Differentiating Familial Chylomicronemia Syndrome From Multifactorial Severe Hypertriglyceridemia by Clinical Profiles.

CONTEXT: Differentiation between familial chylomicronemia syndrome (FCS, type 1 hyperlipoproteinemia), a rare metabolic disorder, and the more common multifactorial severe hypertriglyceridemia (sHTG, type 5 hyperlipoproteinemia) is challenging because of their overlapping symptoms but important in patient management. OBJECTIVE: To assess whether readily obtainable clinical information beyond triglycerides can effectively diagnose and differentiate patients with FCS from those with sHTG, based on well-curated data from two intervention studies of these conditions. METHODS: The analysis included 154 patients from two phase 3 clinical trials of patients with sHTG, one cohort with genetically confirmed FCS (n = 49) and one with multifactorial sHTG (n = 105). Logistic regression analyses were performed to determine the ability of variables (patient demographics, medical history, and baseline lipids, individually or in sets) to differentiate the patient populations. Receiver operating characteristics were used to determine the variable sets with the highest accuracy (percentage of times actual values matched predicted) and optimal sensitivity and specificity. RESULTS: The primary model diagnosed 45 of 49 patients with FCS and 99 of 105 patients with sHTG correctly. Optimal sensitivity for all available parameters (n = 17) was 91.8%, optimal specificity was 94.3%, and accuracy was 93.5%. Fasting low-density lipoprotein cholesterol (LDL-C) provided the highest individual predictability. However, a three-variable set of ultracentrifugally measured LDL-C, body mass index, and pancreatitis history differentiated the diseases with a near similar accuracy of 91.0%, and adding high-density lipoprotein cholesterol and very low-density lipoprotein cholesterol for a five-variable set provided a small incremental increase in accuracy (92.2%). CONCLUSIONS: In the absence of genetic testing, hypertriglyceridemic patients with FCS and sHTG can be differentiated with a high degree of accuracy by analyzing readily obtainable clinical information.

Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome.

BACKGROUND: Familial chylomicronemia syndrome is a rare genetic disorder that is caused by loss of lipoprotein lipase activity and characterized by chylomicronemia and recurrent episodes of pancreatitis. There are no effective therapies. In an open-label study of three patients with this syndrome, antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels. METHODS: We conducted a phase 3, double-blind, randomized 52-week trial to evaluate the safety and effectiveness of volanesorsen in 66 patients with familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 ratio, to receive volanesorsen or placebo. The primary end point was the percentage change in fasting triglyceride levels from baseline to 3 months. RESULTS: Patients receiving volanesorsen had a decrease in mean plasma apolipoprotein C-III levels from baseline of 25.7 mg per deciliter, corresponding to an 84% decrease at 3 months, whereas patients receiving placebo had an increase in mean plasma apolipoprotein C-III levels from baseline of 1.9 mg per deciliter, corresponding to a 6.1% increase (P<0.001). Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% confidence interval [CI], 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) (P<0.001). At 3 months, 77% of the patients in the volanesorsen group, as compared with 10% of patients in the placebo group, had triglyceride levels of less than 750 mg per deciliter (8.5 mmol per liter). A total of 20 of 33 patients who received volanesorsen had injection-site reactions, whereas none of the patients who received placebo had such reactions. No patients in the placebo group had platelet counts below 100,000 per microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels below 25,000 per microliter. No patient had platelet counts below 50,000 per microliter after enhanced platelet-monitoring began. CONCLUSIONS: Volanesorsen lowered triglyceride levels to less than 750 mg per deciliter in 77% of patients with familial chylomicronemia syndrome. Thrombocytopenia and injection-site reactions were common adverse events. (Funded by Ionis Pharmaceuticals and Akcea Therapeutics; APPROACH Clinical Trials.gov number, NCT02211209.).

Achievement of Target A1C <7.0% (<53 mmol/mol) by U.S. Type 2 Diabetes Patients Treated With Basal Insulin in Both Randomized Controlled Trials and Clinical Practice.

