Neuropsychiatric safety with liraglutide 3.0 mg for weight management: Results from randomized controlled phase 2 and 3a trials.

AIMS: Liraglutide, a GLP-1 receptor agonist, regulates appetite via receptors in the brain. Because of concerns regarding the potential of centrally-acting anti-obesity medications to affect mental health, pooled neuropsychiatric safety data from all phase 2 and 3a randomized, double-blind trials with liraglutide 3.0 mg were evaluated post hoc. METHODS: Data from the liraglutide weight-management programme were pooled. Across trials, individuals with a body mass index ≥30 or ≥27 kg/m2 with weight-related comorbidities were randomized to once-daily subcutaneous liraglutide 3.0 mg (n = 3384) or placebo (n = 1941), both with a 500 kcal/d deficit diet, plus exercise. Adverse events related to neuropsychiatric safety were collected in all trials. Additionally, in the phase 3a trials, validated mental-health questionnaires were prospectively and systematically administered. RESULTS: In the pooled analysis of 5325 randomized and exposed individuals, rates of depression (2.1 vs 2.1 events/100 person-years) and anxiety (1.9 vs 1.7 events/100 person-years) through adverse event reporting were similarly low in liraglutide and placebo groups. Nine (0.3%) individuals receiving liraglutide and 2 (0.1%) receiving placebo reported adverse events of suicidal ideation or behaviour. In phase 3a trials, mean baseline Patient Health Questionnaire-9 scores of 2.8 ± 3.0 vs 2.9 ± 3.1 for liraglutide vs placebo improved to 1.8 ± 2.7 vs 1.9 ± 2.7, respectively, at treatment end; 34/3291 individuals (1.0%) receiving liraglutide 3.0 mg vs 19/1843 (1.0%) receiving placebo reported suicidal ideation on the Columbia-Suicide Severity Rating Scale. CONCLUSIONS: Results of this exploratory pooled analysis provide no cause for concern regarding the neuropsychiatric safety of treatment with liraglutide 3.0 mg in patients similar to those included in the examined trials. Although there was a small numerical imbalance in suicidal ideation with liraglutide through adverse event reporting, no between-treatment imbalances in suicidal ideation/behaviour or depression were noted through prospective questionnaire assessments.

Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6).

BACKGROUND: Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist. METHODS: Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1.8 mg once a day (n=233) or exenatide 10 microg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA(1c)). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882. FINDINGS: Mean baseline HbA(1c) for the study population was 8.2%. Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]; estimated treatment difference -1.01 mmol/L; 95% CI -1.37 to -0.65; p<0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide -3.24 kg vs exenatide -2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode. INTERPRETATION: Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations. FUNDING: Novo Nordisk A/S.

The prevalence of cardiovascular disease by vascular bed and impact on healthcare costs in a large, real-world population with type 2 diabetes.

INTRODUCTION: The purpose of this study was to assess prevalence of atherosclerotic cardiovascular disease (ASCVD) according to number of affected vascular beds and the impact on healthcare utilization and costs in persons with type 2 diabetes mellitus (type 2 DM) and established ASCVD. METHODS: In this retrospective, cross-sectional analysis, adults with type 2 DM and ASCVD in a large US administrative claims database were categorized by number of ASCVD-affected vascular beds (brain, heart, peripheral vasculature). Annual healthcare utilization and costs for 2015 were determined, including subgroup analyses by age group (18-44, 45-64, ≥65 years). RESULTS: Among 539 089 individuals with type 2 DM and ASCVD, 47.0% had ASCVD affecting >1 vascular bed. The most prevalent ASCVD diagnoses were acute coronary syndrome (26.6%), peripheral arterial disease (24.5%) and stroke (18.6%). Mean annual total healthcare costs per person increased with increasing number of vascular beds, from 1 ($17 741) to 2 ($25 877) to 3 ($33 412). A similar pattern of increased healthcare utilization with increasing number of vascular beds was observed. Among individuals with 1 affected vascular bed, mean total healthcare costs per person were comparable across age subgroups; however, if >1 vascular bed was affected, the mean total healthcare costs were highest in the youngest age cohort. CONCLUSIONS: These real-world data showed that almost half of individuals with type 2 DM and ASCVD had ASCVD affecting >1 vascular bed. A higher number of affected vascular beds were associated with higher mean total healthcare costs and utilization, with a disproportionate increase noted in younger relative to older people.

