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1.  Lipid and lipoprotein levels and trends in rheumatoid arthritis compared to the general population 
Arthritis care & research  2013;65(12):2046-2050.
Differences in lipid levels associated with cardiovascular (CV) risk between rheumatoid arthritis (RA) and the general population remain unclear. Determining these differences is important in understanding the role of lipids in CV risk in RA.
We studied 2,005 RA subjects from two large academic medical centers. We extracted electronic medical record (EMR) data on the first low density lipoprotein (LDL), total cholesterol (TChol) and high density lipoprotein (HDL) within 1 year of the LDL. Subjects with an electronic statin prescription prior to the first LDL were excluded.
We compared lipid levels in RA to levels from the general United States population (Carroll, et al., JAMA 2012), using the t-test and stratifying by published parameters, i.e. 2007–2010, women. We determined lipid trends using separate linear regression models for TChol, LDL and HDL, testing the association between year of measurement (1989–2010) and lipid level, adjusted by age and gender. Lipid trends were qualitatively compared to those reported in Carroll, et al.
Women with RA had a significantly lower Tchol (186 vs 200mg/dL, p=0.002) and LDL (105 vs 118mg/dL, p=0.001) compared to the general population (2007–2010). HDL was not significantly different in the two groups. In the RA cohort, Tchol and LDL significantly decreased each year, while HDL increased (all with p<0.0001), consistent with overall trends observed in Carroll, et al.
RA patients appear to have an overall lower Tchol and LDL than the general population, despite the general overall risk of CVD in RA from observational studies.
PMCID: PMC4060244  PMID: 23925980
2.  Characterization of lipid parameters in diabetes mellitus – a Nigerian report 
Diabetes mellitus (DM) is a disorder that is often associated with cardiovascular events and underlying lipid abnormalities. Cardiovascular complications are common causes of DM deaths in Nigeria yet dyslipidaemia is one aspect of DM that is underdiagnosed and undertreated in our patients. This report seeks to determine the prevalence and pattern of lipid abnormalities in Nigerians with types I and 2 DM.
A total of 600 patients with DM aged between 22 – 79 years were evaluated for lipid abnormalities. The anthropometric indices, glycosylated haemoglobin, pattern of DM treatment and co-morbidities were noted. Total cholesterol (TCHOL), triglyceride (TG), high density lipoproteins (HDL-C), low density lipoproteins cholesterol (LDL-C) levels and the atherogenic indices levels were documented. Test statistic used included student's t test and χ2.
Well over half (89%) of the study subjects had lipid abnormalities and there was no statistically significant difference in the proportions of subjects with type 1 and 2 DM with lipid abnormalities. Elevated LDL-C, TCHOL, TG and reduced HDL-C were noted in 74%, 42%, 13%, and 53% respectively of the study subjects. The commonly noted combined lipid abnormalities were elevated TG and reduced HDL-C. Hypertension, significant histories of smoking and alcohol ingestion were found to be potential determinants of the occurrence of dyslipidaemia. Age, sex, type of DM and anthropometric indices were found to be determinants of the the pattern of dyslipidaemia. Only a small proportion – (8%)-of the subjects with dyslipidaemia were on treatment for it.
Having defined the scope of dyslipidaemia in our patients and also highlighting its gross undertreatment, we hope that our data will help sensitize health care practitioners on screening for and treating dyslipidaemia. Elevated LDL-C and reduced HDL-C should be the primary targets of treatment in our patients with dyslipidaemia.
PMCID: PMC2734749  PMID: 19619328
3.  Low-Density Lipoprotein Apheresis 
Executive Summary
To assess the effectiveness and safety of low-density lipoprotein (LDL) apheresis performed with the heparin-induced extracorporeal LDL precipitation (HELP) system for the treatment of patients with refractory homozygous (HMZ) and heterozygous (HTZ) familial hypercholesterolemia (FH).
Background on Familial Hypercholesterolemia
Familial hypercholesterolemia is a genetic autosomal dominant disorder that is caused by several mutations in the LDL-receptor gene. The reduced number or absence of functional LDL receptors results in impaired hepatic clearance of circulating low-density lipoprotein cholesterol (LDL-C) particles, which results in extremely high levels of LDL-C in the bloodstream. Familial hypercholesterolemia is characterized by excess LDL-C deposits in tendons and arterial walls, early onset of atherosclerotic disease, and premature cardiac death.
Familial hypercholesterolemia occurs in both HTZ and HMZ forms.
Heterozygous FH is one of the most common monogenic metabolic disorders in the general population, occurring in approximately 1 in 500 individuals1. Nevertheless, HTZ FH is largely undiagnosed and an accurate diagnosis occurs in only about 15% of affected patients in Canada. Thus, it is estimated that there are approximately 3,800 diagnosed and 21,680 undiagnosed cases of HTZ FH in Ontario.
In HTZ FH patients, half of the LDL receptors do not work properly or are absent, resulting in plasma LDL-C levels 2- to 3-fold higher than normal (range 7-15mmol/L or 300-500mg/dL). Most HTZ FH patients are not diagnosed until middle age when either they or one of their siblings present with symptomatic coronary artery disease (CAD). Without lipid-lowering treatment, 50% of males die before the age of 50 and 25% of females die before the age of 60, from myocardial infarction or sudden death.
In contrast to the HTZ form, HMZ FH is rare (occurring in 1 case per million persons) and more severe, with a 6- to 8-fold elevation in plasma LDL-C levels (range 15-25mmol/L or 500-1000mg/dL). Homozygous FH patients are typically diagnosed in infancy, usually due to the presence of cholesterol deposits in the skin and tendons. The main complication of HMZ FH is supravalvular aortic stenosis, which is caused by cholesterol deposits on the aortic valve and in the ascending aorta. The average life expectancy of affected individuals is 23 to 25 years. In Ontario, it is estimated that there are 13 to 15 cases of HMZ FH. An Ontario clinical expert confirmed that 9 HMZ FH patients have been identified to date.
There are 2 accepted clinical diagnostic criterion for the diagnosis of FH: the Simon Broome FH Register criteria from the United Kingdom and the Dutch Lipid Network criteria from the Netherlands. The criterion supplement cholesterol levels with clinical history, physical signs and family history. DNA-based-mutation-screening methods permit a definitive diagnosis of HTZ FH to be made. However, given that there are over 1000 identified mutations in the LDL receptor gene and that the detection rates of current techniques are low, genetic testing becomes problematic in countries with high genetic heterogeneity, such as Canada.
The primary aim of treatment in both HTZ and HMZ FH is to reduce plasma LDL-C levels in order to reduce the risk of developing atherosclerosis and CAD.
The first line of treatment is dietary intervention, however it alone is rarely sufficient for the treatment of FH patients. Patients are frequently treated with lipid-lowering drugs such as resins, fibrates, niacin, statins and cholesterol absorption-inhibiting drugs (ezetimibe). Most HTZ FH patients require a combination of drugs to achieve or approach target cholesterol levels.
A small number of HTZ FH patients are refractory to treatment or intolerant to lipid-lowering medication. According to clinical experts, the prevalence of refractory HTZ FH in Ontario is between 1 to 5%. Using the mean of 3%, it is estimated that there are approximately 765 refractory HTZ FH patients in Ontario, of which 115 are diagnosed and 650 are undiagnosed.
Drug therapy is less effective in HMZ FH patients since the effects of the majority of cholesterol-lowering drugs are mediated by the upregulation of LDL receptors, which are often absent or function poorly in HMZ FH patients. Some HMZ FH patients may still benefit from drug therapy, however this rarely reduces LDL-C levels to targeted levels.
Existing Technology: Plasma Exchange
An option currently available in Ontario for FH patients who do not respond to standard diet and drug therapy is plasma exchange (PE). Patients are treated with this lifelong therapy on a weekly or biweekly basis with concomitant drug therapy.
Plasma exchange is nonspecific and eliminates virtually all plasma proteins such as albumin, immunoglobulins, coagulation factors, fibrinolytic factors and HDL-C, in addition to acutely lowering LDL-C by about 50%. Blood is removed from the patient, plasma is isolated, discarded and replaced with a substitution fluid. The substitution fluid and the remaining cellular components of the blood are then returned to the patient.
The major limitation of PE is its nonspecificity. The removal of HDL-C prevents successful vascular remodeling of the areas stenosed by atherosclerosis. In addition, there is an increased susceptibility to infections, and costs are incurred by the need for replacement fluid. Adverse events can be expected to occur in 12% of procedures.
Other Alternatives
Surgical alternatives for FH patients include portocaval shunt, ileal bypass and liver transplantation. However, these are risky procedures and are associated with a high morbidity rate. Results with gene therapy are not convincing to date.
The Technology Being Reviewed: LDL Apheresis
An alternative to PE is LDL apheresis. Unlike PE, LDL apheresis is a selective treatment that removes LDL-C and other atherogenic lipoproteins from the blood while minimally impacting other plasma components such as HDL-C, total serum protein, albumin and immunoglobulins. As with PE, FH patients require lifelong therapy with LDL apheresis on a weekly/biweekly basis with concomitant drug therapy.