OBJECTIVE: Many patients with type 2 diabetes do not reach glycemic goals despite basal insulin treatment. This study assessed the achievement of a target A1C <7.0% (<53 mmol/mol) after initiation of basal insulin in two settings. METHODS: This was a retrospective analysis of pooled randomized controlled trial (RCT) data, from 11 24-week studies of patients initiating basal insulin performed between 2000 and 2005 and of outpatient electronic medical record (EMR) data from the General Electric Centricity database for insulin-naive patients initiating basal insulin between 2005 and 2012. Baseline characteristics stratified by target A1C and fasting plasma glucose (FPG) attainment were compared descriptively. RESULTS: In the RCT dataset, 49.0% of patients failed to achieve the target A1C at 6 months versus 72.4% and 72.9% at 6 and 12 months in the EMR dataset, respectively. Despite this, in the RCT dataset, 79.4% of patients achieved the target A1C and/or an FPG <130 mg/dL. In the EMR dataset, only 47.6% and 47.3% of patients achieved an A1C <7.0% and/or FPG <130 mg/dL at 6 and 12 months, respectively. Overall, patients with an A1C >7.0% had a longer diabetes duration and were more likely to be female, nonwhite, and self-funding or covered by Medicaid. Among patients with an A1C >7.0%, more RCT patients (58.0%) had an FPG <130 mg/dL than EMR patients at 6 months (27.8%) and 12 months (27.7%). CONCLUSION: Unmet needs remain after basal insulin initiation, particularly in real-world settings, where many patients require further insulin titration. In both populations, patients failing to achieve the target A1C despite attaining an FPG <130 mg/dL require interventions to improve postprandial control.

Characterizing familial chylomicronemia syndrome: Baseline data of the APPROACH study.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare metabolic disorder caused by mutations in lipoprotein lipase (LPL) or genes required for LPL functionality and is characterized by hyperchylomicronemia that results in recurrent episodes of acute pancreatitis. Owing to the rarity of FCS, there are few case series describing the phenotypic variability in FCS patients in detail. OBJECTIVE: To provide baseline characteristics in the largest study population to date of patients with FCS. METHODS: We analyzed baseline demographic and clinical characteristics of adult FCS patients in the phase 3 APPROACH study of volanesorsen sodium (antisense inhibitor of apolipoprotein C-III). RESULTS: Sixty-six patients were included in the analysis. Mean (SD) age was 46 (13) years; and mean body mass index was 24.9 (5.7) kg/m2. We identified causal mutations in 79% (52) of patients, with LPL mutations accounting for 62% (41) of cases. Median age at diagnosis was 24 years, 54% were females, and 81% were Caucasian. All patients followed a low-fat diet, 43% received fibrates, 27% fish oils, and 21% statins. Median fasting triglyceride levels (P25, P75) were 1985 (1179, 3047 mg/dL). Overall, 76% of patients reported ≥1 lifetime episode of acute pancreatitis; 23 patients reported a total of 53 pancreatitis events in the 5 years before enrollment. CONCLUSIONS: Our data emphasize the severe hypertriglyceridemia characteristic of FCS patients despite restrictive low-fat diets and frequent use of existing hypolipemic therapies. Acute pancreatitis and recurrent acute pancreatitis are frequent complications of FCS. Diagnosis at an older age suggests likely underdiagnosis and underappreciation of this rare disorder.

Clinical and biochemical features of different molecular etiologies of familial chylomicronemia.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is an ultra-rare phenotype that is usually caused by biallelic mutations in the LPL gene encoding lipoprotein lipase, or less often in APOC2, APOA5, LMF1, or GPIHBP1 genes encoding cofactors or interacting proteins. OBJECTIVES: We evaluated baseline phenotypes among FCS participants in a phase 3 randomized placebo-controlled trial of volanesorsen (NCT02211209). METHODS: Baseline clinical, fasting, and postfat load metabolic markers were assessed. Targeted next-generation DNA sequencing plus custom bioinformatics was used to genotype subjects. RESULTS: Among 52 FCS individuals, 41 had biallelic LPL gene mutations (LPL-FCS patients): 82%, 7%, and 11% were missense, nonsense, and splicing variants, respectively. Eleven individuals had non-LPL-FCS; 2 had mutations in APOA5, 5 in GPIHBP1, and 1 each in LMF1 and APOC2 genes, respectively. Two other individuals were double heterozygotes, each with 1 normal LPL allele. All subjects had extremely high triglycerides (TGs) and chylomicrons, but very low levels of other lipoproteins. Compared with LPL-FCS individuals, non-LPL-FCS individuals were very similar for most traits, but had significantly higher postheparin LPL activity, higher 4-hour postprandial insulin and C-peptide levels; and higher low-density lipoprotein cholesterol levels. In non-LPL-FCS individuals compared to those with LPL-FCS, there were also nonsignificant trends toward lower levels of total and chylomicron TGs, lower 4-hour postprandial chylomicron TG levels, and higher very-low-density lipoprotein TG levels. CONCLUSION: Thus, LPL FCS and non-LPL FCS are largely phenotypically similar. However, LPL FCS patients have lower postheparin LPL activity and a trend toward higher TGs, whereas low-density lipoprotein cholesterol was higher in non-LPL-FCS patients.