Impact of atherosclerotic cardiovascular disease on healthcare resource utilization and costs in patients with type 2 diabetes mellitus in a real-world setting.

BACKGROUND: This study evaluated the impact of atherosclerotic cardiovascular disease (ASCVD) on healthcare resource utilization and costs in patients with type 2 diabetes mellitus (T2DM). METHODS: This study was a retrospective, cross-sectional study using US claims data. Adult patients with T2DM were stratified by presence or absence of ASCVD and compared regarding annual (2015) healthcare resource utilization and associated costs. Subgroup analyses were conducted for three age groups (18-44, 45-64, and ≥ 65 years). RESULTS: Among 1,202,596 eligible patients with T2DM, 45.2% had documented ASCVD. The proportions of patients with inpatient and ER-based resource utilization during 2015 were three-to-four times greater in the ASCVD cohort as compared to the non-ASCVD cohort for the categories of inpatient visits (15.6% vs 4.4% of patients), outpatient ER visits (18.4% vs 5.2% of patients), and inpatient ER visits (4.3% vs 0.9% of patients). Outpatient utilization also was higher among patients with ASCVD as compared to those without ASCVD (mean number of annual office visits per patient, 9.1 vs 5.6), and more than twice as many patients with ASCVD had ≥ 9 office visits (43.5% vs 19.8%). Average per-patient total healthcare cost was $22,977 for ASCVD vs $9735 for non-ASCVD, with medical costs primarily driving the difference ($17,849 vs $6079); the difference in pharmacy costs was smaller ($5128 vs $3656). In the 18-44, 45-64, and ≥ 65 age subgroups respectively, total annual healthcare costs were 143, 127, and 114% higher in ASCVD vs non-ASCVD patients. CONCLUSIONS: These findings indicate significantly higher healthcare resource utilization and associated costs in patients having T2DM with ASCVD compared to T2DM without ASCVD.

The prevalence of cardiovascular disease and antidiabetes treatment characteristics among a large type 2 diabetes population in the United States.

OBJECTIVES: The purpose of this study was to assess atherosclerotic cardiovascular disease (ASCVD) prevalence, antidiabetes medication usage and physician specialty encounters among individuals with type 2 diabetes mellitus (T2DM) in the United States during 2015. DESIGN: Retrospective, cross-sectional analysis. PATIENTS: Adults with T2DM in a large US administrative claims database. Patients were divided into ASCVD and non-ASCVD groups. Subgroup analyses were conducted for three age groups (18-44, 45-64 and 65+ years). RESULTS: Of 1 202 596 patients with T2DM, 45.2% had established ASCVD. About 40% of T2DM patients with ASCVD had visited a cardiologist during 2015, compared to 11% in the non-ASCVD group. The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter 2 inhibitors (SGLT-2is) was low overall (<12%), and even lower in the ASCVD group (<9%). The prevalence of ASCVD was 15%, 36% and 71% in the 18-44, 45-64 and 65+ year age groups, respectively. GLP-1RA and SGLT-2i use was ≤5% in the 65+ subgroup, regardless of ASCVD status. CONCLUSIONS: These real-world data showed a high prevalence of ASCVD among T2DM patients, and confirmed, as a baseline assessment, low use of GLP-1RAs and SGLT-2is in these at-risk patients prior to the 2017 American Diabetes Association guidelines recommending use of agents with proven cardiovascular benefits.

Maintenance of weight loss or stability in subjects with obesity: a retrospective longitudinal analysis of a real-world population.