Heparin-Induced Extracorporeal LDL Precipitation
Heparin-induced extracorporeal LDL precipitation (HELP) is one of the most widely used methods of LDL apheresis. It is a continuous closed-loop system that processes blood extracorporeally. It operates on the principle that at a low pH, LDL and lipoprotein (a) [Lp(a)] bind to heparin and fibrinogen to form a precipitate which is then removed by filtration. In general, the total duration of treatment is approximately 2 to 3 hours.
Results from early trials indicate that LDL-C concentration is reduced by 65% to 70% immediately following treatment in both HMZ and HTZ FH and then rapidly begins to rise. Typically patients with HTZ FH are treated every 2 weeks while patients with HMZ FH require weekly therapy. Heparin-induced extracorporeal LDL precipitation also produces small transient decreases in HDL-C, however levels generally return to baseline within 2 days. After several months of therapy, long-term reductions in LDL-C and increases in HDL-C have been reported.
In addition to having an impact on plasma cholesterol concentrations, HELP lowers plasma fibrinogen, a risk factor for atherosclerosis, and reduces concentrations of cellular adhesion molecules, which play a role in early atherogenesis.
In comparison with PE, HELP LDL apheresis does not have major effects on essential plasma proteins and does not require replacement fluid, thus decreasing susceptibility to infections. One study noted that adverse events were documented in 2.9% of LDL apheresis treatments using the HELP system compared with 12% using PE. As per the manufacturer, patients must weigh at least 30kgs to be eligible for treatment with HELP.
Regulatory Status
The H.E.L.P.® System (B.Braun Medizintechnologie GmbH, Germany) has been licensed by Health Canada since December 2000 as a Class 3 medical device (Licence # 26023) for performing LDL apheresis to acutely remove LDL from the plasma of 3 high-risk patient populations for whom diet has been ineffective and maximum drug therapy has either been ineffective or not tolerated. The 3 patient groups are as follows:
Functional hypercholesterolemic homozygotes with LDL-C >500 mg/dL (>13mmol/L);
Functional hypercholesterolemic heterozygotes with LDL-C >300 mg/dL (>7.8mmol/L);
Functional hypercholesterolemic heterozygotes with LDL-C >200 mg/dL (>5.2mmol/L) and documented CAD
No other LDL apheresis system is currently licensed in Canada.
Review Strategy
The Medical Advisory Secretariat systematically reviewed the literature to assess the effectiveness and safety of LDL apheresis performed with the HELP system for the treatment of patients with refractory HMZ and HTZ FH. A standard search methodology was used to retrieve international health technology assessments and English-language journal articles from selected databases.
The GRADE approach was used to systematically and explicitly make judgments about the quality of evidence and strength of recommendations.
Summary of Findings
The search identified 398 articles published from January 1, 1998 to May 30, 2007. Eight studies met the inclusion criteria. Five case series, 2 case series nested within comparative studies, and one retrospective review, were included in the analysis. A health technology assessment conducted by the Alberta Heritage Foundation for Medical Research, and a review by the United States Food and Drug Administration were also included.
Large heterogeneity among the studies was observed. Studies varied in inclusion criteria, baseline patient characteristics and methodology.
Overall, the mean acute1 relative decrease in LDL-C with HELP LDL apheresis ranged from 53 to 77%. The mean acute relative reductions ranged as follows: total cholesterol (TC) 47 to 64%, HDL-C +0.4 to -29%, triglycerides (TG) 33 to 62%, Lp(a) 55 to 68% and fibrinogen 56 to 65%.
The mean chronic2 relative decreases in LDL-C and TC with HELP LDL apheresis ranged from 9 to 46% and 5 to 34%, respectively. Familial hypercholesterolemia patients treated with HELP did not achieve the target LDL-C value set by international guidelines (LDL-C < 2.5mmol/L, 100mg/dL). The chronic mean relative increase in HDL-C ranged from 12 to 27%. The ratio of LDL:HDL and the ratio of TC:HDL are 2 measures that have been shown to be important risk factors for cardiac events. In high-risk patients, the recommended target LDL:HDL ratio is less than or equal to 2, and the target TC:HDL ratio is less than 4. In the studies that reported chronic lipid changes, the LDL:HDL and TC:HDL ratios exceeded targeted values.
Three studies investigated the effects of HELP on coronary outcomes and atherosclerotic changes. One noted that twice as many lesions displayed regression in comparison to those displaying progression. The second study found that there was a decrease in Agatston scores3 and in the volume of coronary calcium. The last study noted that 2 of 5 patients showed regression of coronary atherosclerosis, and 3 of the 5 patients showed no change as assessed by a global change score.
Adverse effects were typically mild and transient, and the majority of events were related to problems with vascular access. Of the 3 studies that provided quantitative information, the proportion of adverse events ranged from 2.9 to 5.1%.
GRADE Quality of Evidence
In general, studies were of low quality, i.e., case series studies (Tables 1-3). No controlled studies were identified and no studies directly compared the effectiveness of the HELP system with PE or with diet and drug therapy. Conducting trials with a sufficiently large control group would not have been feasible or acceptable given that HELP represents a last alternative in these patients who are resistant to conventional therapeutic strategies.
A major limitation is that there is limited evidence on the effectiveness and safety of HELP apheresis in HMZ FH patients. However, it is unlikely that better-quality evidence will become available, given that HMZ FH is rare and LDL apheresis is a last therapeutic option for these patients.
Lastly, there is limited data on the long-term effects of LDL apheresis in FH patients. No studies with HELP were identified that examined long-term outcomes such as survival and cardiovascular events. The absence of this data may be attributed to the rarity of the condition, and the large number of subjects and long duration of follow-up that would be needed to conduct such trials.
Homozygous Familial Hypercholesterolemia - Lipid Outcomes
Heterozygous Familial Hypercholesterolemia - Lipid Outcomes
Heterozygous Familial Hypercholesterolemia - Coronary Artery Disease Outcomes
Economic Analysis
A budget-impact analysis was conducted to forecast future costs for PE and HELP apheresis in FH patients. All costs are reported in Canadian dollars. Based on epidemiological data of 13 HMZ, 115 diagnosed HTZ and 765 cases of all HTZ patients (diagnosed + undiagnosed), the annual cost of weekly treatment was estimated to be $488,025, $4,332,227 and $24,758,556 respectively for PE. For HELP apheresis, the annual cost of weekly treatment was estimated to be $1,025,338, $9,156,209 and $60,982,579 respectively. Costs for PE and HELP apheresis were halved with a biweekly treatment schedule.
The cost per coronary artery disease death avoided over a 10-year period in HTZ FH-diagnosed patients was also calculated and estimated to be $37.5 million and $18.7 million for weekly and biweekly treatment respectively, when comparing HELP apheresis with PE and with no intervention. Although HELP apheresis costs twice as much as PE, it helped to avoid 12 deaths compared with PE and 22 deaths compared with no intervention, over a period of 10 years.
Ontario Health System Impact Analysis
Low-density lipoprotein apheresis using the HELP system is currently being funded by the provinces of Quebec and Alberta. The program in Quebec has been in operation since 2001 and is limited to the treatment of HMZ FH patients. The Alberta program is relatively new and is currently treating HMZ FH patients, but it is expanding to include refractory HTZ FH patients.
Low-density lipoprotein apheresis is a lifelong treatment and requires considerable commitment on the part of the patient, and the patient’s family and physician. In addition, the management of FH continues to evolve. With the advent of new more powerful cholesterol-lowering drugs, some HTZ patients may be able to sufficiently control their hypercholesterolemia. Nevertheless, according to clinical experts, HMZ patients will likely always require LDL apheresis.
Given the substantial costs associated with LDL apheresis, treatment has been limited to HMZ FH patients. However, LDL apheresis could be applied to a much larger population, which would include HTZ FH patients who are refractory to diet and drug therapy. HTZ FH patients are generally recruited in a more advanced state, demonstrate a longer natural survival than HMZ FH patients and are older.
For HMZ FH patients, the benefits of LDL apheresis clearly outweigh the risks and burdens. According to GRADE, the recommendation would be graded as strong, with low- to very low-quality evidence (Table 4).
In both HMZ and HTZ FH patients, there is evidence of overall clinical benefit of LDL apheresis from case series studies. Low-density lipoprotein apheresis has several advantages over the current treatment of PE, including decreased exposure to blood products, decreased risk of adverse events, conservation of nonatherogenic and athero-protective components, such as HDL-C and lowering of other atherogenic components, such as fibrinogen.
In contrast to HMZ FH patients, there remains a lot of uncertainty in the social/ethical acceptance of this technology for the treatment of refractory HTZ FH patients. In addition to the substantial costs, it is unknown whether the current health care system could cope with the additional demand. There is uncertainty in the estimates of benefits, risks and burdens. According to GRADE, the recommendation would be graded as weak with low- to very-low-quality evidence (Table 5).