Antisense Inhibition of Protein Tyrosine Phosphatase 1B With IONIS-PTP-1BRx Improves Insulin Sensitivity and Reduces Weight in Overweight Patients With Type 2 Diabetes.

OBJECTIVE: To evaluate safety and efficacy of IONIS-PTP-1BRx, a second-generation 2'-O-methoxyethyl antisense inhibitor of protein tyrosine phosphatase 1B, as add-on therapy in overweight patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea therapy. RESEARCH DESIGN AND METHODS: In this phase II, double-blind, randomized, placebo-controlled, multicenter trial, overweight and obese patients (BMI ≥27 kg/m2) with type 2 diabetes (HbA1c ≥7.5% [58 mmol/mol] and ≤10.5% [91 mmol/mol]) on a stable dose of metformin alone or with sulfonylurea were randomized 2:1 to IONIS-PTP-1BRx 200 mg (n = 62) or placebo (n = 30) once weekly for 26 weeks. RESULTS: Mean baseline HbA1c was 8.6% (70 mmol/mol) and 8.7% (72 mmol/mol) in placebo and active treatment, respectively. At week 27, IONIS-PTP-1BRx reduced mean HbA1c levels by -0.44% (-4.8 mmol/mol; P = 0.074) from baseline and improved leptin (-4.4 ng/mL; P = 0.007) and adiponectin (0.99 µg/mL; P = 0.026) levels compared with placebo. By week 36, mean HbA1c was significantly reduced (-0.69% [-7.5 mmol/mol]; P = 0.034) and accompanied by reductions in fructosamine (-33.2 µmol/L; P = 0.005) and glycated albumin (-1.6%; P = 0.031) versus placebo. Despite both treatment groups receiving similar lifestyle counseling, mean body weight significantly decreased from baseline to week 27 with IONIS-PTP-1BRx versus placebo (-2.6 kg; P = 0.002) independent of HbA1c reduction (R2 = 0.0020). No safety concerns were identified in the study. CONCLUSIONS: Compared with placebo, IONIS-PTP-1BRx treatment for 26 weeks produced prolonged reductions in HbA1c, improved medium-term glycemic parameters, reduced leptin and increased adiponectin levels, and resulted in a distinct body weight-reducing effect.

Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides.

BACKGROUND: Epidemiologic and genomewide association studies have linked loss-of-function variants in ANGPTL3, encoding angiopoietin-like 3, with low levels of plasma lipoproteins. METHODS: We evaluated antisense oligonucleotides (ASOs) targeting Angptl3 messenger RNA (mRNA) for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants (with triglyceride levels of either 90 to 150 mg per deciliter [1.0 to 1.7 mmol per liter] or >150 mg per deciliter, depending on the dose group) were randomly assigned to receive subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg per week for 6 weeks). The main end points were safety, side-effect profile, pharmacokinetic and pharmacodynamic measures, and changes in levels of lipids and lipoproteins. RESULTS: The treated mice had dose-dependent reductions in levels of hepatic Angptl3 mRNA, Angptl3 protein, triglycerides, and low-density lipoprotein (LDL) cholesterol, as well as reductions in liver triglyceride content and atherosclerosis progression and increases in insulin sensitivity. After 6 weeks of treatment, persons in the multiple-dose groups had reductions in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, P<0.01 for all doses vs. placebo) and in levels of triglycerides (reductions of 33.2 to 63.1%), LDL cholesterol (1.3 to 32.9%), very-low-density lipoprotein cholesterol (27.9 to 60.0%), non-high-density lipoprotein cholesterol (10.0 to 36.6%), apolipoprotein B (3.4 to 25.7%), and apolipoprotein C-III (18.9 to 58.8%). Three participants who received the antisense oligonucleotide and three who received placebo reported dizziness or headache. There were no serious adverse events. CONCLUSIONS: Oligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov number, NCT02709850 .).

Lixisenatide reduces glycaemic variability in insulin-treated patients with type 2 diabetes.

