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Plasma lipoprotein levels, including remnant-like particle (RLP) cholesterol and RLP triglycerides, were assessed in fasting (12 hours) and postprandial (PP) (4 hours after a fat-rich meal) states in 88 patients with coronary heart disease (CHD) and 88 controls. All lipoproteins were assessed by direct methods. We hypothesized that patients with CHD would have greater percent increases in their triglyceride levels, RLP cholesterol, and RLP triglycerides, in response to a fat-rich meal. In the fasting state, triglycerides, RLP cholesterol, RLP triglycerides, and low-density lipoprotein (LDL) cholesterol levels were all significantly higher in cases versus controls by 51%, 35%, 39%, and 40%, respectively. These levels were 57%, 37%, 64%, and 37% higher in the PP state, respectively. Mean high-density lipoprotein (HDL) cholesterol values were 27% lower in cases in both the fasting and PP states. After eating, triglycerides, RLP cholesterol, and RLP triglycerides increased 64%, 71%, and 290% in controls, respectively, whereas in cases these levels increased by 71%, 94%, and 340%, respectively (all p <0.0001). Percent increases in the PP state were not significantly different in cases versus controls. Following the fat-rich meal, LDL and HDL cholesterol decreased by 5% and 4% in controls, and by 7% and 6% in patients, with no significant difference in percent changes between groups. Fasting values correlated very highly with PP values for all parameters (all p <0.0001). Our data indicate that although patients with CHD have higher fasting and PP levels of triglycerides, RLP cholesterol, and RLP triglycerides than controls, the response (percent increase) to a fat-rich meal is comparable in both groups. Thus, a feeding challenge is not essential for assessment of these lipoproteins. Moreover, it is not necessary to obtain a fasting sample to assess direct LDL and HDL cholesterol. [ABSTRACT FROM AUTHOR]

Background: Hyperuricemia is frequently observed in patients with type 2 diabetes (T2D) and is associated with increased risk of gout and cardiovascular disease (CVD). Empagliflozin lowers serum urate levels by enhancing its urinary excretion., Objective: To compare initiators of empagliflozin vs dipeptidyl peptidase-4 inhibitor (DPP4i) and initiators of empagliflozin vs glucagon-like peptide-1 receptor agonist (GLP-1RA) with respect to the risk of incident gout events., Design and Participants: Using three claims-based datasets from 08/2014 to 09/2019, we generated two cohorts (cohort 1: empagliflozin vs DPP4i; cohort 2: empagliflozin vs GLP-1RA) of adult patients with T2D and without prior history of gout or gout-specific medication dispensing separately in each dataset. To assess the risk of incident gout, we estimated hazard ratios (HR) and rate differences (RD) per 1000 person-years (PY) with their 95% confidence intervals (CI) before and after 1:1 propensity score (PS) matching adjusting for 141 baseline covariates., Key Results: We identified 102,262 pairs of 1:1 propensity score-matched adults in cohort 1 and 131,216 pairs in cohort 2. Over a mean follow-up period of 8 months on treatment, the risk of gout was lower in patients initiating empagliflozin compared to DPP4i (HR = 0.69: 95% CI (0.60-0.79); RD =  - 2.27: 95% CI (- 3.08, 1.46)) or GLP-1RA (HR = 0.83: 95% CI (0.73-0.94); RD =  - 0.99: 95% CI (- 1.66, - 0.32)). Results were consistent across subgroups (sex, age, body mass index, chronic kidney disease, heart failure, cardiovascular disease, and concurrent diuretic use) and sensitivity analyses., Conclusions: Among adults with T2D, the initiation of empagliflozin vs a DPP4i or GLP-1RA was associated with lower risk of incident gout, complementing results from a post hoc analysis of the EMPA-REG OUTCOME trial and previously published observational research focusing on the sodium-glucose co-transporter-2 inhibitor class in more narrowly defined study populations., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Background: The economic burden associated with type 2 diabetes mellitus (T2DM) and concurrent cardiovascular disease (CVD) among patients with COVID-19 is unclear. Objective: We compared healthcare resource utilization (HCRU) and costs in patients with COVID-19 and T2DM and CVD (T2DM + CVD), T2DM only, or neither T2DM nor CVD (T2DM/CVD). Methods: A retrospective observational study in COVID-19 patients using data from the Healthcare Integrated Research Database (HIRD®) was conducted. Patients with COVID-19 were identified between March 1, 2020, and May 31, 2021, and followed from first diagnosis or positive lab test to the end of health plan enrollment, end of study period, or death. Patients were assigned one of 3 cohorts: pre-existing T2DM+CVD, T2DM only, or neither T2DM/CVD. Propensity score matching and multivariable analyses were performed to control for differences in baseline characteristics. Study outcomes included all-cause and COVID-19-related HCRU and costs. Results: In all, 321 232 COVID-19 patients were identified (21 651 with T2DM + CVD, 28 184 with T2DM only, and 271 397 with neither T2DM/CVD). After matching, 6967 patients were in each group. Before matching, 46.0% of patients in the T2DM + CVD cohort were hospitalized for any cause, compared with 18.0% in the T2DM-only cohort and 6.3% in the neither T2DM/CVD cohort; the corresponding values after matching were 34.2%, 26.0%, and 21.2%. The proportion of patients with emergency department visits, telehealth visits, or use of skilled nursing facilities was higher in patients with COVID-19 and T2DM + CVD compared with the other cohorts. Average all-cause costs during follow-up were 12   324 , 7882, and $7277 per-patient-per-month after matching for patients with T2DM + CVD, T2DM-only, and neither T2DM/CVD, respectively. COVID-19-related costs contributed to 78%, 75%, and 64% of the overall costs, respectively. The multivariable model showed that per-patient-per-month all-cause costs for T2DM + CVD and T2DM-only were 54% and 21% higher, respectively, than those with neither T2DM/CVD after adjusting for residual confounding. Conclusion: HCRU and costs in patients were incrementally higher with COVID-19 and pre-existing T2DM + CVD compared with those with T2DM-only and neither T2DM/CVD, even after accounting for baseline differences between groups, confirming that pre-existing T2DM + CVD is associated with increased HCRU and costs in COVID-19 patients, highlighting the importance of proactive management.

