DETERMINING INSULIN DOSE AT THE TIME OF DISCHARGE IN A HIGH-RISK POPULATION: IS THERE ROOM FOR IMPROVEMENT?

OBJECTIVE: To evaluate the adequacy of the insulin dose prescribed at hospital discharge in a high-risk population and assess patient characteristics that influence insulin dose requirement in the immediate postdischarge period. METHODS: This was a retrospective study conducted at Parkland Health System. We included all patients admitted to a medical floor who received an insulin prescription at discharge and had at least one follow-up visit within 6 months of discharge. All data were extracted by a detailed manual review of each electronic medical record. RESULTS: At the postdischarge follow-up (N = 797, median 33 days from discharge), 60% of patients required an insulin dose adjustment; 47% of the patients required a dose decrease. Significant predictors of a decrease insulin requirement postdischarge included (multiple regression beta coefficient [95% confidence interval]): newly diagnosed diabetes, -12.7 (-17.7, -7.7); ketosis-prone diabetes, -8.4 (-15, -1.8); glycated hemoglobin A1c (HbA1c), <10% (86 mmol/mol) -7.0 (-11.4, -2.6); discharge insulin total daily dose, -5.3 (-9.3, -1.3); and metformin prescription, -4.9 (-8.4, -1.3). CONCLUSION: An insulin dose adjustment (most commonly a decrease) was necessary shortly after discharge in more than half of our patients. A better model to estimate insulin dose at discharge is needed along with short-term follow-up after discharge for insulin titration. A pre-emptive insulin dose reduction at discharge should be considered for patients with newly diagnosed diabetes, ketosis-prone diabetes, metformin prescription, and those with HbA1c <10% at presentation. ABBREVIATIONS: DKA = diabetic ketoacidosis; HbA1c = glycated hemoglobin A1c; KPDM = ketosis-prone diabetes mellitus; TDD = total daily dose.

The effect of baseline characteristics on clinical efficacy of liraglutide in patients treated with high-dose insulin.

In patients requiring high-dose insulin treatment, a randomized, double-blind, placebo-controlled study showed that liraglutide improved glycaemic control and treatment satisfaction while promoting weight loss. We performed a post hoc analysis to evaluate if patients' baseline characteristics impact the efficacy of liraglutide, and which outcomes correlate with treatment satisfaction. We used regression analysis to model the change in HbA1c and weight, with treatment assignment and baseline characteristics [HbA1c, age, body mass index (BMI), total daily dose (TDD) of insulin, duration of insulin treatment, and type of insulin regimen] as independent variables. Improvement in HbA1c was best predicted by treatment with liraglutide, followed by higher baseline HbA1c, BMI and age. Changes in weight were only associated with liraglutide treatment, independent of all baseline characteristics. Improvement in HbA1c was the only significant predictor of improvement in treatment satisfaction, while weight loss, change in TDD of insulin and rate of hypoglycaemia did not influence treatment satisfaction. In patients treated with high-dose insulin, liraglutide significantly improved glycaemic control and led to weight loss regardless of patients' baseline characteristics. Improvement in HbA1c was the most important predictor of patients' treatment satisfaction.

Effect of Adding Liraglutide vs Placebo to a High-Dose lnsulin Regimen in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