GRADE Recommendation - Homozygous Patients
GRADE of recommendation: Strong recommendation, low-quality or very-low-quality evidence
Benefits clearly outweigh risk and burdens
Case series study designs
Strong, but may change when higher-quality evidence becomes available
GRADE Recommendation - Heterozygous Patients
GRADE of recommendation: Weak recommendation, low-quality or very-low-quality evidence
Uncertainty in the estimates of benefits, risks and burden, which these may be closely balanced
Case series study designs
Very weak; other alternatives may be equally reasonable
PMCID: PMC3377562  PMID: 23074505
4.  Relationship of High Sensitivity C-Reactive Protein Levels to Anthropometric and other Metabolic Parameters in Indian Children with Simple Overweight and Obesity 
Context: High senstivity C-reactive protein (hsCRP) levels correlate well other parameters of obesity related metabolic syndrome (MS) and can be used as predictors of future cardiovascular disease risk. There is limited data on hsCRP levels in Indian children with simple obesity.
Aim: To study the relationship of hsCRP levels with various anthropometric as well as metabolic parameters in children with simple overweight and obesity.
Materials and Methods: This case control study was conducted in Paediatric Endocrinology clinic of a tertiary care hospital in Northern India. Levels of hsCRP were estimated in 100 overweight and obese children (BMI between 85th and 95th percentiles according to age & gender specific CDC 2000 growth charts) aged between 6 and 16 years and in 100 nearly age and sex matched healthy controls. These levels were then correlated to various anthropometric (body mass index, BMI; waist circumference, WC; hip circumference, HC; waist hip ratio, WHR; blood pressure) and biochemical (fasting blood glucose, FBG; total cholesterol, TC; high-density lipoprotein-cholesterol, HDL-C; low-density lipoprotein cholesterol, LDL-C; very low-density lipoprotein-cholesterol, VLDL-C; triglycerides, TG) parameters.
Results: Mean levels of hsCRP were significantly higher in the study group (3.92±2.20 versus 2.15±1.05 mg/L) as compared to controls. Significantly more (58% versus 10%) subjects in the study group had hsCRP (>3 mg/L). Of all the parameters studied, only BMI showed a positive correlation with hsCRP levels in the study group. Multiple logistic regression analysis for predicting outcome of high hsCRP showed positive correlation with BMI; with every 1 kg/m2 increase in BMI, odds of high hsCRP level were increased by 37% (OR=1.37; 95% CI 1.23-1.53, p-value <0.0001). Mean values of all the biochemical parameters except HDL-C were significantly higher in the study group.
Conclusion: Levels of hsCRP were significantly elevated in overweight and obese children as compared to non-obese children. In addition, these patients also showed abnormalities of lipid and glucose metabolism.
PMCID: PMC4190765  PMID: 25300641
Childhood obesity; Subclinical inflammation; Hscrp levels
5.  C-reactive protein is associated with low-density lipoprotein cholesterol and obesity in type 2 diabetic Sudanese 
Type 2 diabetes is emerging in Sudan and is associated with obesity. Deregulated lipid metabolism and inflammatory states are suggested risk factors for cardiovascular disease, which is a leading cause of diabetic death. This study aimed to investigate C-reactive protein (CRP) levels and the lipid profile in type 2 diabetic adult Sudanese compared with nondiabetics, and to test their associations with other characteristics.
A cross-sectional study including 70 diabetics and 40 nondiabetics was conducted. Anthropometric measurements were assessed, and demographic and medical data were obtained using a structured questionnaire. Blood specimens were collected and biochemical parameters were analyzed applying standard methods.
CRP and triglycerides were significantly higher in the diabetic group (P<0.001 and P=0.01, respectively). Differences in total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were not statistically significant between the diabetic and nondiabetic groups. In the diabetic group, correlation analysis revealed that the CRP level had a significant positive correlation with LDL-C (r=0.255, P=0.034) and body mass index (r=0.29, P=0.016). Body mass index showed a significant positive correlation with triglycerides (r=0.386, P=0.001). Within the lipid parameters, a number of significant correlations were observed. Elevated levels of CRP, LDL-C, and triglycerides were markedly more prevalent in the diabetic group of patients. Diabetics showed significantly higher CRP levels compared with nondiabetics (odds ratio 5.56, P=0.001).
The high prevalence of obesity among diabetics, together with elevated levels of triglycerides and CRP, suggest coexistence of dyslipidemia and inflammation in diabetes. Our findings emphasize that diabetics were 5.6 times more likely to have high CRP levels than nondiabetics; as CRP is a predictor of cardiovascular disease risk, it can be recognized that diabetics are at more risk of cardiovascular disease than nondiabetics. Considering evaluation of CRP together with the lipid profile in prediction of cardiovascular disease risk in Sudanese diabetics should be further tested in large-scale studies.
PMCID: PMC4567170  PMID: 26379442
C-reactive protein; type 2 diabetes; lipid profile; obesity; cardiovascular disease; Sudanese
6.  Metabolic effects of fluvastatin extended release 80 mg and atorvastatin 20 mg in patients with type 2 diabetes mellitus and low serum high-density lipoprotein cholesterol levels: a 4-month, prospective, open-label, randomized, blinded—end point (probe) trial 
Diabetic dyslipidemia is characterized by greater triglyceridation of all lipoproteins and low levels of plasma high-density lipoprotein cholesterol (HDL-C). In this condition, the serum level of low-density lipoprotein cholesterol (LDL-C) is only slightly elevated. The central role of decreased serum HDL-C level in diabetic cardiovascular disease has prompted the establishment of a target of ≥50 mg/dL in patients with diabetes mellitus (DM).
The aim of the study was to assess the effects of once-daily administration of fluvastatin extended release (XL) 80 mg or atorvastatin 20 mg on serum HDL-C levels in patients with type 2 DM and low levels of serum HDL-C.
This 4-month, prospective, open-label, randomized, blinded—end point (PROBE) trial was conducted at Endocrinology and Diabetology Service, L. Sacco-Polo University Hospital (Milan, Italy). Patients aged 45 to 71 years with type 2 DM receiving standard oral antidiabetic therapy, with serum HDL-C levels <50 mg/dL, and with moderately high serum levels of LDL-C and triglycerides (TG) were enrolled. After 1 month of lifestyle modification and dietary intervention, patients who were still showing a decreased HDL-C level were randomized, using a 1:1 ratio, to receive fluvastatin XL 80-mg tablets or atorvastatin 20-mg tablets, for 3 months. Lipoprotein metabolism was assessed by measuring serum levels of LDL-C, HDL-C, TG, apolipoprotein (apo) A-I (the lipoprotein that carries HDL), and apo B (the lipoprotein that binds very low-density lipoprotein cholesterol, intermediate-density lipoprotein, and LDL on a molar basis). Patients were assessed every 2 weeks for treatment compliance and subjective adverse events. Serum creatine phosphokinase and liver enzymes were assessed before the run-in period, at the start of the trial, and at 1 and 3 months during the study.
One hundred patients were enrolled (50 patients per treatment group; fluvastatin XL group: 33 men, 17 women; mean [SD] age, 58 [12] years; atorvastatin group: 39 men, 11 women; mean [SD] age, 59 [11] years). In the fluvastatin group after 3 months of treatment, mean (SD) LDL-C decreased from 149 (33) to 95 (25) mg/dL (36%; P < 0.01), TG decreased from 437 (287) to 261 (164) mg/dL (40%; P < 0.01), and HDL-C increased from 41 (7) to 46 (10) mg/dL (12%; P < 0.05). In addition, apo A-I increased from 118 (18) to 124 (15) mg/dL (5%; P < 0.05) and apo B decreased from 139 (27) to 97 (19) mg/dL (30%; P < 0.05). In the atorvastatin group, LDL-C decreased from 141 (25) to 84 (23) mg/dL (40%; P < 0.01) and TG decreased from 411 (271) to 221 (87) mg/dL (46%; P < 0.01). Neither HDL-C (41 [7] vs 40 [6] mg/dL; 2%) nor apo A-I (117 [19] vs 114 [19] mg/dL; 3%) changed significantly. However, apo B decreased significantly, from 131 (20) to 92 (17) mg/dL (30%; P < 0.05). Mean changes in HDL-C (+5 [8] vs −1 [2] mg/dL; P < 0.01) and apo A-I (+6 [18] mg/dL vs −3 [21] mg/dL; P < 0.01) were significantly greater in the fluvastatin group than in the atorvastatin group, respectively. However, the decreases in LDL-C (54 [31] vs 57 [32] mg/ dL), TG (177 [219] vs 190 [65] mg/dL), and apo B (42 [26] vs 39 [14] mg/dL) were not significantly different between the fluvastatin and atorvastatin groups, respectively. No severe adverse events were reported.