Aim: To compare adverse outcomes among COVID-19 patients with pre-existing type 2 diabetes (T2D) only, T2D and cardiovascular disease (CVD), or neither., Methods: This retrospective cohort study used administrative claims, laboratory and mortality data from the HealthCore Integrated Research Database. Patients with COVID-19 were identified from 3 January 2020 to 31 May 2021 and stratified by the presence of T2D and CVD. Outcomes included hospitalization, intensive care unit (ICU) admission, mortality and complications following COVID-19 infection. Propensity score matching and multivariable analyses were performed., Results: A total of 321 232 COVID-19 patients were identified (21 651 T2D + CVD, 28 184 T2D only, and 271 397 neither) with a mean (SD) follow-up of 5.4 (3.0) months. After matching, 6 967 patients were identified for each group, and residual baseline differences remained. Adjusted analyses showed that COVID-19 patients with T2D + CVD were 59% more probable to be hospitalized, 74% more probable to be admitted to the ICU, and had a 26% higher mortality risk than those with neither. COVID-19 patients with T2D only were 28% and 32% more probable to be admitted to the hospital and ICU than those with neither, respectively. Among all T2D + CVD patients, acute respiratory distress syndrome (31%) and acute kidney disease (24%) were observed., Conclusion: Our study highlights the incrementally poorer outcomes associated with pre-existing T2D + CVD in COVID-19 patients compared with those without T2D/CVD and suggests consideration of a more optimal management approach in these patients., (© 2023 Carelon Research, Elevance Health and Boehringer Lngelheim Pharmaceuticals Inc. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Heart failure is a common and devastating complication of type 2 diabetes (T2D). Prompt recognition of heart failure may avert hospitalization, facilitate use of guideline-directed therapies, and impact choice of T2D medications. We sought to determine the rate and factors associated with heart failure documentation in T2D patients with evidence of volume overload requiring loop diuretics., Methods: DCR is an on-going, prospective US registry of outpatient T2D patients from > 5000 cardiology, endocrinology, and primary care clinicians (current analysis used data from 2013-2019). Among T2D patients receiving loop diuretics, we examined the rate of chart documentation of heart failure. We used a 3-level hierarchical logistic regression model (patients nested within physician within practice) to examine factors associated with heart failure diagnosis., Results: Among 1,322,640 adults with T2D, 225,125 (17.0%) were receiving a loop diuretic, of whom 91,969 (40.9%) had documentation of heart failure. Male sex, lower body mass index, atrial fibrillation, chronic kidney disease, and coronary artery disease were associated with greater odds of heart failure diagnosis. After accounting for patient factors, patients seen by cardiologists were the most likely to have HF documented followed by PCPs and then endocrinologists., Conclusions: Among US outpatients with T2D, 17% of patients had evidence of volume overload-defined by loop diuretic prescription-of whom fewer than half had a clinical diagnosis of heart failure. While there may be non-heart failure indications for loop diuretics, our data suggest that a substantial proportion of T2D patients may have unrecognized heart failure and therefore could be missing opportunities for targeted therapies that could alter the clinical course of heart failure.

