Parag Garhyan

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.

Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes.

To describe the clinical effects of single and multiple doses of a potent, selective, orally administered, small‐molecule antagonist of the human glucagon receptor, LY2409021, in healthy subjects and in patients with type 2 diabetes.

Basal Insulin Peglispro Demonstrates Preferential Hepatic Versus Peripheral Action Relative to Insulin Glargine in Healthy Subjects

OBJECTIVE We evaluated the endogenous glucose production (EGP) and glucose disposal rate (GDR) over a range of doses of basal insulin peglispro (BIL) and insulin glargine in healthy subjects. RESEARCH DESIGN AND METHODS This was a single-center, randomized, open-label, four-period, incomplete-block, crossover study conducted in eight healthy male subjects. Subjects had 8-h euglycemic clamps performed with primed, continuous infusions of BIL (5.1 to 74.1 mU/min) in three dosing periods and insulin glargine (20 or 30 mU/m2/min) in a fourth period, targeted to achieve 50–100% suppression of EGP. D-[3-3H] glucose was infused to assess rates of glucose appearance and disappearance. RESULTS Mean BIL and insulin glargine concentrations (targeted to reflect the differences in intrinsic affinities of the two basal insulins) ranged from 824 to 11,400 and 212 to 290 pmol/L, respectively, and increased accordingly with increases in dose. Suppression of EGP and stimulation of GDR were observed with increasing concentrations of both insulins. At insulin concentrations where EGP was significantly suppressed, insulin glargine resulted in increased GDR. In contrast, at comparable suppression of EGP, BIL had minimal effect on GDR at lower doses and had substantially less effect on GDR than insulin glargine at higher doses. CONCLUSIONS The novel basal insulin analog BIL has relative hepatopreferential action and decreased peripheral action, compared with insulin glargine, in healthy subjects.

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

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).

Basal insulin peglispro: Overview of a novel long-acting insulin with reduced peripheral effect resulting in a hepato-preferential action.

Basal insulin peglispro (BIL) is a novel basal insulin with a flat, prolonged activity profile. BIL has been demonstrated in a dog model, in healthy men and in patients with type 1 diabetes (T1D) to have significant hepato‐preferential action resulting from reduced peripheral activity. In the IMAGINE‐Phase 3 clinical trial program, more than 6000 patients were included, of whom ~3900 received BIL. Of the 7 pivotal IMAGINE trials, 3 studies were double‐blinded and 3 were in T1D patients. BIL consistently demonstrated a greater HbA1c reduction, less glycaemic variability and a clinically relevant reduction in the rates of nocturnal hypoglycaemia across comparator [glargine and isophane insulin (NPH)] studies. Trials using basal/bolus regimens had higher rates of total hypoglycaemia with BIL due to higher rates of daytime hypoglycaemia. Severe hypoglycaemia rates were similar to comparator among both patients with T1D or type 2 diabetes (T2D). T1D patients lost weight compared with glargine (GL). Patients with T2D tended to gain less weight with BIL than with glargine. Compared to glargine, BIL was associated with higher liver fat, triglycerides and alanine aminotransferase (ALT) levels, including a higher frequency of elevation of ALT ≥3 times the upper limit of normal, but without severe, acute drug‐induced liver injury. Injection site reactions, primarily lipohypertrophy, were more frequent with BIL. In conclusion, BIL demonstrated better glycaemic control with reduced glucose variability and nocturnal hypoglycaemia but higher triglycerides, ALT and liver fat relative to conventional comparator insulin. The hepato‐preferential action of BIL with reduced peripheral activity may account for these findings.

Treatment with the Glucagon Receptor Antagonist LY2409021 Increases Ambulatory Blood Pressure in Patients with Type 2 Diabetes.

To assess the effect of LY2409021 on systolic blood pressure (SBP) in patients with type 2 diabetes.