OBJECTIVES: Characterize patterns of weight change among subjects with obesity. METHODS: A retrospective observational longitudinal study of subjects with obesity was conducted using the General Electric Centricity electronic medical record database. Subjects who were ≥18 years old with BMI ≥30 kg/m2 (first defining index BMI), had no medical conditions associated with unintentional weight loss, and had ≥4 BMI measurements/year for ≥2.5 years were included and categorized into groups (stable weight: within <5% of index BMI; modest weight loss: ≥5 to <10% of index BMI lost; moderate weight loss: ≥10 to <15% of index BMI lost; and high weight loss: ≥15% of index BMI lost) based on weight change during 6 months following index. No interventions were considered. Patterns of weight change were then assessed for 2 years. RESULTS: A total of 177,743 subjects were included: 85.1% of subjects were in the stable weight, 9.3% in the modest, 2.3% in the moderate, and 3.3% in the high weight loss groups. The proportion of subjects who maintained or continued to lose weight decreased over the 2 year observation period; 11% of those with high weight loss continued to lose weight and 19% maintained their weight loss. This group had the lowest percentage of subjects who regained ≥50% of lost weight and the lowest proportion of subjects with weight cycling (defined as not continuously losing, gaining, or maintaining weight throughout the 2 year observation period relative to its beginning). This trend persisted in subgroups with class II-III obesity, pre-diabetes, and type 2 diabetes. CONCLUSION: Weight cycling and regain were commonly observed. Subjects losing the most weight during the initial period were more likely to continue losing weight.

Adaptations to iron deficiency: cardiac functional responsiveness to norepinephrine, arterial remodeling, and the effect of beta-blockade on cardiac hypertrophy.

BACKGROUND: Iron deficiency (ID) results in ventricular hypertrophy, believed to involve sympathetic stimulation. We hypothesized that with ID 1) intravenous norepinephrine would alter heart rate (HR) and contractility, 2) abdominal aorta would be larger and more distensible, and 3) the beta-blocker propanolol would reduce hypertrophy. METHODS: 1) 30 CD rats were fed an ID or replete diet for 1 week or 1 month. Norepinephrine was infused via jugular vein; pressure was monitored at carotid artery. Saline infusions were used as a control. The pressure trace was analyzed for HR, contractility, systolic and diastolic pressures. 2) Abdominal aorta catheters inflated the aorta, while digital microscopic images were recorded at stepwise pressures to measure arterial diameter and distensibility. 3) An additional 10 rats (5 ID, 5 control) were given a daily injection of propanolol or saline. After 1 month, the hearts were excised and weighed. RESULTS: Enhanced contractility, but not HR, was associated with ID hypertrophic hearts. Systolic and diastolic blood pressures were consistent with an increase in arterial diameter associated with ID. Aortic diameter at 100 mmHg and distensibility were increased with ID. Propanolol was associated with an increase in heart to body mass ratio. CONCLUSIONS: ID cardiac hypertrophy results in an increased inotropic, but not chronotropic response to the sympathetic neurotransmitter, norepinephrine. Increased aortic diameter is consistent with a flow-dependent vascular remodeling; increased distensibility may reflect decreased vascular collagen content. The failure of propanolol to prevent hypertrophy suggests that ID hypertrophy is not mediated via beta-adrenergic neurotransmission.

The effect of liraglutide on endothelial function in patients with type 2 diabetes.

This single-centre, 12-week, double-blind, placebo-controlled trial assessed how the human glucagon-like-peptide 1 analogue liraglutide impacted endothelial function in adult patients (n = 49) with type 2 diabetes and no overt cardiovascular disease. Patients were randomized to liraglutide, placebo or glimepiride. At baseline and Week 12, venous occlusion plethysmography was used to measure forearm blood flow (FBF) in response to acetylcholine (ACh) and sodium nitroprusside (SNP) before and after (L)-N(G)-monomethyl arginine (L-NMMA) infusion. At Week 12, ACh-mediated FBF increased with liraglutide and decreased with placebo; however, the between-treatment difference was not significant (p = 0.055). Inhibition of ACh-mediated FBF after L-NMMA infusion increased with liraglutide and decreased with placebo; this between-treatment difference was also not significant (p = 0.149). No change in FBF was observed with SNP. Liraglutide did not significantly impact endothelium-dependent vasodilation after 12 weeks; however, additional investigations looking at the effect of liraglutide on endothelial function in alternative vasculature and during the postprandial period are warranted.