Chronic hyperglycaemia and glucose variability are associated with the development of chronic diabetes-related complications. We conducted a pooled analysis of patient-level data from three 24-week, randomized, phase III clinical trials to evaluate the impact of lixisenatide (LIXI) on glycaemic variability (GV) vs placebo as add-on to basal insulin. The main outcome GV measures were standard deviation (s.d.), mean amplitude of glycaemic excursions (MAGE), mean absolute glucose (MAG) level, area under the curve for fasting glucose (AUC-F), and high (HBGI) and low blood glucose index (LBGI). The change in GV metrics over 24 weeks and relationships among baseline GV, patient characteristics and outcomes were assessed. Data were pooled from 1198 patients (665 LIXI, 533 placebo). Values for s.d., MAG level, MAGE, HBGI, and AUC-F significantly decreased with LIXI vs placebo, while LBGI values were unchanged. Higher baseline GV measures correlated with older age, longer type 2 diabetes duration, lower body mass index, higher baseline glycated/haemogobin, greater reduction in postprandial glucose (PPG) level, and higher rates of symptomatic hypoglycaemia. These data show that LIXI added to basal insulin significantly reduced GV and PPG excursions vs placebo, without increasing the risk of hypoglycaemia (LBGI).

Are patients on basal insulin attaining glycemic targets? Characteristics and goal achievement of patients with type 2 diabetes mellitus treated with basal insulin and physician-perceived barriers to achieving glycemic targets.

AIMS: To investigate treatment patterns and achievement of glycemic targets in patients with type 2 diabetes mellitus treated with basal insulin in a real-world setting, and to determine physicians' beliefs and practices regarding these patients. METHODS: This study had two components; a retrospective analysis using a US claims database of patient and treatment data, and a survey of physicians' beliefs and practices. RESULTS: A total of 39,074 patients treated with basal insulin were included in this analysis. The proportion of patients achieving HbA1c<7.0% (53mmol/mol) was similar in ongoing basal insulin users at baseline (26%) and at 3months follow-up (27%). The number of new initiators achieving HbA1c<7.0% (53mmol/mol) increased from baseline (11%) to 3months (27%). In the physician survey component, the majority of physicians indicated they would continue to increase basal insulin dose as long as was needed to reach HbA1c/fasting blood glucose goals (85% of physicians treating 'not on-goal' patients, 78% of physicians treating 'on-goal' patients). Physician-perceived barriers to insulin intensification included patient's lifestyle, non-adherence, and concerns about out-of-pocket costs. CONCLUSIONS: A large proportion of patients on insulin-based therapy fail to reach glycemic goals. More education of clinicians may improve insulin intensification rates and increase the proportion of patients reaching glycemic targets.

Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes.

OBJECTIVE: To determine the effects of volanesorsen (ISIS 304801), a second-generation 2'-O-methoxyethyl chimeric antisense inhibitor of apolipoprotein (apo)C-III, on triglyceride (TG) levels and insulin resistance in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized, double-blind, placebo-controlled trial was performed in 15 adult patients with type 2 diabetes (HbA1c >7.5% [58 mmol/mol]) and hypertriglyceridemia (TG >200 and <500 mg/dL). Patients were randomized 2:1 to receive volanesorsen 300 mg or placebo for a total of 15 subcutaneous weekly doses. Glucose handling and insulin sensitivity were measured before and after treatment using a two-step hyperinsulinemic-euglycemic clamp procedure. RESULTS: Treatment with volanesorsen significantly reduced plasma apoC-III (-88%, P = 0.02) and TG (-69%, P = 0.02) levels and raised HDL cholesterol (HDL-C) (42%, P = 0.03) compared with placebo. These changes were accompanied by a 57% improvement in whole-body insulin sensitivity (P < 0.001). Importantly, we found a strong relationship between enhanced insulin sensitivity and both plasma apoC-III (r = -0.61, P = 0.03) and TG (r = -0.68, P = 0.01) suppression. Improved insulin sensitivity was sufficient to significantly lower glycated albumin (-1.7%, P = 0.034) and fructosamine (-38.7 µmol/L, P = 0.045) at the end of dosing and HbA1c (-0.44% [-4.9 mmol/mol], P = 0.025) 3 months postdosing. CONCLUSIONS: Volanesorsen reduced plasma apoC-III and TG while raising HDL-C levels. Importantly, glucose disposal, insulin sensitivity, and integrative markers of diabetes also improved in these patients after short-term treatment.

Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results.