Background: Empagliflozin, a sodium-glucose cotransporter 2 inhibitor indicated for type 2 diabetes mellitus (T2DM), can lower blood pressure (BP) and reduce cardiovascular mortality in patients with T2DM and preexisting cardiovascular disease. Its effects in blacks have been understudied., Methods: In this 24-week study, 150 blacks with T2DM and hypertension had glycohemoglobin (primary end point), office and 24-hour ambulatory BP, body weight, and safety assessments. After a 2-week, open-label, placebo run-in, patients were randomly assigned to once daily empagliflozin (10 mg for the first 4 weeks, then force-titrated to 25 mg until week 24) or placebo. A mixed-effects model for repeated measures was performed on the primary and 2 key secondary end points, and an analysis of covariance for nonrepeated measures with last observation carried forward was performed for 2 other key secondary end points. Hierarchical testing was applied for these end points., Results: Overall, 52.7% of participants were men, mean (SD) age, 56.8 (9.3) years; mean duration of T2DM, 9.3 (7.1) years. The baseline values of key parameters (mean [SD]) were as follows: glycohemoglobin, 8.59 (1.02)%; ambulatory systolic BP, 146.3 (11.0) mm Hg; and ambulatory diastolic BP, 89.4 (8.1) mm Hg. By week 24, the mean (standard error) change in glycohemoglobin in the empagliflozin group was -0.77 (0.15%) in comparison with an increase of 0.07 (0.16%) in the placebo group; placebo-corrected difference, -0.78% (95% CI, -1.18 to -0.38; P=0.0002). Reductions in body weight by week 24 were -2.38 (0.38) empagliflozin and -0.80 (0.47) placebo; the placebo-corrected difference was -1.23 kg (95% CI, -2.39 to -0.07; P=0.0382). Empagliflozin significantly reduced 24-hour ambulatory systolic BP versus placebo by weeks 12 and 24 (placebo-corrected difference, -5.21 mm Hg [95% CI, -9.24 to -1.18; P=0.0117] and -8.39 mm Hg [95% CI, -13.74 to -3.04; P=0.0025], respectively). Diastolic BP was also reduced., Conclusions: In blacks with T2DM, empagliflozin reduced glycohemoglobin, body weight, and BP. The effect of empagliflozin on BP increased from 12 to 24 weeks, suggesting a full antihypertensive effect takes ≥6 months to be fully realized. At week 24, the placebo-subtracted BP effect was similar to standard antihypertensive monotherapies, suggesting that empagliflozin may be beneficial for this high-risk population., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02182830.

The 1245.29 Trial recently showed that empaglifozin improved both blood pressure and glucose control in African American (AA) patients with type 2 diabetes (T2D) and hypertension. Using the Diabetes Collaborative Registry, a large-scale US registry of outpatients with diabetes recruited from primary care, cardiology and endocrinology practices, we sought to understand the potential impact of these observations in routine clinical practice. Among 74 290 AA patients with T2D from 368 US clinics, 60.4% had hypertension, of whom 34.5% had systolic blood pressure ≥ 140 mm Hg (20.8% of the total AA T2D population). Only 1.7% of this eligible population had been prescribed a sodium-glucose co-transporter two inhibitor. The mean estimated 5-year risk of cardiovascular death was 7.7%, which could be reduced to 6.2% when modelling the antihypertensive effect of empagliflozin across the eligible population (based on an 8-mm Hg blood pressure reduction). These findings may represent a potential opportunity for better management of cardiovascular risk factors and improved outcomes in this vulnerable cohort., (© 2018 John Wiley & Sons Ltd.)