Efficacy and safety of biphasic insulin aspart 70/30 in type 2 diabetes patients of different race or ethnicity (INITIATEplus trial).

OBJECTIVE: To determine if self-titration using biphasic insulin aspart 70/30 (BIAsp 30) had a different impact on efficacy and safety across different racial/ethnic subgroups. RESEARCH DESIGN/METHODS: This was an exploratory, post hoc analysis by race (White vs. Black/African-American) and ethnicity (Hispanic/Latino vs. non-Hispanic/Latino) of data from the INITIATEplus trial. Participants were treated twice-daily with BIAsp 30 over 24 weeks. TRIAL REGISTRATION: NCT00101751. MAIN OUTCOME MEASURES: Efficacy endpoints included reductions in mean glycated hemoglobin (A1C) and fasting plasma glucose (FPG). Safety endpoints included hypoglycemia rates (events/patient-year) and adverse events. Body weight changes were also measured. RESULTS: Glycemic control improved by a similar extent for all demographic groups. Observed mean decreases in A1C ranged from 2.4% to 2.6% after 24 weeks' treatment. Baseline-adjusted mean A1C decreases for White vs. Black/African-American subjects were 2.56% and 2.13% (p < 0.0001), and for Hispanic/Latino vs. non-Hispanic/Latino subjects were 2.45% and 2.42% (p = 0.677), respectively. Final FPG values were similar among all groups (141-146 mg/dL [7.83-8.10 m mol/L]), and baseline-adjusted FPG decreases were not significantly different (p > 0.025) between groups. Hypoglycemia was low for White, Black/African-American, Hispanic/Latino, and non-Hispanic/Latino subjects (0.08, 0.04, 0.03, and 0.07 major events/patient-year, with 0.60, 0.30, 0.37, and 0.52 minor events/patient-year, respectively). Body weight increases were 3.17 and 3.06 kg (White vs. African-American) and 2.69 and 3.19 kg (Hispanic/Latino vs. non-Hispanic/Latino). Final weight-adjusted total daily insulin doses were 0.60 U/kg for Black/African-American subjects vs. 0.78 U/kg for White subjects (p < 0.0001), and 0.71 U/kg for Hispanic/Latino subjects vs. 0.74 U/kg for non-Hispanic/Latino subjects (p = 0.42). LIMITATIONS: The trial was not designed or powered for comparisons across racial or ethnic groups, subjects were not stratified for pre-baseline medication regimens between each race and ethnic group, and unequal subject numbers and baseline A1C disparities existed between the pairs of groups being compared. CONCLUSIONS: Diabetes self-management with BIAsp 30 using an easily followed self-titration algorithm produced low hypoglycemia rates. All subgroups achieved A1C reductions >2.1% and FPG declines >82 mg/dL that were similar across groups, demonstrating that self-titration of BIAsp 30 can successfully be pursued in a primary care setting by patients who had previously failed to meet ADA A1C targets under oral antidiabetes therapy, with race or ethnicity not an obstacle to achieving better glycemic control.

Mild renal impairment and the efficacy and safety of liraglutide.