Elevated apoC-III levels predict increased cardiovascular risk when present on LDL and HDL particles. We developed novel high-throughput chemiluminescent ELISAs that capture apoB, lipoprotein (a) [Lp(a)], and apoA-I in plasma and then detect apoC-III on these individual lipoproteins as apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoAI complexes, respectively. We assessed the effects on these complexes of placebo or 100-300 mg volanesorsen, a generation 2.0+ antisense drug that targets apoC3 mRNA in patients with hypertriglyceridemia, including familial chylomicronemia syndrome (n = 3), volanesorsen monotherapy (n = 51), and as add-on to fibrate (n = 26), treated for 85 days and followed for 176 days. Compared with placebo, volanesorsen was associated with an 82.3 ± 11.7%, 81.3 ± 15.7%, and 80.8 ± 13.6% reduction in apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoA-I, respectively (300 mg dose;P< 0.001 for all), at day 92. Strong correlations in all assay measures were noted with total plasma apoC-III, chylomicron-apoC-III, and VLDL-apoC-III. In conclusion, novel high-throughput ELISAs were developed to detect lipoprotein-associated apoC-III, including for the first time on Lp(a). Volanesorsen uniformly lowers apoC-III on apoB-100, Lp(a), and apoA-I lipoproteins, and may be a potent agent to reduce triglycerides and cardiovascular risk mediated by apoC-III.

FASTING VERSUS POSTPRANDIAL HYPERGLYCEMIA AS A TREATMENT TARGET TO LOWER ELEVATED HEMOGLOBIN A1C.

OBJECTIVE: Postprandial hyperglycemia (PPHG) may need addressing when glycemic control cannot be maintained in patients with type 2 diabetes mellitus. We investigated whether glycated hemoglobin A1c (A1c) levels ≥7.0% can indicate postprandial defects warranting prandial therapy after optimized basal insulin therapy. METHODS: From 6 clinical trials of insulin glargine treatment, data were pooled from 496 patients with A1c ≥7.0% after 24 weeks. Patient characteristics and clinical outcomes were summarized according to fasting plasma glucose (FPG) target achievement (<130 mg/dL), postprandial blood glucose (PPBG) levels, and PPBG increments (ΔPPBG). Basal and postprandial contributions to hyperglycemia were determined. RESULTS: After 24 weeks of insulin glargine titration, A1c change from baseline was greater in patients with FPG <130 mg/dL versus ≥130 mg/dL (-1.35% versus -1.11%, respectively; P = .0275), but with increased confirmed hypoglycemia rates (blood glucose <70 mg/dL; 4.06 events/patient-year versus 3.31 events/patient-year; P = .0170). However, increased severe hypoglycemia rates were observed in patients with FPG ≥130 mg/dL. At week 24, postprandial contributions to hyperglycemia increased (>60% regardless of PPBG). Patients with high FPG had lower, but substantial, relative postprandial contributions versus patients achieving FPG target. A similar pattern was observed according to whether patients had a ΔPPBG ≥50 mg/dL after any meal. CONCLUSION: After optimized basal insulin therapy, elevated A1c is the most effective indicator of residual PPHG, regardless of existent FPG or PPBG. When confronted with an uncontrolled A1c after reasonable titration of basal insulin, clinicians should be aware of probable postprandial contributions to hyperglycemia and consider prandial therapy.

Sensitivity of Traditional and Risk-Based Glycemic Variability Measures to the Effect of Glucose-Lowering Treatment in Type 2 Diabetes Mellitus.

BACKGROUND: Here we assess associations between glycemic variability (GV) measures and outcomes from glucose-lowering therapy in patients with type 2 diabetes (T2DM) to identify the metrics most sensitive to treatment response. METHODS: Data from 1699 patients in 6 previously reported studies in adults with T2DM treated with basal insulin and/or oral glucose-lowering drugs were included in a post hoc meta-analysis. Using 7-point blood glucose (BG) profiles we compared the GV metrics standard deviation (SD), mean amplitude of glycemic excursion (MAGE), mean absolute glucose (MAG), low and high BG risk indices (LBGI, HBGI), and average daily risk range (ADRR). Treatment-related changes in GV and risk status and associations between end-of-trial GV/risk metrics with treatment outcomes (end-of-trial glycated hemoglobin A1c[A1C] level ≥7.0%, hypoglycemia, and composite outcome of A1C <7.0% and no hypoglycemia), were evaluated. RESULTS: Significant changes from baseline to end of treatment were observed in all measures (all P < .0001), with the largest reduction following treatment for HBGI (-65.5%) and ADRR (-43.3%). The baseline risk classification for hyperglycemia based on the risk categories of HBGI improved for 66.8%, remained unchanged for 29.8%, and deteriorated for 3.3% of patients (chi-square P < .0001), while the risk for hypoglycemia did not change. HBGI showed the strongest association with A1C ≥7.0% at the end of treatment, and LBGI showed the strongest association with symptomatic hypoglycemia. CONCLUSIONS: During glucose-lowering therapy in T2DM, HBGI and LBGI offer insights into hyperglycemia and trends toward hypoglycemia, respectively; ADRR may be the optimal GV measure responsive to hypo- and hyperglycemic treatment effects.