Objectives: To examine the proportion of older adults with diabetes mellitus treated with tight glucose control and the factors associated with this practice., Design: Cross-sectional analysis., Setting: Outpatient sites in the Diabetes Collaborative Registry (N=151)., Participants: Adults aged 75 and older with type 2 diabetes mellitus (N=42,669)., Measurements: Participants were categorized based on glycosylated hemoglobin (HbA1c) and glucose-lowering medications: poor control (HbA1c >9%), moderate control (HbA1c 8-9%), conservative control (HbA1c 7-8%), tight control (HbA1c <7%) with low-risk agents (low risk for hypoglycemia), tight control with high-risk agents, and diet control (HbA1c <7% taking no glucose-lowering medications). We used hierarchical logistic regression to examine participant and site factors associated with tight control and high-risk agents versus conservative or tight control and low-risk agents., Results: Of 30,696 participants without diet-controlled diabetes, 5,596 (18%) had moderate or poor control, 9,227 (30%) had conservative control, 7,893 (26%) had tight control taking low-risk agents, and 7,980 (26%) had tight control taking high-risk agents. Older age, male sex, heart failure, chronic kidney disease, and coronary artery disease were each independently associated with greater odds of tight control with high-risk agents. There were no differences according to practice specialty (endocrinology, primary care, cardiology) in how aggressively participants were managed., Conclusion: One-quarter of U.S. older adults with type 2 diabetes mellitus are tightly controlled with glucose-lowering medications that have a high risk of hypoglycemia. These results suggest potential overtreatment of a substantial proportion of people and should encourage further efforts to translate guidelines to daily practice., (© 2018, Copyright the Authors Journal compilation © 2018, The American Geriatrics Society.)

Objective: Black/African American individuals have a higher prevalence of type 2 diabetes mellitus (T2DM), diabetes-related complications and hypertension, but they are often underrepresented in clinical trials. The sodium-glucose co-transporter 2 inhibitor, empagliflozin, was associated with significant improvements in glucose control (via hemoglobin [Hb] A 1c ) and reductions in blood pressure (BP; via office and ambulatory BP monitoring) in a primarily white population with T2DM and hypertension. The aim of this ongoing study is to assess the safety and efficacy of empagliflozin in terms of glucose- and BP-lowering in a self-identified black/African American population with T2DM and hypertension., Methods: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3b study carried out at 85 centers in the USA. It was designed to assess the safety and efficacy of empagliflozin (10 or 25 mg/day) versus placebo in black/African American patients with uncontrolled T2DM and hypertension. Patients receiving stable glucose-lowering therapy prestudy continued at the same dose during the trial; BP-lowering medication was also held stable. The primary endpoint was the change from baseline in HbA 1c at Week 24. Key secondary endpoints were change from baseline in: mean 24-hour ambulatory systolic BP (SBP) at Week 12, mean trough ambulatory SBP at Week 12, body weight at Week 24 and trough seated SBP at Week 12., Results: The study will report final data in 2018., Conclusions: Results of this study will add to our understanding of the efficacy and safety of empagliflozin in self-identified black/African American patients with T2DM and hypertension. (ClinicalTrials.gov identifier: NCT02182830.).

1. The absorption, biotransformation and excretion of empagliflozin, an SGLT2 inhibitor, were evaluated in eight healthy subjects following a single 50 mg oral dose of empagliflozin containing ∼100 µCi [(14)C]-empagliflozin. 2. Radioactivity was rapidly absorbed, with plasma levels peaking 1 h post-dose. Total exposure was lower in blood versus plasma, consistent with moderate (28.6-36.8%) red blood cell partitioning. Protein binding was 80.3-86.2%. 3. Most of the radioactive dose was recovered in urine (54.4%) and faeces (41.1%). Unchanged empagliflozin was the most abundant drug-related component in plasma, representing 75.5-77.4% of plasma radioactivity and 79.6% plasma radioactivity AUC0-12 h. Unchanged empagliflozin was the most abundant drug-related component in urine and faeces, representing 43.5% (23.7% of dose) and 82.9% (34.1% of dose) of radioactivity in urine and faeces, respectively. Six metabolites were identified in plasma: three glucuronide conjugates representing 4.7-7.1% of AUC0-12 h and three less abundant metabolites (<0.2-1.9% AUC0-12 h). The most abundant metabolites in urine were two glucuronide conjugates (7.8-13.2% of dose) and in faeces was a tetrahydrofuran ring-opened carboxylic acid metabolite (1.9% of dose). 4. To conclude, empagliflozin was rapidly absorbed and excreted primarily unchanged in urine and faeces. Unchanged parent was the major drug-related component in plasma. Metabolism was primarily via glucuronide conjugation.

