A Study of the Effect of LY2189265 on Two Blood Pressure Drugs

Pharmacokinetic and Pharmacodynamic Effect of LY2189265 on Lisinopril in Subjects With Hypertension and Metoprolol in Healthy Subjects

The purpose of this study is twofold:

1. To evaluate the effect of LY2189265 on how the body absorbs a blood pressure lowering drug (lisinopril) in participants with high blood pressure who are currently taking lisinopril.
2. To evaluate the effect of LY2189265 on heart rate and blood pressure in healthy volunteers when taken with a Beta-blocker drug (metoprolol).

In Part 1, participants will receive four weekly injections of LY2189265 with continued use of normal lisinopril therapy.

Part 2 is a cross-over study design. Participants will receive a single injection of LY2189265 in one period, and seven daily doses of metoprolol and a single injection of LY2189265 in another period.

Inclusion Criteria:

• Male participants: agree to use a reliable method of birth control during the study and for 3 months following the last dose of the investigational product
• Female participants: women not of child-bearing potential due to menopause or surgical sterilization (at least 6 weeks post surgical bilateral oophorectomy, hysterectomy or tubal ligation) confirmed by medical history
• Have a body mass index (BMI) of 18.5 to 40.0 kilograms/square meter (kg/m^2), inclusive at the time of screening
• Have clinical laboratory test results within normal reference range for the population or investigator site, or results with acceptable deviations that are judged to be not clinically significant by the investigator
• Have venous access sufficient to allow for blood sampling as per the protocol
• Are reliable and willing to make themselves available for the duration of the study and are willing to follow study restrictions
• Have given written informed consent on an informed consent form (ICF) approved by Lilly and the corresponding ethics committee (EC) or ethical review board (ERB) governing the site

Part 1 only:

• Have controlled mild to moderate hypertension (supine blood pressure [BP] less than or equal to 140/90 millimeter of mercury (mm Hg) at screening, or results with acceptable deviations that are judged not to be clinically significant by the investigator).
• Males and females with stable medical problems (including Type 2 Diabetes Mellitus [T2DM]) that, in the investigator's opinion, will not significantly alter the disposition of the drug, will not place the participant at increased risk by participating in the study, and will not interfere with interpretation of the data may be included
• Have been on oral antihypertensive medication (lisinopril daily [QD]) for at least 3 months prior to screening, have been on a stable dose for at least 1 month prior to screening, and are, in the investigator's opinion, able to safely adhere to a QD morning dosing regimen. Additional medication may be permitted as indicated

T2DM Participants (Part 1 only):

• Have T2DM controlled with diet or exercise alone or stable on a single oral agent antihyperglycemic medication (metformin, sulfonylureas, repaglinide, nateglinide, acarbose [or other disaccharidase inhibitors] or thiazolidinediones) for at least 3 weeks (3 months for thiazolidinediones) prior to admission
• Have a hemoglobin A1c (HbA1c) value of 6.0% to 9.5% at screening or within 4 weeks prior to screening
• Clinical laboratory test results within normal range or deemed clinically insignificant by the investigator. Abnormalities of serum glucose, serum lipids, urinary glucose, and urinary protein consistent with T2DM are acceptable

Part 2 only:

• Are overtly healthy, as determined by medical history and physical examination

Exclusion Criteria:

• Are currently enrolled in, have completed or discontinued within the last 30 days from, a clinical trial involving an investigational product; or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
• Have known allergies to Glucagon-like peptide-1 (GLP-1)-related compounds, including LY2189265, or any components of the formulation
• Are participants who have previously completed or withdrawn from this study, or have taken part in any other study investigating LY2189265 or GLP-1-related compounds within the last 3 months
• Have an abnormality in the 12-lead electrocardiogram (ECG) that, in the opinion of the investigator, increases the risks associated with participating in the study
• Have a history or presence of gastrointestinal disorder (including pancreatitis [history of chronic pancreatitis or idiopathic acute pancreatitis] or gall bladder disease) or gastrointestinal disease that impacts gastric emptying (GE) (e.g. gastric bypass surgery, pyloric stenosis) or could be aggravated by GLP-1 analogs (for example; esophageal reflux). Participants having had cholecystectomy (removal of gall bladder) in the past with no further sequelae, may be included in the study at the discretion of the screening physician
• Have a history or presence of thyroid disease, unless have been on a stable dose of thyroxine replacement therapy for at least 1 month
• Show history or evidence of significant active neuropsychiatric disease
• Have personal or family history of medullary thyroid cancer (MTC) or a genetic condition that predisposes to MTC
• Regularly use known drugs of abuse and/or show positive findings on urinary drug screening
• Show evidence of human immunodeficiency virus (HIV) infection and/or positive human HIV antibodies
• Show evidence of hepatitis C and/or positive hepatitis C antibody
• Show evidence of hepatitis B and/or positive hepatitis B surface antigen
• Intend to start new concomitant medication during the study, including over-the-counter and herbal medication, use drugs that directly reduce gastrointestinal motility or who regularly use systemic corticosteroids, or potent, inhaled, or intranasal steroids known to have a high rate of systemic absorption
• Have donated more than 500 milliliters (mL) of blood within the month prior to screening
• Have a nondominant arm circumference of greater than 42 centimeters (cm)
• Have an average weekly alcohol intake that exceeds 21 units per week (males up to age 65) and 14 units per week (males over 65 and females), or are unwilling to stop alcohol consumption from 48 hours before each admission until discharge from the unit, and to limit alcohol intake to a maximum of 2 units/day on all other days from screening through 48 hours prior to the follow-up visit. (1 unit = 12 ounces [oz] or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits)
• Are participants who, in the opinion of the investigator, are in any way unsuitable to participate in the study

Part 1 only:

• Have any medical conditions, medical history or are taking any medication which are contraindicated within the lisinopril product information leaflet

Part 2 only:

• Intend to use over-the-counter medication (with the exception of paracetamol and/or antacids) within 7 days prior to dosing or prescription medication (with the exception of vitamin/mineral supplements and/or hormone replacement therapy and/or thyroid replacement therapy) within 14 days prior to dosing of the investigational product
• Have any medical conditions, medical history or are taking any medication which are contraindicated within the metoprolol product information leaflet