Type 2 diabetes mellitus treatment patterns in U.S. nursing home residents.

BACKGROUND: The prevalence of type 2 diabetes mellitus (diabetes) in nursing home residents (NHRs) is increasing, concurrently with obesity and other comorbid conditions. NHR would benefit greatly from antidiabetic medications that would improve glycemic control and give a lower risk of hypoglycemia but that do not contribute to weight gain in obese individuals. OBJECTIVE: To examine the prescription patterns to NHRs with diabetes, including the use of newer injectable therapies such as glucagon-like peptide-1 (GLP-1) receptor agonists. METHODS: Treatment patterns of diabetes in NHR were analyzed using Minimum Data Set records and prescription claims from the Omnicare Senior Health Outcomes data repository (May 2011-September 2012). RESULTS: The prevalence of diabetes in this population of 229,283 NHRs was 35.4%. Among the 44,665 NHRs with diabetes and prescription claims data, the prevalence of obesity (40.3%) and multiple comorbidities (100%) was high. Approximately 20% of the NHRs with diabetes were aged <65 years. Overall, 20% of NHRs had diabetes that was untreated with medications during the study period. Insulin was the mainstay of treatment (>80%), followed by oral agents (54%). GLP-1 receptor agonist use was low (0.5%) and associated with poor treatment persistence. CONCLUSION: Considerations other than glycemic control may drive prescribing decisions, contrary to recommendations from the American Diabetes Association, American Medical Directors Association, and European Association for the Study of Diabetes.

How well do glucose variability measures predict patient glycaemic outcomes during treatment intensification in type 2 diabetes?

AIM: Despite links to clinical outcomes in patients with type 2 diabetes mellitus (T2DM), the clinical utility of glycaemic variability (GV) measures is unknown. We evaluated the correlation between baseline GV, and glycated haemoglobin (HbA1c) attainment and hypoglycaemic events during treatment intensification in a large group of patients. METHODS: Patient-level data from six 24-week clinical trials of T2DM patients undergoing treatment intensification with basal insulin or comparators (N=1699) were pooled. Baseline GV measures included standard deviation (SD), mean amplitude of glycaemic excursions (MAGE), mean absolute glucose (MAG), coefficient of variation (CV), high blood glucose index (HBGI), and low blood glucose index (LBGI) were correlated with HbA1c change and hypoglycaemic events. RESULTS: All mean GV measures, excluding CV which worsened, improved significantly from baseline to Week 24, with the largest proportional reduction obtained for HBGI (-65.5%). When assessed as mean individual percentage changes only HBGI improved significantly. Baseline GV correlated positively with Week 24 HbA1c for SD, MAGE, and HBGI. Baseline HBGI and CV correlated negatively and positively, respectively, with Week 24 HbA1c change. Correlations also existed between most baseline GV measures and age, body mass index, Week 24 fasting plasma glucose, Week 24 postprandial plasma glucose, and hypoglycaemic events; statistical significance depended on the specific measure. CONCLUSIONS: Pre-treatment GV is associated with glycaemic outcomes in T2DM patients undergoing treatment intensification over 24 weeks. HBGI might be the most robust predictor, warranting validation in dedicated prospective studies or randomized trials to assess the predictive value of measuring GV.

How well do glucose variability measures predict patient glycaemic outcomes during treatment intensification in type 2 diabetes?