Fluvastatin XL 80 mg and atorvastatin 20 mg achieved mean serum LDL-C (≤ 100 mg/dL) and apo B target levels (≤ 100 mg/dL) in the majority of this population of patients with type 2 DM, but mean serum HDL-C level was increased significantly only with fluvastatin—16 patients (32%) in the fluvastatin group compared with none in the atorvastatin group achieved HDL-C levels ≥50 mg/dL. The increase in HDL-C in the fluvastatin-treated patients was associated with an increase in apo A-I, suggesting a potential pleiotropic and selective effect in patients with low HDL-C levels.
PMCID: PMC3964538  PMID: 24672088
fluvastatin XL; atorvastatin; type 2 DM; HDL; LDL; triglycerides; apo A-I; apo B
7.  Genotype specific peripheral lipid profile changes with hepatitis C therapy 
World Journal of Gastroenterology  2016;22(46):10226-10231.
To evaluate magnitude/direction of changes in peripheral lipid profiles in patients undergoing direct acting therapy for hepatitis C by genotype.
Mono-infected patients with hepatitis C were treated with guideline-based DAAs at a university-based liver clinic. Patient characteristics and laboratory values were collected before and after the treatment period. Baseline demographics included age, ethnicity, hypertension, diabetes, hyperlipidemia, treatment regimen, and fibrosis stage. Total cholesterol (TCHOL), high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (TG), and liver function tests were measured prior to treatment and ETR. Changes in lipid and liver function were evaluated by subgroups with respect to genotype. Mean differences were calculated for each lipid profile and liver function component (direction/magnitude). The mean differences in lipid profiles were then compared between genotypes for differences in direction/magnitude. Lipid profile and liver function changes were evaluated with Levene’s test and student’s t test. Mean differences in lipid profiles were compared between genotypes using ANOVA, post hoc analysis via the Bonferroni correction or Dunnett T3.
Three hundred and seventy five patients enrolled with 321 (85.6%) achieving sustained-viral response at 12 wk. 72.3% were genotype 1 (GT1), 18.1% genotype 2 (GT2), 9.7% genotype 3 (GT3). Baseline demographics were similar. Significant change in lipid profiles were seen with GT1 and GT3 (ΔGT1, p and ΔGT3, p), with TCHOL increasing (+5.3, P = 0.005 and +16.1, P < 0.001), HDL increasing (+12.5, P < 0.001 and +7.9, P = 0.038), LDL increasing (+7.4, P = 0.058 and +12.5, P < 0.001), and TG decreasing (-5.9, P = 0.044 and -9.80 P = 0.067). Among genotypes (ΔGT1 v. ΔGT2 v. ΔGT3, ANOVA), significant mean differences were seen with TCHOL (+5.3 v. +0.1 v. +16.1, P = 0.017) and HDL (+12.3 v. +2 v. +7.9, P = 0.040). Post-hoc, GT3 was associated with a greater increase in TCHOL than GT1 and GT2 (P = 0.028 and P = 0.019).
Successful DAA therapy results in increases in TCHOL, LDL, and HDL and decrease in TG, particularly in GT1/GT3. Changes are most pronounced in GT3.
PMCID: PMC5155182  PMID: 28028371
Hepatitis C genotypes; Lipids; Metabolic syndrome
8.  Comparison of lipid profile parameters and oxidized low-density lipoprotein between normal and preeclamptic pregnancies in a tertiary care hospital in Nepal 
Preeclampsia is a pregnancy-specific complication that significantly contributes to maternal and perinatal morbidity and mortality worldwide, even more so in developing countries such as Nepal. The potential contribution of dyslipidemia and elevated levels of oxidized low-density lipoprotein (oxLDL) in the pathogenesis of preeclamptic pregnancies has been observed in several studies. The aim of this study was to compare the maternal lipid profile parameters and particularly oxLDL between preeclamptic and healthy pregnancies and also correlate oxLDL with other lipid profile parameters.
Patients and methods
A total of 54 preeclamptic women were selected as cases for this cross-sectional study. Age and gestational week-matched 60 pregnant women were enrolled as controls. Preeclampsia was defined as per Australasian Society Consensus Statement research definition. The serum lipid parameters were measured using automated enzymatic systems and a competitive enzyme-linked immunosorbent assay was used to determine oxLDL concentrations in the serum. Student’s t-test was used to compare oxLDL levels between preeclamptic and healthy pregnancies, and Pearson’s correlation analysis was carried out to assess the relation between oxLDL and other variables.
The mean values of serum total cholesterol, triglyceride, non-high-density lipoprotein-cholesterol (non-HDL-c) and oxLDL were significantly higher in the preeclamptic cases (P<0.01). However, the levels of low-density lipoprotein cholesterol (LDL-c and HDL-c) did not significantly differ between the two groups. oxLDL had a significant positive correlation (P<0.01) with total cholesterol, triglyceride, LDL-c and non-HDL-c, and a negative correlation with HDL-c.
The atherogenic type of dyslipidemia and high oxLDL levels are associated with preeclamptic pregnancies. The lipid parameters, however, seem to be poor markers of the severity of preeclampsia. Further prospective studies are needed to see if the observed dyslipidemia has a causal role in preeclampsia and imparts a long-term cardiovascular risk.
PMCID: PMC5089828  PMID: 27822126
preeclampsia; oxLDL; dyslipidemia; Nepal
9.  Impact of dyslipidemic components of metabolic syndrome, adiponectin levels, and anti-diabetes medications on malondialdehyde-modified low-density lipoprotein levels in statin-treated diabetes patients with coronary artery disease 
A residual risk of cardiovascular disease tends to persist despite standard prevention therapy with statins. This may stem partly from increased oxidized low-density lipoprotein (LDL) levels. However, how oxidized LDL can be further reduced beyond statin therapy in high-risk diabetes patients remains unclear. We aimed to clarify the clinical factors associated with oxidized LDL levels in statin-treated high-risk diabetes patients.
This cross-sectional observational study included 210 diabetes patients with coronary artery diseases (CAD) who were treated with statins. We determined serum malondialdehyde-modified LDL (MDA-LDL), LDL cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride (TG), remnant lipoprotein cholesterol, hemoglobin (Hb) A1c, adiponectin, and C-reactive protein (CRP) levels and investigated the factors influencing the MDA-LDL level.
In univariate analysis, the MDA-LDL level was significantly correlated with LDL cholesterol (p < 0.0001), TG (p < 0.0001), HDL cholesterol (p = 0.017), and adiponectin (p = 0.001) levels but not with age, body mass index, waist circumference, blood pressure, or HbA1c levels. Even after adjusting for the LDL cholesterol level, the correlations between the MDA-LDL level and the TG, HDL cholesterol, and adiponectin levels were still significant. Among these significant factors, multivariate analysis revealed that the MDA-LDL level was independently associated with the LDL cholesterol, TG, and HDL cholesterol but not with adiponectin levels. The MDA-LDL level was also significantly associated with the CRP level (p = 0.014) and the remnant lipoprotein cholesterol level (p < 0.0001) independently of the LDL cholesterol level. The number of metabolic syndrome (MS) components was significantly associated with the MDA-LDL/LDL cholesterol ratio (p < 0.0001). Furthermore, the use of metformin and α-glucosidase inhibitors was inversely associated with high MDA-LDL levels (p = 0.033 and 0.018, respectively).
In statin-treated diabetes patients with CAD, the MDA-LDL level was significantly correlated with TG and HDL cholesterol levels. Adiponectin level was also significantly associated with the MDA-LDL level, but not independent of the above-mentioned factors. The management of dyslipidemic MS components, including the use of metformin or α-glucosidase inhibitors, may be important for reducing the oxidized LDL levels beyond statin therapy in high-risk diabetes patients.
PMCID: PMC4029151  PMID: 24314067
MDA-LDL; Metabolic syndrome; Triglycerides; HDL cholesterol; Adiponectin; Diabetes mellitus; Coronary artery disease; Statins
10.  Serum uric acid and low-density lipoprotein cholesterol levels are independent predictors of coronary artery disease in Asian Indian patients with type 2 diabetes mellitus 
We aimed to identify the predictors of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (type 2 DM).
About fifty Asian Indian patients with type 2 DM patients aged >40 years and fifty sex- and age-matched nondiabetic controls were enrolled for this study. Following complete medical history and baseline clinical data, laboratory investigations were performed to assess fasting and postprandial plasma glucose levels, lipid profile, blood urea, serum creatinine, and serum uric acid levels.
Body mass index (BMI), waist-to-hip ratio, serum uric acid, serum total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, very LDL cholesterol were significantly higher among diabetic patients compared to controls. On univariate analysis, serum LDL cholesterol (odds ratio [OR]: 29.67, P < 0.001), serum uric acid (OR: 25.65, P < 0.001), low high-density lipoprotein (HDL) cholesterol (OR: 21.12, P < 0.001), hypertension (OR: 17.06, P < 0.001), family history of cardiovascular disease (CVD) (OR: 9.43, P = 0.002), and duration of diabetes (OR: 4.65, P = 0.03) were identified as predictors of CVD among diabetic patients. On multivariate regression, only LDL cholesterol (OR: 1.51, P = 0.002) and serum uric acid (OR: 1.21, P = 0.01) were the independent predictors of CAD among diabetic patients. Significant positive correlation of serum uric acid with duration of diabetes (r = 0.38, P = 0.006), BMI (r = 0.35, P = 0.01), triglycerides (r = 0.356, P = 0.01), LDL cholesterol (r = 0.38, P = 0.007), HDL cholesterol (r = −0.514, P < 0.001), and hypertension (r = 0.524, P < 0.001) was observed.