Introduction: This study examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of empagliflozin, a potent and highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM)., Methods: A total of 48 patients with T2DM were randomized to receive one of four doses of empagliflozin (2.5, 10, 25, or 100 mg qd) or placebo over 8 days. In every dose group, nine patients received active drug and three received placebo. The primary endpoint was safety and tolerability. Pharmacokinetic and pharmacodynamic parameters were measured as secondary endpoints., Results: Empagliflozin was rapidly absorbed, reaching peak levels 1.5-3.0 h after dosing and showed a biphasic decline. The mean terminal elimination half-life ranged from 10 to 19 h. Increases in exposure (area under the plasma concentration-time curve [AUC] and maximum concentration of analyte in plasma [C max]) were approximately proportional with dose. Empagliflozin increased the rate and total amount of glucose excreted in urine compared to placebo. After administration of a single dose of empagliflozin, cumulative amounts of glucose excreted in urine over 24 h ranged from 46.3 to 89.8 g, compared with 5.84 g with placebo. Similar results were seen after multiple doses. Fasting plasma glucose levels decreased by 17.2-25.8% with empagliflozin and by 12.7% with placebo. The frequency of adverse events was 33.3-66.7% with empagliflozin and 41.7% with placebo. There were no changes in urine volume or micturition frequency under the controlled study conditions., Conclusion: Overall, pharmacokinetic assessments demonstrated a dose-proportional increase in drug exposure and support once-daily dosing. Elevated urinary glucose excretion was observed with all doses. Multiple once-daily oral doses of empagliflozin (2.5-100 mg) reduced plasma glucose and were well tolerated in patients with T2DM. EudraCT (2007-000654-32).

Introduction: To evaluate the pharmacodynamics, pharmacokinetics, safety and tolerability of empagliflozin in Japanese patients with type 2 diabetes mellitus., Materials and Methods: In this 4-week, multiple dose, randomized, parallel-group, double-blind, placebo-controlled trial, patients (n = 100) were randomized to receive 1, 5, 10 or 25 mg of empagliflozin, or placebo once daily. Key end-points were urinary glucose excretion (UGE), fasting plasma glucose (FPG) and eight-point glucose profile., Results: Data are presented for 1, 5, 10, 25 mg of empagliflozin and placebo groups, respectively. Adjusted mean changes from baseline to day 27 in UGE were 40.8, 77.1, 80.9, 93.0 and -2.1 g (P < 0.0001 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 28 in FPG were -1.56, -1.96, -2.31, -2.37 and -0.86 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Adjusted mean changes from baseline to day 27 in eight-point glucose profile were -1.96, -2.21, -2.42, -2.54 and -0.97 mmol/L (P < 0.01 for all empagliflozin groups vs placebo). Empagliflozin reached peak plasma concentration 1.5-2 h after dosing. Mean steady state terminal elimination half-lives ranged from 13.2 to 18.0 h. Of 100 patients, 25 experienced an adverse event, occurring more frequently for empagliflozin (29.1%) than placebo (9.5%); frequency was not dose related., Conclusions: In Japanese patients with type 2 diabetes mellitus, empagliflozin at doses up to 25 mg once daily for 4 weeks was well tolerated and resulted in significant improvements in glycemic control compared with placebo. This trial was registered with ClinicalTrials.gov (no. NCT00885118).

