indicated by a low ∆I(30)/∆G(30), would indicate that this patient cohort requires add-on therapy that can maintain beta-cell function.

The beta-specific protein kinase C inhibitor ruboxistaurin (LY333531) suppresses glucose-induced adhesion of human monocytes to endothelial cells in vitro.

AIMS: Strong evidence shows that late diabetic complications in diabetes mellitus are substantially related to an increased synthesis of diacylglycerol with a subsequent activation of protein kinase C (PKC) beta. Several studies have shown that specific inhibition of the PKC isoform beta by ruboxistaurin is able to attenuate the development of microvascular complications under diabetic conditions. The aim of this in vitro study was to investigate the effect of ruboxistaurin on glucose-induced adhesion of monocytes to endothelial cells, representing one of the first pivotal steps in the course of atherogenesis. METHODS: Human umbilical venous endothelial cells were isolated and cultured to confluence in microtiter plates. After coincubation with monocytes in the presence of 0, 10, or 400 ng ruboxistaurin to achieve PKC beta-specific and -unspecific PKC inhibition, cells were fixed and monocyte adhesion was determined by means of a standardized chemiluminescence assay. Expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin) was also measured by chemiluminescence methods. RESULTS: Adhesion of monocytes to endothelial cells cultured under hyperglycemic conditions (27.7 mM glucose) was increased by 30.9 +/- 5.1% (p < 0.001) versus endothelial cells cultured under normoglycemic (NG) conditions (5.5 mM). Pretreatment of endothelial cells with 10 nM (PKC beta-specific concentration) and 400 nM (PKC beta-unspecific concentration) led to a significant reduction of glucose-induced adhesion of monocytes to endothelial cells that was statistically not different from endothelial adhesion under NG conditions (-7.2 +/- 3.1 and -8.1 +/- 2.6%, respectively; not significant vs NG). A nonsignificant tendency to lower the expression of adhesion molecules was seen with 10 ng of ruboxistaurin. CONCLUSIONS: We conclude that monocyte adhesion to endothelial cells under hyperglycemic conditions is at least mediated by PKC beta activation. Ruboxistaurin is able to suppress this monocyte adhesion even in a PKC beta-specific concentration. Further studies should evaluate these potential effects of ruboxistaurin in vivo.

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.

Impact of insulin on microvascular blood flow and endothelial cell function in the postprandial state in patients with Type 1 diabetes.

The aim of the present study was to investigate postprandial microvascular blood flow following a standardized test meal in nondiabetic subjects and in patients with Type 1 diabetes after regular insulin or insulin lispro. In this open-label, randomised cross-over study, 20 nondiabetic participants and 20 patients with Type 1 diabetes were enrolled. To valuate the postprandial time course of skin microvascular blood flow, laser Doppler flux (LDF) readings were obtained at baseline and every 30 min following a standardized test meal. Furthermore, the microvascular response to acetylcholine (Ach) was measured, and blood was collected for the measurement of serum insulin and blood glucose levels. Patients with Type 1 diabetes received single doses of regular insulin or insulin lispro, respectively, in a randomised sequence, while in nondiabetics, no insulin substitution was performed. In nondiabetic participants, skin microvascular blood flow showed an early increase in LDF by median 6.0 arbitrary units (AU; interquartile range: 1.8-14.0 AU) within the first postprandial hour. The microvascular response to Ach also increased with a median response of 26.0 (19.0-49.3) AU at 30 min pp and 50.0 (31.7-65.1) AU at 60 min pp. In patients with Type 1 diabetes, the time course of postprandial LDF measurements observed after the administration of insulin lispro was nearly similar to the one observed in nondiabetic controls and differed from that after subcutaneous regular insulin treatment. The postprandial microvascular response to Ach was stronger following insulin lispro compared with regular insulin [30 min pp: 26.0 (19.0-49.3) vs. 20.9 (9.7-26.1) AU, P=.0001]. Postprandial microvascular blood flow is disturbed in patients with Type 1 diabetes. Improvement of postprandial metabolic control was found to improve postprandial microvascular function.