18. Glucagon Receptor Antibody LY2786890 Reduced Glucose Levels in Type 2 Diabetes Mellitus Patients (106-LB)

SamenvattingGlucagon levels are often elevated in type 2 diabetes mellitus (T2DM) and may contribute to hyperglycemia. LY2786890 (LY) is a humanized IgG4 monoclonal glucagon receptor antibody that displays antagonistic activity against the human glucagon receptor. A Phase 1, randomized, double-blind, placebo-controlled study examined the safety and efficacy of single doses of LY in healthy subjects (n = 10, intravenous [IV] 0.05 mg/kg) and T2DM patients (n = 44; IV 0.05, 0.1, 0.3, 0.55 mg/kg; subcutaneous [SC] 0.1, 0.55 mg/kg; mean fasting blood glucose [FBG] 126 mg/dL; hemoglobin A1c 7.3%). LY was safe and well tolerated. Hypoglycemia was infrequent and mild. Dose dependent elevations in aminotransferase levels were seen in T2DM patients; levels returned to baseline during follow up with no clinical signs of liver injury or significant elevations in bilirubin or alkaline phosphatase. Pharmacokinetic and pharmacodynamic (PD) profiles of LY supported once weekly SC dosing. The half-life (4 to 26 days) and PD time-action were concentration dependent. Absolute bioavailability after SC administration was estimated to be 50%. In T2DM patients, LY significantly reduced FBG (Fig ure) and increased plasma glucagon up to approximately 3-fold by day 2. As seen with oral glucagon receptor an tagonists, these data demonstrate that blocking glucagon action effectively lowers blood glucose in T2DM subjects.

Dose Unit Establishment for a New Basal Insulin Using Joint Modeling of Insulin Dose and Glycemic Response

Background: For new insulin analogs with properties that vary from human insulin, defining activity in units of human insulin based on glycemic lowering efficacy may be challenging. Here we present a new method that can be used to quantify a unit dose of an experimental insulin when the traditional euglycemic clamp method is not adequate. Methods: Joint modeling of insulin dose and the glycemic outcome variable hemoglobin A1c (HbA1c), where both were response variables, was used to evaluate insulin unit potency for basal insulin peglispro (BIL). The data were from the Phase 3 program for BIL, which included greater than 5500 patients with type 1 or type 2 diabetes who were treated for 26 or 52 weeks with BIL or a comparator insulin. Both basal-bolus and basal insulin only studies were included, and some type 2 diabetes patients were insulin-naïve. Results: The analysis showed that 1 unit of BIL, composed of 9 nmol of active ingredient, had similar or slightly greater potency compared to 1 unit insulin glargine or NPH insulin for all populations. Conclusions: Despite some limitations, the joint modeling of HbA1c and insulin dose provides a reasonable approach to estimate the relative potency of a new basal insulin versus an established basal insulin.

Basal insulin peglispro increases lipid oxidation, metabolic flexibility, thermogenesis and ketone bodies compared to insulin glargine in subjects with type 1 diabetes mellitus

When treated with basal insulin peglispro (BIL), patients with type 1 diabetes mellitus (T1DM) exhibit weight loss and lower prandial insulin requirements versus insulin glargine (GL), while total insulin requirements remain similar. One possible explanation is enhanced lipid oxidation and improved ability to switch between glucose and lipid metabolism with BIL. This study compared the effects of BIL and GL on glucose and lipid metabolism in subjects with T1DM.

Attenuated Suppression of Lipolysis Explains Increases in Triglyceride Secretion and Concentration with Basal Insulin Peglispro (BIL) Relative to Insulin Glargine Treatment in Patients with Type 1 Diabetes

To test the hypothesis that, as well as lowering weight and increasing plasma triglyceride (TG) levels and hepatic fat compared with insulin glargine (GL) in patients with type 1 diabetes, the attenuated peripheral effects of basal insulin peglispro (BIL) may include increased free fatty acid flux to the liver, causing increased very‐low‐density lipoprotein (VLDL)‐TG secretion and lipid oxidation, and decreased TG adipose tissue deposition.