AIM: Despite links to clinical outcomes in patients with type 2 diabetes mellitus (T2DM), the clinical utility of glycaemic variability (GV) measures is unknown. We evaluated the correlation between baseline GV, and glycated haemoglobin (HbA1c) attainment and hypoglycaemic events during treatment intensification in a large group of patients. METHODS: Patient-level data from six 24-week clinical trials of T2DM patients undergoing treatment intensification with basal insulin or comparators (N = 1699) were pooled. Baseline GV measures included standard deviation (SD), mean amplitude of glycaemic excursions (MAGE), mean absolute glucose (MAG), coefficient of variation (CV), high blood glucose index (HBGI), and low blood glucose index (LBGI) and were correlated with HbA1c change and hypoglycaemic events. RESULTS: All mean GV measures, excluding CV which worsened, improved significantly from baseline to Week 24, with the largest proportional reduction obtained for HBGI (-65.5%). When assessed as mean individual percentage changes, only HBGI improved significantly. Baseline GV correlated positively with Week 24 HbA1c for SD, MAGE, and HBGI. Baseline HBGI and CV correlated negatively and positively, respectively, with Week 24 HbA1c change. Correlations also existed between most baseline GV measures and age, body mass index, Week 24 fasting plasma glucose, Week 24 postprandial plasma glucose, and hypoglycaemic events; statistical significance depended on the specific measure. CONCLUSIONS: Pre-treatment GV is associated with glycaemic outcomes in T2DM patients undergoing treatment intensification over 24 weeks. HBGI might be the most robust predictor, warranting validation in dedicated prospective studies or randomized trials to assess the predictive value of measuring GV.

Adding Rapid-Acting Insulin or GLP-1 Receptor Agonist to Basal Insulin: Outcomes in a Community Setting.

OBJECTIVE: To evaluate real-world outcomes in patients with type 2 diabetes mellitus (T2DM) receiving basal insulin who initiate add-on therapy with a rapid-acting insulin (RAI) or a glucagon-like peptide 1 (GLP-1) receptor agonist. METHODS: Data were extracted retrospectively from a U. S. health claims database. Adults with T2DM on basal insulin who added an RAI (basal + RAI) or GLP-1 receptor agonist (basal + GLP-1) were included. Propensity score matching (with a 1 up to 3 ratio) was used to control for differences in baseline demographics, clinical characteristics, and health resource utilization. Endpoints included prevalence of hypoglycemia, pancreatic events, all-cause and diabetes-related resource utilization, and costs at 1-year follow-up. RESULTS: Overall, 6,718 matched patients were included: 5,013 basal + RAI and 1,705 basal + GLP1. Patients in both groups experienced a similar proportion of any hypoglycemic event (P = .4079). Hypoglycemic events leading to hospitalization were higher in the basal + RAI cohort (2.7% vs. 1.8%; P = .0444). The basal + GLP-1 cohort experienced fewer all-cause (13.55% vs. 18.61%; P<.0001) and diabetes-related hospitalizations (11.79% vs. 15.68%; P<.0001). The basal + GLP-1 cohort had lower total all-cause health care costs ($18,413 vs. $20,821; P = .0002) but similar diabetes-related costs ($9,134 vs. $8,985; P<.0001) compared with the basal + RAI cohort. CONCLUSIONS: Add-on therapy with a GLP-1 receptor agonist in T2DM patients receiving basal insulin was associated with fewer hospitalizations and lower total all-cause costs compared with add-on therapy using an RAI and could be considered as an alternative to an RAI in certain patients with T2DM who do not achieve effective glycemic control with basal insulin.

Patterns of postprandial hyperglycemia after basal insulin therapy: individual and regional differences.

BACKGROUND: Treatment of postprandial hyperglycemia could be needed when basal insulin added to oral therapy does not maintain glycated haemoglobin (HbA1C ) targets in type 2 diabetes mellitus. Knowing individual and regional patterns of postprandial hyperglycemia in this setting might improve therapeutic decisions. METHODS: Patient-level self-monitored blood glucose data were pooled from six studies of insulin glargine for patients with HbA1C ≥ 7.0% after 24 weeks. Percentages of participants with highest daily postprandial blood glucose and greatest postprandial increments after each of the three daily meals were calculated and compared between four geographical regions; USA, Canada, Germany, and other European countries. RESULTS: For 494 participants (mean age 60.1 years, diabetes duration 9.6 years, and BMI 29.8 kg/m(2) ), mean endpoint HbA1C was 7.8%. On insulin glargine treatment, highest postprandial blood glucose most often occurred post-dinner (44% of participants) and greatest postprandial increments post-breakfast (46% of participants) in all regions. Participants with greatest postprandial increments post-breakfast were older and experienced less HbA1C improvement with insulin glargine than those with greatest postprandial increments after other meals. Post-breakfast and post-dinner postprandial blood glucose was higher in the USA and Canada versus Germany, and in the USA versus Other European countries (all p < 0.05). Postprandial increments after dinner were greater in the USA versus all other regions. CONCLUSIONS: Generally, highest postprandial blood glucose follows dinner and greatest postprandial increments follow breakfast. Variations in patient characteristics and eating patterns might underlie differences both within and between regions. Awareness of regional differences and evaluation of an individual's typical eating pattern might facilitate appropriate prandial therapy.