IMPORTANCE: An increasing number of patients with type 2 diabetes are treated with high doses of insulin. Such treatment is associated with weight gain, hypoglycemia, and high treatment burden. OBJECTIVE: To assess the effectiveness and safety of adding a glucagon-like peptide 1 receptor agonist to the treatment regimen of patients with type 2 diabetes requiring therapy with high-dose insulin. DESIGN, SETTING, AND PARTICIPANTS: This clinical trial was a double-blind, placebo-controlled, randomized (1:1) study with 6 months of follow-up, conducted from August 13, 2012, to February 9, 2015, at ambulatory clinics at the University of Texas Southwestern Medical Center and Parkland Hospital. Participants were 71 patients with uncontrolled type 2 diabetes (glycated hemoglobin level, 7.5%-11.0%) using more than 1.5 U/kg/d of insulin. INTERVENTIONS: Subcutaneous injection of liraglutide (1.8 mg/d) or matching placebo for 6 months. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in glycated hemoglobin level. Secondary outcomes were changes in weight, hypoglycemia rate, insulin dosage, and quality-of-life measures. RESULTS: Among 71 patients, 45 (63%) were female. The mean (SD) age of patients was 54.2 (7.4) years, with a mean (SD) type 2 diabetes duration of 17.9 (8.4) years and a mean (SD) total daily dose of insulin of 247.0 (95.1) U. Ninety-three percent (66 of 71) of participants completed all scheduled visits. The glycated hemoglobin level improved from a mean (SD) of 9.0% (1.2%) to 7.9% (1.1%) in the liraglutide group (P < .001) and remained unchanged (8.9%) in the placebo group, with an estimated treatment difference of 0.9% (95% CI, -1.5 to -0.4) (P = .002). Weight decreased from a mean (SD) of 114.6 (21.4) kg to 113.6 (20.8) kg in the liraglutide group vs a mean (SD) increase from 116.1 (26.6) kg to 117.2 (27.2) kg in the placebo group, with a treatment difference of -2.3 kg (95% CI, -4.3 to -0.4 kg) (P = .02). The total daily dose of insulin decreased 11.5% (95% CI, -21.8% to -1.1%) in the liraglutide group (P = .20). The hypoglycemia rate was higher in the first month after initiation of liraglutide compared with placebo (2.30 vs 0.91 events per person-month, P = .01), while the overall hypoglycemia rate over the entire follow-up was similar between groups (P = .11). Glycemia control perception, satisfaction with insulin treatment, and willingness to continue insulin use improved more in the liraglutide group. CONCLUSIONS AND RELEVANCE: Liraglutide added to high-dose insulin therapy improved glycemic control, decreased body weight, and enhanced treatment satisfaction in this difficult-to-treat patient population with high-dose insulin requirements. Further studies are warranted to confirm these findings and evaluate the long-term risk and benefit of this treatment option. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01505673.

Mechanisms of Action of Liraglutide in Patients With Type 2 Diabetes Treated With High-Dose Insulin.

CONTEXT: The mechanisms of action of incretin mimetics in patients with long-standing type 2 diabetes (T2D) and high insulin requirements have not been studied. OBJECTIVE: To evaluate changes in ß-cell function, glucagon secretion, and fat distribution after addition of liraglutide to high-dose insulin. DESIGN: A single-center, randomized, double-blind, placebo-controlled trial. SETTING: University of Texas Southwestern and Parkland Memorial Hospital clinics. PATIENTS: Seventy-one patients with long-standing (median, 17 years) T2D requiring high-dose insulin treatment (>1.5 U/kg/d; average, 2.2 ± 0.9 U/kg/d). INTERVENTION: Patients were randomized to liraglutide 1.8 mg/d or matching placebo for 6 months. MAIN OUTCOME MEASURES: We measured changes in insulin and glucagon secretion using a 4-hour mixed-meal challenge test. Magnetic resonance-based techniques were used to estimate sc and visceral fat in the abdomen and ectopic fat in the liver and pancreas. RESULTS: Glycosylated hemoglobin improved significantly with liraglutide treatment, with an end-of-trial estimated treatment difference between groups of −0.9% (95% confidence interval, −1.5, −0.4%) (P = .002). Insulin secretion improved in the liraglutide group vs placebo, as measured by the area under the curve of C-peptide (P = .002) and the area under the curves ratio of C-peptide to glucose (P = .003). Insulin sensitivity (Matsuda index) and glucagon secretion did not change significantly between groups. Liver fat and sc fat decreased in the liraglutide group vs placebo (P = .0006 and P = .01, respectively), whereas neither visceral nor pancreatic fat changed significantly. CONCLUSIONS: Treatment with liraglutide significantly improved insulin secretion, even in patients with long-standing T2D requiring high-dose insulin treatment. Liraglutide also decreased liver and sc fat, but it did not alter glucagon secretion.