Sex differences in the presentation, treatment and outcomes of patients with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal semi-dominant lipid metabolism disorder characterized by extremely high low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease. The objective of this study was to investigate sex-differences in the treatment and outcomes of patients with HoFH. METHODS: We examined clinical characteristics, lipid-lowering therapy (LLT), and cardiovascular events using descriptive statistics of patients in the Canadian HoFH registry. Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, non-fatal myocardial infarction, and stroke. Sex differences between continuous and categorical variables were analyzed using Mann-Whitney U test and Fisher's Exact test, respectively. RESULTS: This study included 48 patients (27 (56%) female). The median age at diagnosis in females was 14.0 (interquartile range (IQR) 9.0-30.0) and in males was 8.0 (IQR 2.0-23.0) (p = 0.07). Baseline clinical characteristics were comparable between both sexes. The median baseline LDL-C was 12.7 mmol/L (10.0-18.3) in females and 15.3 (10.5-20.0) in males (p = 0.51). Follow up LDL-C levels were 7.6 mmol/L (IQR 4.8-11.0) in females and 6.3 (IQR 4.6-7.5) in males (p = 0.1). Most patients were taking 3 or more LLTs, with comparable proportions in both sexes (p = 0.26). Apheresis was similar in both sexes, 14 (51.8%) vs. 10 (47.6%) (p = 0.2). Over a mean of 10 years of follow-up, MACE occurred in 3 females (11.1%) and 4 males (19.1%) (p = 0.2). CONCLUSION: Lipid levels and treatment were similar between sexes. MACE occurred in similar proportions between sexes, indicating that HoFH offsets the inherently lower cardiovascular risk in pre-menopausal females. Further investigation into sex-differences in HoFH in larger sample sizes is warranted.

Homozygous Familial Hypercholesterolemia in Canada: An Observational Study.

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by very high levels of low-density lipoprotein cholesterol (LDL-C). Untreated patients present with extensive xanthomas and premature atherosclerosis. Lipid-lowering therapy is highly efficacious and has dramatically increased life expectancy of patients with HoFH. Objectives: The aim of the study was to obtain a comprehensive registry of HoFH in Canada, known to have several founder effect regions, and describe the clinical characteristics and cardiovascular outcomes of this population over time. Methods: Clinical and genetic data on patients with HoFH were collected via a standardized questionnaire sent to academic sites participating in the Familial Hypercholesterolemia Canada network. Results: A total of 48 patients with HoFH were enrolled. The median age at diagnosis was 12 years (interquartile range [IQR]: 5-24) and untreated LDL-C levels were 15.0 mmol/L (IQR: 10.5-18.6 mmol/L; 580 mg/dL IQR: 404-717 mg/dL). At last follow-up visit, median age was 40 years (IQR: 26-54 years). Treated LDL-C levels were 6.75 mmol/L (IQR: 4.73-9.51 mmol/L; 261 mg/dL IQR: 183-368 mg/dL) with 95.5% of patients on statins, 88.6% on ezetimibe, 34.1% on proprotein convertase subtilisin/kexin type 9 inhibitors, 27.3% on lomitapide, 13.6% on evinacumab, and 56.8% were treated with low-density lipoprotein apheresis or plasmapheresis. Deaths were reported in 7 (14.5%) and major adverse cardiovascular events were observed in 14.6% of patients with the average onset at 30 years (IQR: 20-36 years). Aortic stenosis was reported in one-half the patients (47.9%) and 10 (20.8%) underwent aortic valve replacement. Conclusions: This HoFH patient registry in Canada will provide important new health-related knowledge about the phenotypic manifestations and determinants of cardiovascular risk in this population, allowing for closer examination of quality of life and burden to the health care system.

Haptoglobin Phenotype Modifies the Influence of Intensive Glycemic Control on Cardiovascular Outcomes.

