In type 2 diabetes treated with high-dose insulin, liraglutide reduced HBA1c

Question In patients with uncontrolled type 2 diabetes treated with high doses of insulin, what is the effect of adding liraglutide on glycated hemoglobin (Hb) A1c levels? Methods Design Randomized placebo-controlled trial. ClinicalTrials.gov NCT01505673. Allocation {Concealed}*. Blinding Blinded (patients, {health care providers, data collectors, outcome assessors, and data safety committee}*). Follow-up period 6 months. Setting {Outpatient clinics, University of Texas Southwestern Medical Center, Texas, USA}*. Patients 71 patients 18 years of age (mean age 54 y, 63% women) who had type 2 diabetes, HbA1c level 7.5% to 11.0% (9.3 to 14.9 mmol/L), and were receiving a total daily dose (TDD) of insulin >1.5 U/kg/d and stable doses of all antihyperglycemic agents for 3 months. Exclusion criteria included history of pancreatic disease, lipase level >3 times above normal, creatinine clearance 30 mL/min/1.73m2 (0.501 mL/s/m2), incretin therapy in the previous 90 days, and decompensated comorbidities. Intervention Subcutaneous liraglutide, 1.8 mg/d (n =35), or placebo (n =36). For patients with HbA1c8.0% (10.1 mmol/L), TDD of insulin was reduced by 20% at baseline and increased to baseline level at 1 month if no hypoglycemia events occurred. Insulin was titrated if patients had recurring hypoglycemia. During the study, baseline hypoglycemic medications were continued. Outcomes Primary outcome was HbA1c level. Secondary outcomes included weight, reaching target HbA1c <7.0% (8.6 mmol/L), and hypoglycemia (capillary glucose level <70 mg/dL). Patient follow-up 93% (intention-to-treat analysis). Main results The main results are in the Table. Conclusion In patients with uncontrolled type 2 diabetes treated with high doses of insulin, adding liraglutide reduced glycated hemoglobin levels by 0.9% and reduced weight. Liraglutide vs placebo in patients with uncontrolled type 2 diabetes treated with high doses of insulin Outcomes Mean change from baseline At 6 mo Liraglutide Placebo Mean difference (95% CI) HbA1c (%) 0.9% 0.0% 0.9% (1.5 to 0.4) Weight (kg) 2.0 0.4 2.3 (4.3 to 0.4) Event rates RBI (CI) HbA1c <7.0% 22% 3% 644% (30 to 4418) RRI (CI) Any hypoglycemia 86% 69% 23% (4 to 65) Hb = hemoglobin; RBI = relative benefit increase; other abbreviations defined in Glossary. RBI, RRI, and CI calculated from event rates in article. Number needed to treat (6, CI 3 to 28) calculated from event rates in article. Capillary glucose level <70 mg/dL. Commentary Patients with diabetes receiving intensive insulin therapy with various combinations of basal and prandial insulin can be caught in a vicious but common cycle, whereby insulin requirements increase over time, and this in turn contributes to weight gain and hypoglycemia and further increases in insulin dosing. At this stage, clinicians observe a practical limit to the efficacy of insulin titration alone on glucose-lowering and often add or continue metformin to reduce insulin resistance; use concentrated insulin, such as U-500 insulin; or consider weight loss surgery if patients meet criteria. Injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as liraglutide, are a relatively new addition to our treatment armamentarium. These drugs improve postmeal glucose control and insulin sensitivity and contribute to weight loss (1). Treatment with basal insulin plus GLP-1 RAs is well-established in diabetes guidelines (2) and may be as effective as adding prandial insulin therapy (1). When GLP-1 RAs are started, a preemptive reduction in insulin dosage by 25% to 30% in patients with HbA1c <9% may reduce the risk for hypoglycemia. The trial by Vanderheiden and colleagues supports previous findings of reduced insulin requirements and improved glucose control and weight loss in patients who required high doses of insulin and received liraglutide (3). Weight loss, although modest for some patients, is an important outcome and may increase patient satisfaction. GLP-1 RAs should not be used in patients with a history of pancreatitis, gastroparesis, personal or family history of medullary thyroid cancer, or multiple endocrine neoplasia type 2 (2). Gastrointestinal side effects, additional burden of injections, risk for hypoglycemia, and high cost may be barriers to use (1). The US Food and Drug Administration may soon approve combination basal insulin with a GLP-1 RA, and this may simplify therapy for patients with severe insulin resistance. Future research should assess the effects of GLP-1 RAs combined with multiple daily insulin regimens over longer periods to determine cardiovascular safety and if they improve patient-important outcomes.