OBJECTIVE: To determine the effect of mild renal impairment (RI) on the efficacy and safety of liraglutide in patients with type 2 diabetes mellitus. METHODS: In this meta-analysis, we examined the 6 LEAD (Liraglutide Effect and Action in Diabetes) studies. Data from patients with type 2 diabetes who had normal renal function, mild RI, or moderate or severe RI were pooled for analysis. Renal function was measured by creatinine clearance as determined by the Cockcroft-Gault equation: normal renal function = creatinine clearance >89 mL/min; mild RI = 60 mL/min ≤ creatinine clearance ≤ 89 mL/min; and moderate or severe RI = creatinine clearance <60 mL/min. The meta-analysis included patients administered once-daily liraglutide (1.2 or 1.8 mg) or placebo as either monotherapy or in combination with oral antidiabetic drugs for 26 weeks. In addition, a pooled analysis of all phase 2 and 3 liraglutide trials was done to examine rates of altered renal function. RESULTS: Mild RI did not affect the estimated treatment differences in hemoglobin A1c. Patients with normal renal function demonstrated decreases in body weight and systolic blood pressure with either dosage of liraglutide, whereas patients in either RI group also demonstrated a decrease in body weight and systolic blood pressure, but these differences were not significant compared with differences observed in the placebo group. Liraglutide treatment vs placebo was safe and well tolerated in patients with mild RI, as there were no significant differences in rates of renal injury, minor hypoglycemia, or nausea. A trend towards increased nausea was observed in patients with moderate or severe RI receiving liraglutide, although the number of patients in this treatment group was too low to determine significance. CONCLUSION: Mild RI, as determined by the Cockcroft-Gault equation, had no effect on the efficacy and safety of liraglutide in this meta-analysis.

Comparison of the efficacy and tolerability profile of liraglutide, a once-daily human GLP-1 analog, in patients with type 2 diabetes ≥65 and <65 years of age: a pooled analysis from phase III studies.

BACKGROUND: Managing elderly patients with type 2 diabetes poses particular challenges, so it is important to evaluate the efficacy and tolerability profile of antidiabetic therapies specifically in this patient population. OBJECTIVE: The aim of our study was to compare the efficacy and tolerability profile of liraglutide, a GLP-1 analog, in elderly (≥65 years) and younger (<65 years) patients with type 2 diabetes. METHODS: A pooled analysis of 6 randomized, placebo-controlled, multinational trials included data from 3967 patients aged18 to 80 years with type 2 diabetes and glycosylated hemoglobin (HbA(1c)) of 7% to 11%. Of these, 552 patients ≥65 years received liraglutide 1.8 mg, liraglutide 1.2 mg, or placebo; 2231 patients <65 years received liraglutide 1.8 mg, liraglutide 1.2 mg, or placebo for 26 weeks. End points were: change in HbA(1c), fasting plasma glucose, body weight, and blood pressure: as marked to identify elements tracked for change from baseline; hypoglycemic episodes; and adverse events. RESULTS: Reduction in HbA(1c) from baseline was significantly greater with liraglutide 1.8 mg versus placebo (least squares mean difference: ≥65 years, 0.91% [95% CI, 0.69-1.12]; <65 years, 1.17% [95% CI, 1.06-1.28]; both, P < 0.0001) and with liraglutide 1.2 mg versus placebo (≥65 years, 0.87% [95% CI, 0.64-1.11]; <65 years, 1.10% [95% CI, 0.98-1.22]; both, P < 0.0001). For fasting plasma glucose, comparable results were observed between liraglutide 1.8 mg or 1.2 mg and placebo for both age groups (P < 0.0001). No statistically significant difference in body weight change was seen with liraglutide between the age groups. The proportion of patients reporting minor hypoglycemia was low and appeared comparable between the ≥65-year-old (4.3%-15.2%) and <65-year-old (8%-13.2%) groups. Likewise, adverse events appeared comparable in nature and frequency. CONCLUSION: Liraglutide provides effective glycemic control and is well tolerated in patients ≥65 and <65 years of age with type 2 diabetes. These data suggest that liraglutide may be a suitable treatment option for older patients who may have additional age-related complications.

Liraglutide treatment is associated with a low frequency and magnitude of antibody formation with no apparent impact on glycemic response or increased frequency of adverse events: results from the Liraglutide Effect and Action in Diabetes (LEAD) trials.