BACKGROUND: Whereas there exists a direct relationship between glycated hemoglobin and cardiovascular disease (CVD), clinical trials targeting glycated hemoglobin to near-normal levels using intensive therapy have failed to prevent CVD and have even increased mortality, making clinical decision making difficult. A common polymorphism at the haptoglobin (Hp) genetic locus is associated with CVD, especially coronary heart disease, in the setting of hyperglycemia. OBJECTIVES: This study sought to determine whether the treatment difference of intensive versus standard glucose-lowering therapy on risk of CVD events in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study depended on Hp phenotype. METHODS: Hp phenotype was measured within 5,806 non-Hispanic white ACCORD participants using a validated assay. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) estimated from stratified Cox regression models were used to quantify the association between intensive therapy and incident CVD for the 2 different Hp phenotype groups (Hp2-2, Hp1 carriers). RESULTS: Compared with standard therapy, intensive therapy was associated with a lower risk of incident coronary heart disease among participants with the Hp2-2 phenotype (n = 2,133; aHR: 0.71; 95% CI: 0.55 to 0.91; p = 0.006), but not among the other 2 phenotypes (Hp1 allele carriers) (n = 3,673; aHR: 0.95; 95% CI: 0.79 to 1.13; p = 0.550). The same pattern was observed for CVD. Conversely, intensive therapy was associated with an increased risk of fatal CVD (aHR: 1.50; 95% CI: 1.00 to 2.25; p = 0.049) and total mortality (aHR: 1.40; 95% CI: 1.08 to 1.81; p = 0.011) among the Hp1 carriers, whereas this risk was not increased in the Hp2-2 phenotype (fatal CVD: aHR: 1.02; 95% CI: 0.59 to 1.77; p = 0.931; total mortality: aHR: 0.98; 95% CI: 0.68 to 1.41; p = 0.908). CONCLUSIONS: Intensive glucose-lowering therapy was effective at preventing incident coronary heart disease and CVD events in ACCORD study participants with the Hp2-2 phenotype but not in Hp1 carriers, who had increased mortality risk from intensive therapy.

Outcome of stereotactic radiotherapy for patients with uncontrolled acromegaly.

OBJECTIVE: Linear accelerator based stereotactic radiation therapy (SRT) has been used for the treatment of pituitary tumours; however, little is known concerning the use of this modality for the treatment of patients with acromegaly. We have prospectively studied the short-term outcome of SRT in 12 acromegaly patients who failed to achieve biochemical remission despite surgery and/or pharmacologic therapy. METHODS: We identified all patients who had biochemically uncontrolled acromegaly and were treated with SRT between April 2003 and December 2006. All patients were followed prospectively based on a pre-defined protocol that included Goldman visual field examination, MRI of the sella, and pituitary hormone testing at 3, 6, 12 months, and then yearly. RESULTS: A total of 12 patients with acromegaly were treated with SRT. There were 9 females and the median age of the group was 50 years. The median follow-up was 28.5 months during which time the mean tumor volume decreased by 40%, the median GH fell from 4.1 microg/L to 1.3 microg/L (p = 0.003) and the median IGF-1 dropped more than half from 545.5 microg/L to 260.5 microg/L (p = 0.002). Four patients achieved normal, while an additional 2 achieved near-normal, IGF-1 levels. One patient was able to discontinue and two were able to reduce their acromegaly medications while maintaining a normal IGF-1. A new pituitary hormonal deficit was found at 24 months in one patient who developed hypoadrenalism requiring corticosteroid replacement. CONCLUSION: Based on our early experience, we believe that SRT should be considered in treating patients with uncontrolled acromegaly.

Blood Pressure Management in Adults With Type 2 Diabetes: Insights From the Diabetes Mellitus Status in Canada (DM-SCAN) Survey.