Data from five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with type 2 diabetes mellitus (T2DM; N = 974; 1-100 mg q.d.; ≤12 weeks) were used to develop a population pharmacokinetic (PK) model for empagliflozin. The model consisted of two-compartmental disposition, lagged first-order absorption and first-order elimination, and incorporated appropriate covariates. Population estimates (interindividual variance, CV%) of oral apparent clearance, central and peripheral volumes of distribution, and inter-compartmental clearance were 9.87 L/h (26.9%), 3.02 L, 60.4 L (30.8%), and 5.16 L/h, respectively. An imposed allometric weight effect was the most influential PK covariate effect, with a maximum effect on exposure of ±30%, using 2.5th and 97.5th percentiles of observed weights, relative to the median observed weight. Sex and race did not lend additional description to PK variability beyond allometric weight effects, other than ∼25% greater oral absorption rate constant for Asian patients. Age, total protein, and smoking/alcohol history did not affect PK parameters. Predictive check plots were consistent with observed data, implying an adequate description of empagliflozin PKs following multiple dosing in patients with T2DM. The lack of marked covariate effects, including weight, suggests that no exposure-based dose adjustments were required within the study population and dose range., (© The Author(s) 2013 John Wiley & Sons, Ltd.)

Empagliflozin is an orally available, selective inhibitor of sodium glucose cotransporter 2. In this study, single oral doses of empagliflozin from 0.5 to 800 mg were not associated with any clinically significant safety concerns in healthy male volunteers. The incidence of adverse events (AEs) was similar in subjects receiving placebo (22.2%) or empagliflozin (25.0%) in the single rising dose part of the study and after 50 mg empagliflozin under fed (28.6%) or fasted (28.6%) conditions. The most frequent AE was headache. No clinically relevant changes in laboratory or electrocardiogram (ECG) measurements were observed. Single oral doses of empagliflozin were rapidly absorbed, reaching peak levels after 1.0-2.1 hours. Increases in empagliflozin exposure were roughly dose-proportional and a dose-dependent increase in urinary glucose excretion was observed for empagliflozin doses up to 100 mg. After ingestion of 50 mg empagliflozin in conjunction with a high-fat, high-calorie meal, no clinically relevant changes in exposure were found, indicating that empagliflozin can be administered independent of food. Empagliflozin up to 800 mg did not generate clinically significant safety concerns in healthy male subjects. The pharmacokinetic properties of empagliflozin support once daily administration independent of food., (© The Author(s) 2013.)

Introduction: Enhance Fitness (EF) (formerly the Lifetime Fitness Program) is an evidence-based community exercise program for older adults. From 1998 to 2005, participation of ethnic older adults increased significantly. However, little research is available about what ethnic older adults want or need to continue participation in exercise programs. The purpose of this study was to examine how physical environment, social environment, and individual biology and behavior influence adherence to exercise for ethnic older adults participating in EF., Methods: Six focus groups were conducted with 52 older adults participating in EF. Facilitators asked questions about factors that helped participants continue exercising in EF. Interviews were audiotaped and transcribed. Transcripts were systematically reviewed using content analysis., Results: Focus group participants were Chinese (n = 21, 40%), African American (n = 18, 35%), white (n = 10, 19%), and Japanese (n = 3, 6%). Mean (SD) age was 76 years (7.4). Participants had, on average, participated in EF for 44 months (SD = 37.8). Results revealed four themes related to adherence. First, environmental factors that promoted adherence were location of the classes, transportation, weather, and the facility. Second, design of the exercise program that encouraged adherence included exercise content and type of delivery. Third, social support factors that encouraged adherence were the socializing and support between class participants and support from family, health care providers, and the class instructors. Finally, individual factors that encouraged adherence were personality traits and feelings, past physical activity experience, health benefits, and mental stimulation., Conclusion: Findings from this study suggest strategies for developing community-based physical activity programs for older adults from ethnically diverse communities.

Extract: Over the past two decades, urbanization has prompted the availability of an abundance of high caloric foods and has promoted increasingly more sedentary lifestyles, resulting in the rise of obesity as the most common nutritional disorder in the urbanized world. Presently, the majority of people in the United States are considered overweight or obese, making obesity and its complications a major health concern. Consequently, the World Health Organization (WHO) has identified obesity as a major chronic disease, now emerging as a pandemic. Today, there are over one billion overweight people worldwide, 300 million of which are obese. At present rates, the number of obese people is expected to double by 2025 (WHO). In addition to adult obesity, adolescent or childhood obesity has doubled in the past 10 years, with a corresponding doubling of adolescent type 2 diabetes (T2D). The prevalence of obesity in children is on the rise in most urbanized populations, which will impact obesity-associated morbidity and mortality even more in the decades to come.