CONTEXT: Therapeutic proteins/peptides can produce immunogenic responses that may increase the risk of adverse events or reduce efficacy. OBJECTIVE: The objectives were to measure and characterize antibody formation to liraglutide, a glucagon-like peptide-1 receptor agonist, to investigate the impact on glycemic control and safety, and to compare it with exenatide, an agent in the same class. DESIGN: Antibody data were collected during six Liraglutide Effect and Action in Diabetes (LEAD) trials (26-104 wk duration). SETTING: Samples for determination of antibody formation were collected at LEAD trial sites and analyzed at central laboratories. PARTICIPANTS: Antibodies were measured in LEAD trial participants with type 2 diabetes. INTERVENTIONS: Interventions included once-daily liraglutide (1.2 or 1.8 mg) or twice-daily exenatide (10 µg). MAIN OUTCOME MEASURES: The main outcome measures included the proportion of patients positive for anti-liraglutide or anti-exenatide antibodies, a glucagon-like peptide-1 cross-reacting effect, and an in vitro liraglutide- or exenatide-neutralizing effect. Change in glycosylated hemoglobin A(1c) (HbA(1c)) by antibody status and magnitude [negative, positive (high or low level)]. RESULTS: After 26 wk, 32 of 369 (8.7%) and 49 of 587 (8.3%) patients had low-level antibodies to liraglutide 1.2 and 1.8 mg, respectively [mean 3.3% antibody-bound radioactivity out of total radioactivity (%B/T), range 1.6-10.7%B/T], which did not attenuate glycemic efficacy (HbA(1c) reductions 1.1-1.3% in antibody-positive vs. 1.2% in antibody-negative patients). In LEAD-6, 113 of 185 extension patients (61%) had anti-exenatide antibodies at wk 26 (range 2.4-60.2%B/T). High levels of anti-exenatide antibodies were correlated with significantly smaller HbA(1c) reductions (P = 0.0022). After switching from exenatide to liraglutide, anti-exenatide antibodies did not compromise a further glycemic response to liraglutide (additional 0.4% HbA(1c) reduction). CONCLUSIONS: Liraglutide was less immunogenic than exenatide; the frequency and levels of anti-liraglutide antibodies were low and did not impact glycemic efficacy or safety.

Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes.

OBJECTIVE: This retrospective study examined the association between ICD-9-CM-coded outpatient hypoglycemic events (HEs) and acute cardiovascular events (ACVEs), i.e., acute myocardial infarction, coronary artery bypass grafting, revascularization, percutaneous coronary intervention, and incident unstable angina, in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Data were derived from healthcare claims for individuals with employer-sponsored primary or Medicare supplemental insurance. A baseline period (30 September 2006 to 30 September 2007) was used to identify eligible patients and collect information on their clinical and demographic characteristics. An evaluation period (1 October 2007 to 30 September 2008) was used to identify HEs and ACVEs. Patients aged ≥ 18 years with type 2 diabetes were selected for analysis by a modified Healthcare Effectiveness Data and Information Set algorithm. Data were analyzed with multiple logistic regression and backward stepwise selection (maximum P = 0.01) with adjustment for important confounding variables, including age, sex, geography, insurance type, comorbidity scores, cardiovascular risk factors, diabetes complications, total baseline medical expenditures, and prior ACVEs. RESULTS: Of the 860,845 patients in the analysis set, 27,065 (3.1%) had ICD-9-CM-coded HEs during the evaluation period. The main model retained 17 significant independent variables. Patients with HEs had 79% higher regression-adjusted odds (HE odds ratio [OR] 1.79; 95% CI 1.69-1.89) of ACVEs than patients without HEs; results in patients aged ≥65 years were similar to those for the entire population (HE OR 1.78, 95% CI 1.65-1.92). CONCLUSIONS: ICD-9-CM-coded HEs were independently associated with an increased risk of ACVEs. Further studies of the relationship between hypoglycemia and the risk of ACVEs are warranted.