Serum LDL cholesterol and hyperuricemia may serve as independent predictors of CAD among Asian Indian subjects with type 2 DM.
PMCID: PMC4934106  PMID: 27433067
Coronary artery disease; cardiovascular disease; hyperuricemia; low-density lipoprotein cholesterol; type 2 diabetes mellitus
11.  Lipoprotein Particle Profiles Mark Familial and Sporadic Human Longevity 
PLoS Medicine  2006;3(12):e495.
Genetic and biochemical studies have indicated an important role for lipid metabolism in human longevity. Ashkenazi Jewish centenarians and their offspring have large low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles as compared with control individuals. This profile also coincided with a lower prevalence of disease. Here, we investigate whether this observation can be confirmed for familial longevity in an outbred European population and whether it can be extended to sporadic longevity in the general population.
Methods and Findings
NMR-measured lipoprotein profiles were analyzed in 165 families from the Leiden Longevity Study, consisting of 340 long-lived siblings (females >91 y, males >89 y), 511 of their offspring, and 243 partners of the offspring. Offspring had larger (21.3 versus 21.1 nm; p = 0.020) and fewer (1,470 versus 1,561 nmol/l; p = 0.011) LDL particles than their same-aged partners. This effect was even more prominent in the long-lived siblings (p < 10−3) and could be pinpointed to a reduction specifically in the concentration of small LDL particles. No differences were observed for HDL particle phenotypes. The mean LDL particle sizes in 259 90-y-old singletons from a population-based study were similar to those in the long-lived siblings and thus significantly larger than in partners of the offspring, suggesting that the relevance of this phenotype extends beyond familial longevity. A low concentration of small LDL particles was associated with better overall health among both long-lived siblings (p = 0.003) and 90-y-old singletons (p = 0.007).
Our study indicates that LDL particle profiles mark both familial and sporadic human longevity already in middle age.
Offspring of families from the Leiden Longevity Study had larger and fewer LDL particles than same-aged partners, suggesting that even in middle age LDL particle profiles are associated with longevity.
Editors' Summary
It is not clear why some people go on to live longer than others do. Some studies have shown that close relatives of long-lived people are themselves more likely to live for a long time; these findings suggest that there is probably a genetic basis for long life. However, the actual mechanisms involved have not yet been worked out. Some genes coding for proteins involved in fat metabolism, such as APOE, APOB, and CETP, have been associated with long life, suggesting a link between the way fat gets metabolized and the aging process. One study that supports this idea found that the children of 100-year-old people had larger lipoprotein particles (assemblies of proteins and fats that carry cholesterol and triglycerides in the blood) than similarly aged control individuals. However, studies such as this are very prone to “false positive” findings and therefore need to be backed up by confirmatory evidence. In addition, the previous study was performed in a very specific population (Ashkenazi Jewish people), and it is important to find out whether the findings are also true in other populations.
Why Was This Study Done?
The research group carrying out this study wanted to address several distinct questions to do with the genetics of aging. Firstly, they wanted to see if they could confirm previous findings associating large lipoprotein particles with longer life, but looking at people who were more representative of the general European population and not from a genetically isolated population. Secondly, they wanted to see whether this association applied to only long-lived people whose family members were also long-lived, or to long-lived people in general. Finally, they wanted to find out if the large lipoprotein particles were associated with better health.
What Did the Researchers Do and Find?
In the study, the researchers looked at long-lived people from across The Netherlands whose relatives were also long-lived. For this, they recruited 340 men aged over 89 and women aged over 91 into the study, all of whom had at least one similarly long-lived sister or brother. Their children (511 individuals), and the partners of their children (243 people), were also recruited into the study, with the partners acting as “controls.” The researchers also studied 259 people who had just turned 90 years old; these people were included to see whether particular characteristics of lipoproteins existed in long-lived people whose longevity did not run in families. All the participants gave blood samples, and the researchers then measured the size and amount of different lipoprotein particles in these samples. Two types of lipoprotein particles were looked at: low-density lipoprotein (LDL, often termed “bad cholesterol”) and high-density lipoprotein (HDL, sometimes called “good cholesterol”). The researchers found that the children from the long-lived people had larger and fewer LDL particles than their partners (the “control” individuals) just like their long-lived parents. Thus even though the children were not long-lived themselves, LDL particles marked the fact that they have a higher chance of becoming long-lived in the future. Similar changes in LDL particles were found for long-lived people whose relatives were not also long-lived. Interestingly, simply the level of cholesterol—the classical risk factor for cardiovascular disease—did not appear to play a role. Thus it seems that it is not the amount of cholesterol that is important in longevity but how it is packaged. Better health status was also associated with a lower proportion of small LDL particles in the blood, supporting these findings. No characteristics of the HDL particles seemed to be associated with longevity.
What Do These Findings Mean?
These findings confirm those from a previous study in Ashkenazi Jewish people that suggested that the size of LDL particles in the blood was associated with long life. The nature of this association is not clear; some studies indicated that small LDL particles increase the risk of cardiovascular disease but small LDL particles may also be harmless themselves and reflect the efficiency of other processes causally related to aging.
Additional Information.
Please access these Web sites via the online version of this summary at
Wikipedia chapter on senescence (biology of aging) (note that Wikipedia is a free Internet encyclopedia that anyone can edit)
US National Institute on Aging provides information on healthy aging, details of publicly funded research into aging, and other resources for the public
Help the Aged information on research into aging
PMCID: PMC1716190  PMID: 17194192
12.  Cardiovascular disease risk factors in homeless people 
Upsala Journal of Medical Sciences  2011;116(3):200-207.
Cardiovascular diseases (CVD) are associated with significant morbidity and mortality, which is highest in Eastern Europe including Estonia. Accumulating evidence suggests that life-style is associated with the development of CVD. The aim of this study was to evaluate the informative power of common CVD-related markers under unhealthy conditions.
Subjects (n = 51; mean age 45 years; 90% men) were recruited from a shelter for homeless people in Tallinn, Estonia, and consisted of persons who constantly used alcohol or surrogates, smoked, and were in a bad physical condition (amputated toes, necrotic ulcers, etc.).
Blood pressure, pulse rate, and waist circumference were measured, and body mass index (BMI) was calculated. The following markers were measured in blood serum: total cholesterol (TChol), high-density lipoprotein cholesterol (HDL-Chol), low-density lipoprotein cholesterol (LDL-Chol), plasma triglycerides (TG), apolipoproteins A-l (ApoA1) and B (ApoB), lipoprotein(a) (Lp(a)), glycated hemoglobin (HbA1c), glucose (Gluc), high-sensitivity C-reactive protein (hsCRP), serum carbohydrate-deficient transferrin (CDT), gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Except smoking, the anamnestic information considering eating habits, declared alcohol consumption and medication intake were not included in the analysis due to the low credibility of self-reported data.
More than half of the investigated patients had values of measured markers (hsCRP, TChol, LDL-Chol, TG, HbA1c, ApoA1, ApoB, Lp(a), Gluc) within normal range. Surprisingly, 100% of subjects had HDL-Chol within endemic norm.
This study demonstrates that traditional markers, commonly used for prediction and diagnosis and treatment of CVD, are not always applicable to homeless people, apparently due to their aberrant life-style.
PMCID: PMC3128724  PMID: 21692678
Atherosclerosis; cardiac diseases; inflammation; pathology
13.  Increased Production Rates of LDL Are Common in Individuals With Low Plasma Levels of HDL Cholesterol, Independent of Plasma Triglyceride Concentrations 
Arteriosclerosis and Thrombosis  1993;13(6):842-851.