Background: Increased plasma lipoprotein(a) [Lp(a)] concentrations have been reported to be an independent risk factor for coronary heart disease (CHD) in some prospective studies, but not in others. These inconsistencies may relate to a lack of standardization and the failure of some immunoassays to measure all apolipoprotein(a) isoforms equally., Methods: We measured plasma Lp(a)-cholesterol [Lp(a)-C] in a Caucasian population of offspring and spouses of the Framingham Heart Study participants, using a lectin-based assay (LipoproTM). We compared the prevalence of increased Lp(a)-C to the presence of sinking pre-beta-lipoprotein (SPB). We also related Lp(a)-C concentrations to the prevalence of CHD risk in the entire population., Results: The mean (+/- SD) Lp(a)-C concentration in the Framingham population (n = 3121) was 0.186 +/- 0.160 mmol/L, with no significant gender or age differences. The mean Lp(a)-C concentrations in the absence or presence of SPB were 0.158 +/- 0. 132 mmol/L and 0.453 +/- 0.220 mmol/L, respectively (P <0.0001). The mean Lp(a)-C concentration in men with CHD (n = 156) was 0.241 +/- 0. 204 mmol/L, which was significantly (P <0.001) higher, by 34%, than in controls. The odds ratio for CHD risk in men with Lp(a)-C >/=0. 259 mmol/L (>/=10 mg/dL), after adjusting for age, HDL-cholesterol, LDL-cholesterol, smoking, diabetes, blood pressure, and body mass index, was 2.293 (confidence interval, 1.55-3.94; P <0.0005). Lp(a)-C values correlated highly with a Lp(a)-mass immunoassay [ApotekTM Lp(a); r = 0.832; P <0.0001; n = 1000]., Conclusions: An increased Lp(a)-C value >/=0.259 mmol/L (>/=10 mg/dL) is an independent CHD risk factor in men with a relative risk of more than 2, but was inconclusive in women. Lp(a)-C measurements offer an alternative to Lp(a)-mass immunoassays and can be performed on automated analyzers.

Although lipoprotein(a) [Lp(a)] was first described more than 35 years ago, adequate prospective data have only recently supported Lp(a) as an independent risk factor for coronary heart disease (CHD). In vitro studies suggest that Lp(a) contributes to atherogenesis directly by cholesterol uptake and indirectly by the inhibition of fibrinolysis. In patients with CHD or a significant risk for CHD, Lp(a) should be measured and treated with either niacin or estrogen if the patient has Lp(a) cholesterol levels of more than 10 mg/dL or an Lp(a) mass of more than 30 mg/dL. In addition, homocysteine and remnantlike lipoprotein cholesterol are strongly supported by prospective or population-based prevalence data as independent risk factors for CHD. Homocysteine levels of more than 14 mumol/L should be treated with vitamin supplements of folate, B6, and B12. Remnantlike lipoprotein cholesterol is the product of a novel immunoassay that separates the partially hydrolyzed triglyceride-rich remnant particles. The association of these particles with CHD risk in women may explain the small independent CHD risk that triglycerides have in women in the Framingham Heart Study. A clear therapeutic intervention has not been documented but may include diet, fibric acid derivatives, or hydroxymethylglutamyl coenzyme A reductase inhibitors.