Efficacy of antihyperglycemic therapies and the influence of baseline hemoglobin A(1C): a meta-analysis of the liraglutide development program.

OBJECTIVE: To compare liraglutide versus common antihyperglycemic treatments in reducing hemoglobin A1c (A1C) values across multiple levels of baseline glycemic control and in reaching glycemic targets. METHODS: Pooled patient data from 7 phase 3, multinational, randomized controlled trials in patients with type 2 diabetes were stratified by baseline A1C values into 5 categories: ≤7.5%, >7.5% to 8.0%, >8.0% to 8.5%, >8.5% to 9.0%, and y9.0%. The changes in A1C from baseline to week 26 of treatment and patient proportions reaching A1C targets of <7.0% and ≤6.5% were compared between liraglutide (1.8 mg daily) and sitagliptin, glimepiride, rosiglit-azone, exenatide, and insulin glargine across all baseline A1C categories. RESULTS: Irrespective of treatment, reductions in A1C levels were generally greater in groups with higher baseline A1C values. After 26 weeks of treatment, liraglutide produced the greatest reductions in A1C values across all baseline categories, ranging from 0.7% to 1.8% (baseline A1C categories ≤7.5% to >9.0%, respectively), followed by insulin glargine (0.3% to 1.5%) and then by glimepiride (0.4% to 1.3%). Generally, larger percentages of patients achieved the A1C target of ≤6.5% with liraglutide therapy across all baseline categories (from 62% of patients with A1C values ≤7.5% to 10% of patients with A1C values >9.0%) in comparison with other treatments (ranging from 49% to 0% of patients, respectively). Similarly, greater proportions of patients also reached the A1C target of <7.0% with liraglutide therapy across all baseline categories (from 83% of patients with A1C values ≤7.5% to 25% of patients with A1C values >9.0%) versus comparators (from 74% to 5% of patients, respectively). CONCLUSION: Across a wide spectrum of baseline A1C categories, liraglutide is an efficacious treatment option for patients with type 2 diabetes.

A(1c) control in a primary care setting: self-titrating an insulin analog pre-mix (INITIATEplus trial).

PURPOSE: To study glycemic control and hypoglycemia development upon initiation of insulin through a self-titration schedule in a 24-week trial, conducted with 4875 insulin-naïve patients with poorly controlled type 2 diabetes, predominantly in a primary care setting. METHODS: Subjects initiated twice-daily biphasic insulin aspart 70/30 with 6 units prebreakfast and 6 units presupper, self-titrating according to self-measured blood glucose values. Subjects were randomized (1:1:1) to telephone counseling provided by a registered dietician: no counseling (NC), 1 counseling session (1C), or 3 sessions (3C). RESULTS: Mean baseline HbA(1c) (9.9% across groups) decreased approximately 2.5% to 7.49% + or - 1.48, 7.48% + or - 1.50, and 7.44% + or - 1.46 in the NC, 1C, and 3C groups, respectively. Within these groups, a hemoglobin A(1c) (HbA(1c)) value <7% was achieved by 40.2%, 41.6%, and 41.8% of subjects, respectively. Eight-point blood glucose profiles were substantially improved from baseline for all groups. Hypoglycemia was experienced by 10.2%-11.4% of the subjects in each group. Rates of minor and major hypoglycemia were low but decreased as dietary counseling increased (minor hypoglycemia: 56 vs 50 vs 45 episodes per 100 patient-years; major hypoglycemia, 9 vs 6 vs 4 episodes per 100 patient-years, for the NC vs 1C vs 3C groups, respectively; P <.001, 3C vs NC). Weight increased by 3.13, 3.40, and 2.88 kg for the NC, 1C, and 3C groups, respectively. CONCLUSION: In the primary care setting, self-titration of biphasic insulin aspart 70/30 was effective in achieving recommended HbA(1c) goals even with minimal dietary counseling.