Prandial insulin versus glucagon-like peptide-1 added to basal insulin: comparative effectiveness in the community practice setting.

BACKGROUND: Real-world data on emerging combination approaches for type 2 diabetes mellitus (T2DM) management are limited. The objective of the current study was to document the characteristics and clinical outcomes of patients with T2DM initiating prandial insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist while on basal insulin. METHODS: This was a retrospective analysis of an electronic medical records database of patients with T2DM managed in a community practice setting in the United States. The main outcome measures were glycated hemoglobin (HbA1c), body weight, hypoglycemia, and health care resource utilization at baseline and at 6-month and 1-year follow-up. RESULTS: A total of 33 810 patients were included in the study: 31 848 on prandial insulin and 1962 on a GLP-1 receptor agonist. At baseline there were significant differences in mean age (60 vs 56 years), mean Charlson Comorbidity Index score (1.1 vs 0.7), mean HbA1c (8.8% vs 8.4%), and mean body weight (99 vs 112 kg) between the prandial insulin and GLP-1 receptor agonist groups, respectively (P < 0.001 for each). After matching for baseline differences, significant and similar changes from baseline were observed between the prandial insulin and the GLP-1 receptor agonist groups during follow-up at the 6 months/1 year post-index date for HbA1c (-0.45/-0.60% vs -0.44/-0.58%, respectively; P = 0.907/0.723 between groups). Body weight changes between the groups were significantly different at 6 months/1 year (+1.7/-1.7 vs -0.9/-3.7 kg; P < 0.001). Hypoglycemia incidence and health care resource utilization were significantly greater in the prandial insulin versus GLP-1 receptor agonist group. CONCLUSIONS: The results of this real-world analysis of patients with T2DM adding a GLP-1 receptor agonist or prandial insulin to basal insulin suggest an association between adding a GLP-1 receptor agonist with similar glycemic control, greater reduction in body weight, lower hypoglycemia incidence, and lower health care utilization compared with adding prandial insulin.

Contributions of basal and prandial hyperglycemia to total hyperglycemia in older and younger adults with type 2 diabetes mellitus.

OBJECTIVES: To evaluate the relative contributions of basal and prandial components to total hyperglycemia in older and younger adults with type 2 diabetes mellitus. DESIGN: Participant-level data were pooled from six randomized studies of 24 weeks or longer treatment with insulin glargine or an active comparator. SETTING: Prospective, randomized Phase 3 or 4 controlled trials. PARTICIPANTS: One thousand six hundred ninety-nine individuals: 509 (30%) aged 65 and older and 1,190 (70%) younger than 65. MEASUREMENTS: Contributions of basal hyperglycemia (BHG) and postprandial hyperglycemia (PPHG) to total hyperglycemia, defined as the incremental area under the curve of daytime blood glucose (BG) from the overall glucose profile calculated from 7-point self-measured BG profiles, of participants aged 65 and older were compared with those of participants younger than 65. RESULTS: After 24 weeks of treatment, glycosylated hemoglobin (HbA1c) decreased in the older (8.6-7.0%) and younger (8.7-7.1%) groups; the relative contribution of BHG was significantly lower in both age groups (P < .001). The relative contribution of BHG to that of PPHG was significantly smaller in older than in younger participants at baseline (75.4% vs 79.4%; P < .001) and 24 weeks (37.6% vs 44.7%; P < .001). The relative contribution of BHG to total hyperglycemia was not correlated with HbA1c at baseline and after 24 weeks of treatment in older participants but was positively correlated at baseline (correlation coefficient (r) = 0.082; P = .005) and 24 weeks (r = 0.062; P = .03) in younger participants. A significantly lower proportion of older participants reported symptomatic, glucose-confirmed, and nocturnal hypoglycemia during 24 weeks of treatment (P < .001). CONCLUSION: The relative contribution of BHG was lower, and that of PPHG was greater in older than in younger participants, suggesting that different therapeutic approaches may be required to treat hyperglycemia effectively in these different age groups.