Reduced plasma levels of high density lipoprotein (HDL) cholesterol are associated with increased risk for coronary heart disease. Although plasma HDL levels are, in general, inversely related to plasma triglyceride (TG) concentrations, a small proportion of individuals with low HDL cholesterol concentrations have normal plasma TG levels. We wished to determine whether subjects with low plasma levels of HDL cholesterol could be characterized by common abnormalities of lipoprotein metabolism independent of plasma TGs. Therefore, we studied the metabolism of low density lipoprotein (LDL) apolipoprotein B (apo B) and HDL apolipoprotein A-I (apo A-I) in subjects with low plasma HDL cholesterol concentrations with or without hypertriglyceridemia. Nine subjects with low plasma HDL cholesterol levels and normal levels of plasma TGs and LDL cholesterol were studied. Autologous 131I-LDL and 125I-HDL were injected intravenously, and blood samples were collected for 2 weeks. LDL apo B and HDL apo A-I levels were measured by specific radioimmunoassays. Fractional catabolic rates (FCRs, pools per day) and production rates (PRs, milligrams/kilogram · day) for each apolipoprotein were determined. The results were compared with those obtained previously in nine subjects with low plasma HDL cholesterol levels and hypertriglyceridemia and in seven normal subjects. The normal subjects had an HDL apo A-I FCR (mean±SD) of 0.21±0.04. Despite large differences in plasma TG levels, the HDL apo A-I FCRs were similar in the low-HDL, normal-TG group (0.30±0.09) and the low-HDL, high-TG group (0.033±0.10), although only the latter value was significantly increased versus control subjects (p<0.03). Increased apo A-I FCRs were associated with reduced HDL apo A-I levels in both groups of patients. Apo A-I PRs were similar in all groups. In contrast, LDL apo B PR was increased approximately 50% in the low-HDL, normal-TG group (19.3±6.6; p<0.01) compared with normal subjects (12.5±2.6). There was a strong trend toward a greater LDL apo B PR in the low-HDL, high-TG group (17.6±4.5;p=0.06 versus normal subjects) as well. LDL apo B FCRs were similar in all three groups. LDL apo B concentrations were also increased in the group with low HDL cholesterol and normal TG levels. Both groups with low HDL cholesterol levels had cholesterol-depleted LDL and HDL particles. In summary, reduced levels of plasma HDL cholesterol were generally associated with accelerated fractional removal of HDL apo A-I from plasma, increased production of plasma LDL apo B, and evidence of increased cholesteryl ester transfer out of LDL and HDL. The presence of these similar metabolic abnormalities whether or not plasma TG levels were increased suggests that increased apo B production may be a central defect in these patients and that low plasma HDL levels may be closely linked to increased plasma levels of apo B–containing lipoproteins independent of circulating levels of plasma TG.
PMCID: PMC3277740  PMID: 8499404
coronary heart disease; HDL; LDL; apolipoprotein B; apolipoprotein A-I; cholesteryl ester transfer protein; reverse cholesterol transport
14.  Lipid Profile of Type 2 Diabetic and Hypertensive Patients in the Jamaican Population 
Previous studies have shown that diabetes mellitus (DM) increases the risk of cardiovascular diseases in females to a greater extent than in males. In this cross-sectional study, we evaluated the lipid profiles of type 2 diabetic males and females.
Materials and Methods:
The study included 107 type 2 diabetic patients (41 males and 66 females), and 122 hypertensive type 2 diabetic patients (39 males and 83 females), aged 15 years and older. Total cholesterol (TC), triglycerides (TG), low density lipoprotein-cholesterol (LDL-C), very low density lipoprotein-cholesterol (VLDL-C) and high density lipoprotein-cholesterol (HDL-C) concentrations were assayed for each group using standard biochemical methods.
The mean TC, TG, VLDL-C, HDL-C and LDL-C concentrations, TG/HDL and LDL/HDL ratios were higher in type 2 diabetic and hypertensive type 2 diabetic patients compared with non-diabetic, and hypertensive non-diabetic control subjects, although these were not significant (P > 0.05). Hypertensive type 2 diabetic females had significantly higher serum TC (7.42 ± 1.63 mmol/L) than hypertensive non-diabetic males (5.76±1.57 mmol/L; P < 0.05). All the other lipid and lipoprotein parameters except HDL-C were non-significantly higher in females with type 2 DM and those with hypertension and type 2 DM, compared with type 2 diabetic and hypertensive type 2 diabetic males, respectively (P > 0.05).
This study demonstrated that dyslipidemia exists in our type 2 diabetic population with greater TC in hypertensive type 2 diabetic females compared with hypertensive type 2 diabetic males. This suggests that hypertensive type 2 diabetic females are exposed more profoundly to risk factors including atherogenic dyslipidemia compared with males.
PMCID: PMC3147082  PMID: 21814403
Females; hypertension; lipids; lipoprotein; males; type 2 diabetes mellitus
15.  Atorvastatin treatment modulates the interaction between leptin and adiponectin, and the clinical parameters in patients with type II diabetes 
The aim of this study was to examine the effect of atorvastatin treatment on levels of leptin, adiponectin and insulin resistance, and their correlation with clinical parameters, in patients with type II diabetes. Patients with diabetes (n=394) were divided into two groups, comprising 161 patients who received 20 mg/day atorvastatin (statin group), and 233 patients who did not receive statins (statin-free group). The results showed that atorvastatin treatment of patients with diabetes was not associated with changes in leptin, adiponectin, the leptin/adiponectin (L/A) ratio or homeostasis model assessment-insulin resistance (HOMA-IR). However, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and total cholesterol (Tchol) were positively correlated with leptin and L/A ratio in the statin group only (P<0.05). By contrast, high-density lipoprotein cholesterol (HDL-C) showed a significant positive correlation with adiponectin in the statin and statin-free groups (P<0.05). Additionally, a positive correlation was found between HOMA-IR and glycated hemoglobin (HbA1c), and TG, in both groups, whereas Tchol was positively correlated with HOMA-IR in the statin group only (P<0.05). When multivariate analysis was performed with HOMA-IR as the dependent variable, and with adjustment for age, body mass index (BMI) and waist circumference, HbA1c was found to be a significant predictor of HOMA-IR or insulin resistance. In conclusion, atorvastatin treatment may have several effects on the interaction between leptin and adiponectin, and on clinical parameters in patients with type II diabetes.
PMCID: PMC3829757  PMID: 24255692
adiponectin; leptin; statins; insulin resistance; lipid panel
16.  The efficacy and safety of Simvastatin in the treatment of lipid abnormalities in diabetes mellitus 
Notable lipid abnormalities in DM include elevated LDL-C which have been reported to be the prevalent lipid abnormality in DM and elevated total cholesterol levels. Although the Statins are widely used in the management of lipid abnormalities, their effects on the lipid abnormalities in Nigerians with DM has not been extensively evaluated.
This report sets out to determine the effect of Simvor, a brand of Simvastatin in Nigerians with DM and abnormal lipid profiles.
Materials and Methods:
A total of 300 diabetic patients with abnormal lipid profile who were treatment naοve for lipid disorders were longitudinally recruited for the study. They were managed with Simvastatin (Simvor) in doses ranging from 20-40 mg alongside dietary counseling and exercise recommendation.
The mean age (SD) of the study subjects was 58.4 (10 years). The male; female ratio was 99:211. The proportions of lipid abnormalities for LDL-C, TCHOL, HDL-C and TG were 87%, 45%, 53% and 7% respectively. Following Simvastatin (Simvor) treatment, the mean LDL-C value was reduced by 16%, TCHOL by 23%, TG by 6% and HDL-C increased by 10%. Simvastatin (Simvor) was generally well tolerated and no cardiovascular events were noted in the study subjects during the period of the study.
Simvastatin (Simvor) was effective and well tolerated in the management of lipid disorders in Nigerians with DM.
PMCID: PMC3659875  PMID: 23776861
Diabetes mellitus; lipid abnormalities; simvastatin
17.  Adverse anthropometric risk profile in biochemically controlled acromegalic patients: comparison with an age- and gender-matched primary care population 
Pituitary  2010;13(3):207-214.
GH and IGF-1 play an important role in the regulation of metabolism and body composition. In patients with uncontrolled acromegaly, cardiovascular morbidity and mortality are increased but are supposed to be normalised after biochemical control is achieved. We aimed at comparing body composition and the cardiovascular risk profile in patients with controlled acromegaly and controls. A cross-sectional study. We evaluated anthropometric parameters (height, weight, body mass index (BMI), waist and hip circumference, waist to height ratio) and, additionally, cardiovascular risk biomarkers (fasting plasma glucose, HbA1c, triglycerides, total cholesterol, HDL, LDL, and lipoprotein (a), in 81 acromegalic patients (58% cured) compared to 320 age- and gender-matched controls (ratio 1:4), sampled from the primary care patient cohort DETECT. The whole group of 81 acromegalic patients presented with significantly higher anthropometric parameters, such as weight, BMI, waist and hip circumference, but with more favourable cardiovascular risk biomarkers, such as fasting plasma glucose, total cholesterol, triglycerides and HDL levels, in comparison to their respective controls. Biochemically controlled acromegalic patients again showed significantly higher measurements of obesity, mainly visceral adiposity, than age- and gender-matched control patients (BMI 29.5 ± 5.9 vs. 27.3 ± 5.8 kg/m2; P = 0.020; waist circumference 100.9 ± 16.8 vs. 94.8 ± 15.5 cm; P = 0.031; hip circumference 110.7 ± 9.9 vs. 105.0 ± 11.7 cm; P = 0.001). No differences in the classical cardiovascular biomarkers were detected except for fasting plasma glucose and triglycerides. This effect could not be attributed to a higher prevalence of type 2 diabetes mellitus in the acromegalic patient group, since stratified analyses between the subgroup of patients with acromegaly and controls, both with type 2 diabetes mellitus, revealed that there were no significant differences in the anthropometric measurements. Biochemically cured acromegalic patients pertain an adverse anthropometric risk profile, mainly because of elevated adiposity measurements, such as BMI, waist and hip circumference, compared to an age- and gender-matched primary care population.
