Study of Insulin Lispro in Participants With Inadequately Controlled Type 2 Diabetes

Two Approaches to Escalate Lispro Therapy in Patients With Type 2 Diabetes Mellitus Not Achieving Adequate Glycemic Control on Basal Insulin Therapy and Oral Agents Alone (AUTONOMY)

Evidence regarding optimal methods of insulin dose adjustment is lacking in the literature. The purpose of this study is to evaluate the efficacy and safety of two approaches to escalate prandial insulin therapy in participants with type 2 diabetes mellitus not achieving adequate glycemic control on basal insulin.

Participants who enter the study and are already taking insulin glargine with a screening HbA1c >7.0% will be randomized to one of two treatment arms. Both arms will add prandial insulin to existing basal insulin therapy.

Inclusion Criteria:

• Have type 2 diabetes
• Have been treated for at least 90 days with insulin glargine, neutral protamine Hagedorn (NPH), or detemir in combination with oral antihyperglycemic agents as monotherapy, dual, or triple therapy [sulfonylurea, meglitinide, metformin, pioglitazone, or dipeptidyl peptidase-4 (DPP-4) inhibitor] and in the opinion of the investigator requires further intensification of therapy
• Are treated with insulin glargine, NPH, or detemir at least 20 units per day (U/day) at enrollment
• Have an glycated hemoglobin (HbA1c) value greater than 7.0% and less than or equal to 12.0% according to the central laboratory at screening
• Capable of and willing to do the following: inject insulin with a prefilled pen, perform self blood glucose monitoring and record keeping as required by this protocol, as determined by the investigator
• Have given written informed consent to participate in this study in accordance with local regulations

Exclusion Criteria:

• Prior rapid- or short-acting insulin therapy: participants receiving scheduled long-term short-acting or rapid-acting or premixed insulin therapy within the past 6 months will not be eligible to participate in the study. Participants who have previously received short- or rapid-acting insulin as part of short-term insulin therapy (during gestational diabetes, during an acute hospitalization or illness) or occasional use will be allowed to participate in this study. Occasional use (e.g., used to treat acute hyperglycemia) shall be defined as less than daily administration of not more than 1 dose per day of short- or rapid-acting insulin
• Concomitant medications: glucagon-like peptide-1 (GLP-1) receptor agonist, alpha-glucosidase inhibitor, or rosiglitazone use concurrently or within 3 months prior to entry into the study
• Severe hypoglycemia: have had more than one episode of severe hypoglycemia (defined as requiring assistance of a third party due to disabling hypoglycemia) within 6 months prior to entry into the study
• Excessive insulin resistance: received a total daily dose of insulin greater than 2.0 units per kilogram (U/kg) at the time of randomization
• Morbid obesity: defined as a body mass index greater than or equal to 45 kilograms per square meter (kg/m²)
• Malignancy: have active or untreated malignancy, or have been in remission from clinically significant malignancy (other than basal cell or squamous cell skin cancer) for less than 5 years
• Cardiovascular: have cardiac disease with functional status that is New York Heart Association Class III or IV (see New York Heart Association Cardiac Disease Classifications) or have Congestive Heart Failure (CHF) requiring pharmacologic treatment or, in the investigator's opinion, have severe dependent edema (i.e., edema of the feet or ankles) or have any condition associated with hypoperfusion, hypoxemia, dehydration, or sepsis
• Renal: have a history of renal transplantation or are currently receiving renal dialysis or have serum creatinine greater than or equal to 2 milligrams per deciliter (mg/dL) if not on metformin
• Hepatic: have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) greater than 3 times the upper limit of the reference range as defined by the central laboratory
• Hematologic: have known hemoglobinopathy or chronic anemia or other known blood disorder
• Reproductive:(for women) are pregnant or intend to become pregnant during the course of the study; are sexually active women of childbearing potential not actively practicing birth control by a method determined by the investigator to be medically acceptable; or are breastfeeding
• Allergy: have known allergy to insulin lispro, insulin glargine, or excipients contained in these products
• Glucocorticoid therapy: receiving chronic (lasting longer than 2 weeks) systemic glucocorticoid therapy (excluding topical and inhaled preparations) or have received such therapy within 2 weeks immediately before screening
• Adherence to protocol: have any other condition (including known drug or alcohol abuse or psychiatric disorder) that precludes the participant from following and completing the protocol
• Prior participation: are currently enrolled in, or have participated in, an interventional medical, surgical, or pharmaceutical drug or device or off-label use study (an investigational study in which a medical or surgical treatment was given) within 30 days prior to entry into the study, or persons who have previously completed or withdrawn from this study (after having signed the informed consent document). Participants may be ineligible if they are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study
• Non-approved drug: have been treated with a drug within the last 30 days that has not received regulatory approval at the time of study entry