OBJECTIVES: Optimal treatment of blood pressure (BP) and other cardiovascular risk factors, including hyperglycemia, is integral to diabetes management. There are limited data from the primary care setting concerning the contemporary and comprehensive management of type 2 diabetes and other cardiovascular risk factors in relation to guideline-recommended BP target achievement. METHODS: The Diabetes Mellitus Status in Canada (DM-SCAN) survey included 5172 ambulatory patients with type 2 diabetes. Data were collected on patient demographics, medical histories, medication usage, BP levels and laboratory investigations. We stratified the study population based on their attainment of the BP target recommended by the Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada and the Canadian Hypertension Education Program (<130/80 mmHg) and compared patient clinical characteristics and treatments. RESULTS: Of the 5145 patients with available BP data, 36% achieved the BP target. Prevalence of smoking, known coronary artery disease, retinopathy, neuropathy and nephropathy were similar in the groups with BP 130/80 mmHg or higher and BP 130/80 mmHg or lower. Patients with BP 130/80 mmHg or higher were taking more antihypertensive agents and were more likely to be taking angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers, diuretics and calcium channel blockers. They also had significantly higher glycated hemoglobin and low-density lipoprotein-cholesterol levels. Overall, these patients were also less likely to achieve guideline-recommended glycemic and lipid targets. CONCLUSIONS: Only about one-third of patients with diabetes achieved the target BP of below 130/80 mmHg. Patients with BP 130/80 mmHg or higher were also less likely to achieve optimal guideline-recommended glycated hemoglobin and low-density lipoprotein-cholesterol targets. Improved comprehensive management of all risk factors in patients with diabetes is warranted.

Canadian Cardiovascular Society Position Statement on Familial Hypercholesterolemia: Update 2018.

Familial hypercholesterolemia (FH) is the most common monogenic disorder causing premature atherosclerotic cardiovascular disease. It affects 1 in 250 individuals worldwide, and of the approximately 145,000 Canadians estimated to have FH, most are undiagnosed. Herein, we provide an update of the 2014 Canadian Cardiovascular Society position statement on FH addressing the need for case identification, prompt recognition, and treatment with statins and ezetimibe, and cascade family screening. We provide a new Canadian definition for FH and tools for clinicians to make a diagnosis. The risk of atherosclerotic cardiovascular disease in patients with "definite" FH is 10- to 20-fold that of a normolipidemic individual and initiating treatment in youth or young adulthood can normalize life expectancy. Target levels for low-density lipoprotein cholesterol are proposed and are aligned with the Canadian Cardiovascular Society guidelines on dyslipidemia. Recommendation for the use of inhibitors of proprotein convertase kexin/subtilisin type 9 are made in patients who cannot achieve therapeutic low-density lipoprotein cholesterol targets on maximally tolerated statins and ezetimibe. The writing committee used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology in the preparation of the present document, which offers guidance for practical evaluation and management of patients with FH. This position statement also aims to raise awareness of FH nationally, and to mobilize patient support, promote knowledge translation, and availability of treatment and health care resources for this under-recognized, but important medical condition.

Anemia is an independent risk for mortality after acute myocardial infarction in patients with and without diabetes.

INTRODUCTION: Anemia and diabetes are risk factors for short-term mortality following an acute myocardial infarction(AMI). Anemia is more prevalent in patients with diabetes. We performed a retrospective study to assess the impact of the combination of diabetes and anemia on post-myocardial infarction outcomes. METHODS: Data relating to all consecutive patients hospitalized with AMI was obtained from a population-based disease-specific registry. Patients were divided into 4 groups: diabetes and anemia (group A, n = 716), diabetes and no anemia (group B, n = 1894), no diabetes and anemia (group C, n = 869), and no diabetes and no anemia (group D, n = 3987). Mortality at 30 days and 31 days to 36 months were the main outcome measures. RESULTS: 30-day mortality was 32.3% in group A, 16.1% in group B, 21.5% in group C, 6.6% in group D (all p < 0.001). 31-day to 36-month mortality was 47.6% in group A, 20.8% in group B, 34.3% in group C, and 10.4% in group D (all p < 0.001). Diabetes and anemia remained independent risk factors for mortality with odds ratios of 1.61 (1.41-1.85, p < 0.001) and 1.59 (1.38-1.85, p < 0.001) respectively at 36 months. Cardiovascular death from 31-days to 36-months was 43.7% of deaths in group A, 54.1% in group B, 47.0% in group C, 50.8% group D (A vs B, p < 0.05). INTERPRETATION: Patients with both diabetes and anemia have a significantly higher mortality than those with either diabetes or anemia alone. Cardiovascular death remained the most likely cause of mortality in all groups.