PMCID: PMC2913005  PMID: 20131100
Acromegaly; GH; IGF-1; Anthropometric parameters; Cardiovascular risk biomarkers
18.  The oxidation ratio of LDL: A Predictor for Coronary Artery Disease 
Disease markers  2008;24(6):341-349.
Objective: Oxidized LDL cholesterol (ox-LDL-C) is considered to be a key factor of initiating and accelerating atherosclerosis (AS). The purpose of this study is to elucidate the sensitivity and specificity of ox-LDL and oxidation ratio of LDL in the diagnosis of coronary artery disease (CAD). For the first time, we investigated the ratio of ox-LDL to ALB(ox-LDL/ALB).
Methods and results: Blood ox-LDL, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG) and albumin (ALB) were measured in patients with acute myocardial infarction (AMI, n = 80), unstable angina pectoris (UAP, n = 80), stable angina pectoris (SAP, n = 80), normal control (n = 60), and dyslipidemia control (n = 60). Ox-LDL was measured by competitive ELISA. The level of ox-LDL and oxidation ratio of LDL(ox-LDL/TC, ox-LDL/HDL-C, ox-LDL/ LDL-C and ox-LDL/ALB) were significantly higher in each diseased group than controls (P < 0.001). In CAD group, ox-LDL and oxidation ratio of LDL in subjects complicated with hypertension (HT) and/or diabetes mellitus (DM) increased further (P < 0.001). Ox-LDL/ALB in the AMI group was 7 times higher than normal control group (0.068 ± 0.017 vs 0.009 ± 0.007, P < 0.001). The area under the curve (AUC) of receiver operating characteristic curve (ROC curve) is a criterium to evaluate the accuracy of diagnosing a disease. The AUC of ROC curve of ox-LDL/TC, ox-LDL/HDL-C, ox-LDL, ox-LDL/ALB and ox-LDL/ LDL-C for diagnosing CAD were 0.975, 0.975, 0.966, 0.966, 0.957 respectively (P < 0.001). When ox-LDL/TC = 0.175, the sensitivity and specificity of diagnosing CAD were 0.917 and 0.925, which were almost equal to each other, indicating that the rates of missed diagnosis and misdiagnosis for CAD were the lowest.
Conclusions: The level of ox-LDL and the ratio of ox-LDL/TC, ox-LDL/LDL-C, ox-LDL/HDL-C and ox-LDL/ALB are better biomarkers than TC, TG, HDL-C and LDL-C for discriminating between patients with coronary artery disease and healthy subjects. And patients who have a high ratio of ox-LDL /TC may have a higher risk for CAD.
PMCID: PMC3850607  PMID: 18688083
Coronary artery disease; atherosclerosis; oxidized low density lipoprotein; cholesterol
19.  Thyroid Dysfunction and Their Relation to Cardiovascular Risk Factors such as Lipid Profile, hsCRP, and Waist Hip Ratio in Korea 
Thyroid abnormalities affect a considerable portion of the population, and overt hypothyroidism is associated with an elevated risk of cardiovascular disease and adverse changes in blood lipids. Subclinical hypothyroidism is also associated with an increase risk of cardiovascular disease. So, we undertook this study to investigate the prevalence of overt and subclinical thyroid disorders and their associations with cardiovascular risk factors.
This study involved 66260 subjects (43588 men, 22672 women; between 20–80 years of age, mean age 41.5±9.6). Serum free thyroxine (FT4), thyroid stimulating hormone (TSH), total cholesterol, low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C) were measured by RIA using commercial kits. High sensitivity C-reactive protein (hsCRP) levels were determined by nephelometry.
The prevalences of overt thyrotoxicosis, subclinical thyrotoxicosis, overt hypothyroidism and subclinical hypothyroidism were 5/1000 (334 subjects), 6.4/1000 (426 subjects), 1.6/1000 (108 subjects), and 6.4/1000 (375 subjects). Mean plasma total cholesterol and LDL-C were elevated in overt hypothyroidism than in normal controls (202.1 mg/dL and 121.8 mg/dL versus 197.1 mg/dL and 120.1 mg/dL, respectively) (p<0.05). In subclinical hypothyroidism, mean total cholesterol and LDL-C levels were also elevated (201.9 mg/dL and 123.7 mg/dL)(p=0.015, p=0.047). Waist-to-hip ratio (WHR) was lower in overt thyrotoxicosis and higher in hypothyroidism.
The prevalence of thyroid dysfunction in Korea is not significantly different from that reported by other countries. It was also age dependent and higher in women, but this elevation in women was lower than expected. Patients with hypothyroidism exhibited higher waist-to-hip ratios, an index of obesity. Patients with subclinical hypothyroidism exhibited elevated atherogenic parameters (Total cholesterol, LDL-C). Therefore screening and treatment for subclinical hypothyroidism may be warranted due to its adverse effects on lipid metabolism.
PMCID: PMC4531630  PMID: 14619383
Prevalence; thyroid dysfunction; Cardiovascular risk factors
20.  Associations of Circulating Oxidized LDL and Conventional Biomarkers of Cardiovascular Disease in a Cross-Sectional Study of the Navajo Population 
PLoS ONE  2016;11(3):e0143102.
The prevalences of cardiovascular disease (CVD) and type 2 diabetes (T2D) have increased among the Navajo Native American community in recent decades. Oxidized low-density lipoprotein (oxLDL) is a novel CVD biomarker that has never been assessed in the Navajo population. We examined the relationship of oxLDL to conventional CVD and T2D risk factors and biomarkers in a cross-sectional population of Navajo participants. This cross-sectional study included 252 participants from 20 Navajo communities from the Diné Network for Environmental Health Project. Plasma samples were tested for oxLDL levels by a sandwich enzyme-linked immunosorbent assay. Univariate and multivariate analyses were used to determine the relationship of oxLDL and oxidized- to non-oxidized lipoprotein ratios to glycated hemoglobin (HbA1c), C-reactive protein (CRP), interleukin 6 (IL6) and demographic and health variables. Type 2 diabetes, hypertension and obesity are very prevalent in this Navajo population. HbA1c, CRP, body mass index (BMI), high-density lipoprotein, and triglycerides were at levels that may increase risk for CVD and T2D. Median oxLDL level was 47 (36.8–57) U/L. Correlational analysis showed that although oxLDL alone was not associated with HbA1c, oxLDL/HDL, oxLDL/LDL and CRP were significantly associated with HbA1c and glucose. OxLDL, oxLDL/HDL and oxLDL/LDL were significantly associated with CRP. Multivariate analysis showed that triglycerides were a common and strong predictor of oxLDL, oxLDL/HDL and oxLDL/LDL. OxLDL was trended with HbA1c and glucose but did not reach significance, however, HbA1c was an independent predictor of OxLDL/HDL. CRP trended with oxLDL/HDL and was a weak predictor of oxLDL/LDL. This Navajo subset appears to have oxLDL levels comparable to subjects without evidence of CVD reported in other studies. The high prevalence of T2D, hypertension and obesity along with abnormal levels of other biomarkers including HbA1c indicate that the Navajo population has a worsening CVD risk profile.
PMCID: PMC4777541  PMID: 26938991
21.  Effects of patient‐tailored atorvastatin therapy on ameliorating the levels of atherogenic lipids and inflammation beyond lowering low‐density lipoprotein cholesterol in patients with type 2 diabetes 
Recently, patient‐tailored statin therapy was proven effective for achieving target low‐density lipoprotein (LDL) cholesterol levels. It is unclear, however, whether this therapeutic modality would be effective for atherogenic lipid profiles and inflammation in patients with type 2 diabetes.
Materials and Methods
The present study was an 8‐week, multicenter, single‐step titration trial of patient‐tailored atorvastatin therapy (10, 20 and 40 mg) according to baseline LDL cholesterol levels in 440 patients with type 2 diabetes. We measured the LDL particle size by polyacrylamide gel electrophoresis, and used high‐sensitivity C‐reactive protein (hsCRP) and adiponectin as surrogate markers of inflammation.
In the intention‐to‐treat analysis, 91% of the patients achieved their LDL cholesterol targets (<2.6 mmol/L) at week 8. There were significant reductions at week 8 in total cholesterol, triglycerides, non‐high‐density lipoprotein cholesterol (HDL) cholesterol, and the total cholesterol:HDL cholesterol ratio compared with the baseline values for all of the doses. The mean LDL particle size was significantly increased, and the small, dense LDL cholesterol levels were decreased in a dose‐dependent manner over the study period. In addition, the hsCRP levels were decreased in those high‐risk patients with baseline hsCRP levels over 3 mg/L (P < 0.001), and the adiponectin levels tended to increase with all of the doses (P = 0.004) at 8 weeks.
Patient‐tailored atorvastatin therapy based on LDL cholesterol at baseline was effective in ameliorating atherogenic LDL particle size and inflammation, in addition to achieving the target LDL cholesterol level without an undesirable effect on glycemic control in patients with type 2 diabetes. This trial was registered with (no. NCT01239849).