Objective: To establish whether elevated lipoprotein(a) [Lp(a)], detected as a sinking pre-beta-lipoprotein band on electrophoresis of fresh plasma, is an independent risk factor for the development of premature coronary heart disease (CHD) in men., Design and Setting: Prospective study of the Framingham offspring cohort., Participants: A total of 2191 men aged 20 to 54 years old who were free of cardiovascular disease when they were examined between 1971 and 1975., Main Outcome Measures: Incident CHD (myocardial infarction, coronary insufficiency, angina pectoris, or sudden cardiac death) occurring by age 55 years., Results: After a median follow-up of 15.4 years, there were 129 CHD events. The relative risk (RR) estimates (with 95% confidence intervals [CIs]) for premature CHD derived from a proportional hazards model that included age, body mass index, and the dichotomized risk factor covariables elevated plasma Lp(a) level, total cholesterol level of 6.2 mmol/L (240 mg/dL) or more, high-density lipoprotein (HDL) level less than 0.9 mmol/L (35 mg/dL), smoking, glucose intolerance, and hypertension were as follows: elevated Lp(a) level, RR, 1.9 (95% CI, 1.2-2.9), prevalence, 11.3%; total cholesterol level of 6.2 mmol/L or more, RR, 1.8 (95% CI, 1.2-2.7), prevalence, 14.3%; HDL level of less than 0.9 mmol/L, RR, 1.8 (95% CI, 1.2-2.6), prevalence 19.2%; smoking, RR 3.6 (95% CI, 2.2-5.5), prevalence, 46.7%; glucose intolerance, RR, 2.7 (95% CI, 1.4-5.3), prevalence, 2.6%; hypertension, RR, 1.2 (95% CI, 0.8-1.8), prevalence, 26.3%., Conclusions: Elevated plasma Lp(a) is an independent risk factor for the development of premature CHD in men, comparable in magnitude and prevalence (ie, attributable risk) to a total cholesterol level of 6.2 mmol/L (240 mg/dL) or more, or an HDL level less than 0.9 mmol/L (35 mg/dL).

Elevated plasma or serum lipoprotein(a) (Lp(a)) levels have been associated with premature coronary heart disease (CHD). Lp(a) levels can be assessed quantitatively by electrophoresis and quantitatively by immunoassays determining either total Lp(a) mass, apo(a) mass on Lp(a) protein mass, or by precipitation methods followed by measurement of Lp(a) cholesterol. We prefer the latter method because it can be standardized. Electrophoretic methods can detect total Lp(a) values > or = 30 mg/dl. These values correspond to Lp(a) cholesterol values > or = 10 mg/dl. Such values are above the 75th percentile and represent high risk values for CHD. Values above the 90th percentile for middle aged men and women in Framingham (n = 2678) are > or = 38 mg/dl for total Lp(a). About 16% of patients with premature CHD (n = 321) have such values and have familial Lp(a) excess. Lp(a) is atherogenic because it can be deposited in the arterial wall, and it also can interfere with fibrinolysis. Multiple apo(a) isoforms have been found and are due to a variable number of kringle 4 like repeats. Lower molecular weight apo(a) isoforms forms are associated with elevated Lp(a) values and are more frequent in CHD kindreds. Both Lp(a) levels and apo(a) isoforms are highly heritable in this Caucasian population. Lp(a) values can be decreased with niacin, and such therapy should be strongly considered in CHD patients with elevated Lp(a) levels (> or = 30 mg/dl) since niacin treatment has been shown to decrease CHD morbidity and mortality in unselected CHD patients.

Lipoprotein (a) [Lp(a)] was isolated from several donors and its apolipoprotein (a) [apo(a)] dissociated by a reductive treatment, generating the apo(a)-free form of Lp(a) [Lp(a--)] that contains apolipoprotein B (apo B) as its sole protein. Using anti-apo B monoclonal antibodies, the properties of apo B in Lp(a), Lp(a--), and autologous low-density lipoprotein (LDL) were compared. Marked differences in apo B immunoreactivity were found between these lipoproteins, due to the presence of apo(a) in Lp(a). Apo(a) enhanced the expression of two epitopes in the amino-terminal part of apo B while it diminished the immunoreactivity of three other epitopes in the LDL receptor binding domain. Accordingly, the binding of the lipoproteins to the LDL receptor was also decreased in the presence of apo(a). In a different experimental system, the incubation of antibodies that react with 27 distinct epitopes distributed along the whole length of apo B sequence with plastic-bound Lp(a) and Lp(a--) failed to reveal any epitope of apo B that is sterically hindered by the presence of apo(a). Our results demonstrate that the presence of apo(a) modified the organization and function of apo B in Lp(a) particles. The data presented indicate that most likely the modification is not due to a steric hindrance but that some more profound conformational changes are involved. We suggest that the formation of the disulfide bridge between apo B and apo(a) in Lp(a) alters the system of disulfide bonds present in apo B and thereby modifies apo B structure.