PMCID: PMC4025110  PMID: 24843697
Atorvastatin; Low‐density lipoprotein cholesterol; Type 2 diabetes mellitus
22.  Evaluation of Serum Magnesium, Lipid Profile and Various Biochemical Parameters as Risk Factors of Cardiovascular Diseases in Patients with Rheumatoid Arthritis 
Rheumatoid arthritis (RA) is chronic inflammatory disease, associated with increased risk of cardiovascular diseases (CVD) than the general population. Chronic inflammatory conditions are likely to alter magnesium level and various biochemical parameters.
To study the probable changes in serum magnesium, lipid profile and various biochemical parameters and to assess risk factors of CVD in newly diagnosed RA patients compared to controls.
Materials and Methods
We studied 50 newly diagnosed RA adult patients and 50 healthy individuals as controls. Serum magnesium, calcium, lipid profile, uric acid and other biochemical parameters were measured in study subjects. Results were expressed as Mean ± SD and compared between RA subjects and controls by Independent sample t-test and Pearson correlation.
We found decreased serum magnesium and calcium in RA subjects compared to the controls (p < 0.001). RA subjects had atherogenic lipid profile characterized by elevated total cholesterol (p = 0.054), LDL cholesterol (p = 0.008) and decreased HDL cholesterol (p <0.001). Serum uric acid was higher in RA cases compared to controls (p = 0.025). Serum magnesium was negatively correlated with total cholesterol, LDL cholesterol and positively correlated with HDL cholesterol in RA cases.
Decreased magnesium level, dyslipidemia and increased uric acid observed in our study together may be more potent risk factors for CVD in newly diagnosed RA subjects. We recommend that serum magnesium should be investigated as a part of cardiovascular risk management in RA. We suggest that decreased serum magnesium and increased serum uric acid may be considered as nontraditional risk factors of CVD in RA. Further prospective studies are needed to confirm the impact of inflammation on various biochemical parameters and cardiovascular outcomes in patients with RA.
PMCID: PMC4437057  PMID: 26023546
Cardiovascular risk factors; Dyslipidemia; Inflammatory; Uric acid
23.  A Comparative Study of Serum Uric Acid levels and Lipid Ratios in Coronary Artery Disease Patients 
Coronary Artery Disease (CAD) appears to be common in the Indian population of different geographical origins, religions and languages. Measurement of lipid fractions and ratios are widely recommended for risk assessment. A few studies have shown that serum uric acid plays a role in the development of cardiovascular morbidity. Very few reports are cited linking serum uric acid with the lipid fraction in CAD
To find the significance of non-HDL cholesterol, LDL-c/HDL-c ratio, TC/HDL ratio and serum uric acid level in CAD patients
Subjects and Methodology:
In this study, we included fifty CAD patients as subjects and an equal number of controls. Both subjects and controls were assessed for anthropometric, physiological and biochemical parameters
The present study showed significant increased levels of total cholesterol (p=0.002), TAGs (p<0.001), HDL (p=0.005), LDL (p<0.006) and non-HDL cholesterol (p<0.001). LDL-c/HDL-c ratio (p<0.001) and TC/HDL ratio (p<0.001) in CAD patients (subjects) were also significant when compared to controls. Uric acid level in CAD patients was increased (p<0.001).
Serum Uric Acid, TC/HDL and LDL/HDL ratios could be regarded as objective markers, in association with existing atherogenic dyslipidemia in patients with CAD.
PMCID: PMC4092080  PMID: 25018681
Coronary Artery Disease; Serum Uric Acid; Lipid Ratio
24.  Distinct Glucose-Lowering Mechanisms of Ipragliflozin Depending on Body Weight Changes 
Drugs in R&D  2016;16(4):369-376.
Sodium-glucose co-transporter 2 inhibitors have been shown to reduce body weight. However, little is known about whether a reduction in body weight affects glycemic and non-glycemic parameters.
The aim of this study was to investigate the link between the changes in body weight and those in metabolic parameters in drug-naïve subjects with type 2 diabetes mellitus (T2DM) receiving ipragliflozin monotherapy.
Subjects received ipragliflozin monotherapy 25–50 mg/day for 3 months (n = 33). They were then divided into two groups: group L (‘lost’; n = 17) comprised patients who lost weight (change [Δ] in body mass index [BMI] ≤ −0.75, p < 0.00001), and group N (‘neutral’; n = 16) comprised patients who did not lose weight (ΔBMI > −0.75, not significant [NS]).
In these two groups, similar reductions were observed in glycated hemoglobin (HbA1c) levels (group L: 9.76–8.02%, p < 0.00001; group N: 10.07–8.36%, p < 0.0005). Homeostasis model assessment (HOMA)-B levels increased in both groups, with inter-group differences (p < 0.05; +38.91 vs. +96.83% in group L and N, respectively). However, some parameters showed distinct regulatory patterns. For instance, in group L, reductions were observed in HOMA-R (−20.18%, p < 0.04) and uric acid (UA; −8.91%, p < 0.02) levels. Correlations were seen between the change in HOMA-R and those in fasting blood glucose (FBG) levels (R = 0.557, p < 0.02). Non-significant increases in free fatty acid (FFA) levels and decreases in non-high-density lipoprotein cholesterol (non-HDL-C) or low-density lipoprotein cholesterol (LDL-C) levels were also noted. In group N, reductions in FFA levels (−17.07%, p < 0.05) were observed, and negative correlations were seen between ΔHOMA-B and ΔFBG (R = −0.4781, p < 0.05) and between Δ FFA and Δ HOMA-B levels (R = −0.4305, p < 0.05). Non-significant increases in non-HDL-C and LDL-C levels were also noted. Inter-group differences existed between group L and group N in the changes in non-HDL-C and LDL-C levels (both p < 0.05).
These results indicate that ipragliflozin may possess distinct dual glucose-lowering mechanisms depending on body weight changes. Degrees of insulin resistance decrease in subjects who lose weight. Conversely, ipragliflozin reduces lipotoxicity (FFA levels), thereby activating beta-cell function, in subjects who do not lose weight. Similar glycemic efficacies were observed in both cases. In patients who lost weight, ipragliflozin was associated with improvements in the levels of metabolic parameters related to cardiovascular risk factors, including UA and atherogenic lipid levels (non-HDL-C and LDL-C) compared with those who did not lose weight.
PMCID: PMC5114207  PMID: 27798769
25.  Hormonal and Nutritional Effects on Cardiovascular Risk Markers in Young Women 
Cardiovascular (CV) risk markers, including high-sensitivity C-reactive protein (hsCRP), are increasingly important in predicting cardiac events. A favorable CV risk profile might be expected in anorexia nervosa (AN) due to low body weight and dietary fat intake. However, women with AN have decreased IGF-I levels reflecting decreased GH action, and IGF-I deficiency is associated with elevated hsCRP. Moreover, oral estrogens, known to increase hsCRP in other populations, are commonly prescribed in AN. To date, hsCRP levels and their physiological determinants have not been reported in women with AN.
We examined the relationship between CV risk markers, undernutrition, IGF-I, and oral estrogens, specifically hypothesizing that in the setting of undernutrition, AN would be associated with low hsCRP despite low IGF-I levels and that those women taking oral contraceptive pills (OCPs) would have higher hsCRP and lower IGF-I levels.
Design and Setting
We conducted a cross-sectional study at a clinical research center.
Study Participants
Subjects included 181 women: 140 women with AN [85 not receiving OCPs (AN-E) and 55 receiving OCPs (AN+E)] and 41 healthy controls [28 not receiving OCPs (HC-E) and 13 receiving OCPs (HC+E)].
Main Outcome Measures
We assessed hsCRP, IL-6, IGF-I, low-density lipoprotein (LDL), and high-density lipoprotein (HDL).
Despite low weight, more than 20% of AN+E had high-risk hsCRP levels. AN+E had higher hsCRP than AN-E. AN-E had lower mean hsCRP levels than healthy controls (HC+E and HC-E). IL-6 levels were higher in AN+E with elevated hsCRP (>3 mg/liter) than in AN+E with normal hsCRP levels. IGF-I was inversely associated with hsCRP in healthy women, suggesting a protective effect of GH on CV risk. However, this was not seen in AN. Few patients in any group had high-risk LDL or HDL levels.
Although hsCRP levels are lower in AN than healthy controls, OCP use puts such women at a greater than 20% chance of having hsCRP in the high-CV-risk (>3 mg/liter) category. The elevated mean IL-6 in women with AN and high-risk hsCRP levels suggests that increased systemic inflammation may underlie the hsCRP elevation in these patients. Although OCP use in AN was associated with slightly lower mean LDL and higher mean HDL, means were within the normal range, and few patients in any group had high-risk LDL or HDL levels. IGF-I levels appear to be important determinants of hsCRP in healthy young women. In contrast, IGF-I does not appear to mediate hsCRP levels in AN.
PMCID: PMC3211045  PMID: 17519306

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