Improved prediction of early-onset coronary artery disease using APOE epsilon4, BChE-K, PPARgamma2 Pro12 and ENOS T-786C in a polygenic model.

OBJECTIVES: Coronary artery disease (CAD) is often polygenic due to multiple mutations that contribute small effects to susceptibility. Since most prior studies only evaluated the contribution of single candidate genes, we therefore looked at a combination of genes in predicting early-onset CAD [apolipoprotein E (APOE) epsilon4, butyrylcholinesterase (BChE) K, peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala and endothelial nitric oxide synthase (ENOS) T-786C]. DESIGN AND METHODS: We examined the frequencies, individually and in combination, of all four alleles among patients with early-onset CAD (n = 150; <50 years), late-onset CAD (n = 150; >65 years) and healthy controls (n = 150, age range 47-93 years). Differences in the proportion of subjects in each group with the given gene combination were assessed and likelihood ratios (LR) were calculated using logistic regression to combine the results of multiple genes. RESULTS: Early-onset CAD patients had increased, but non-significant, frequencies of PPARgamma2 Pro12/Pro12 (P = 0.39) and ENOS T-786C (P = 0.72), while BChE-K was only significantly higher in early-onset CAD patients compared to controls (P = 0.03). There were significantly more APOE epsilon4 alleles alone (P = 0.02) or in combination with BChE-K (P = 0.02) among early-onset CAD patients compared to late-onset CAD ones or controls. When combined, there was a higher prevalence of all four alleles in early-onset CAD (early-onset CAD patients: 10.7%, late-onset CAD patients: 3.3% and controls: 2.7%, P = 0.01). LR for early-onset CAD for a single allele was relatively small (1.08 for PPARgamma2 to 1.70 for APOE epsilon4). This increased to 2.78 (1.44-5.37) when combining all four alleles, therefore increasing the pre-test probability of CAD from 5% to a post-test probability of 12.7%. CONCLUSIONS: While any single mutation causes only a mildly increased LR (none > 1.7), in combination, the likelihood of early-onset CAD increased to 2.78 with four mutations. The genetics of early-onset CAD appear to be multifactorial, requiring polygenic models to elucidate risk.

An overview of the role of insulin in the treatment of hyperglycemia during acute myocardial ischemia.

Hyperglycemia on admission to the coronary care unit is associated with poor outcome. It has now been reasonably well established that intravenous insulin infusion during acute myocardial infarction has a protective role and reduces mortality. The present article reviews the current understanding of the cardioprotective effect of insulin and the recent advances in this area.

The transcultural diabetes nutrition algorithm: a canadian perspective.

The Transcultural Diabetes Nutrition Algorithm (tDNA) is a clinical tool designed to facilitate implementation of therapeutic lifestyle recommendations for people with or at risk for type 2 diabetes. Cultural adaptation of evidence-based clinical practice guidelines (CPG) recommendations is essential to address varied patient populations within and among diverse regions worldwide. The Canadian version of tDNA supports and targets behavioural changes to improve nutritional quality and to promote regular daily physical activity consistent with Canadian Diabetes Association CPG, as well as channelling the concomitant management of obesity, hypertension, dyslipidemia, and dysglycaemia in primary care. Assessing glycaemic index (GI) (the ranking of foods by effects on postprandial blood glucose levels) and glycaemic load (GL) (the product of mean GI and the total carbohydrate content of a meal) will be a central part of the Canadian tDNA and complement nutrition therapy by facilitating glycaemic control using specific food selections. This component can also enhance other metabolic interventions, such as reducing the need for antihyperglycaemic medication and improving the effectiveness of weight loss programs. This tDNA strategy will be adapted to the cultural specificities of the Canadian population and incorporated into the tDNA validation methodology.

The relationship between bipolar disorder and type 2 diabetes: more than just co-morbid disorders.

Type 2 diabetes mellitus (T2DM) rates are three times higher in patients with bipolar disorder (BD), compared to the general population. This is a major contributing factor to the elevated risk of cardiovascular mortality, the leading cause of death in bipolar patients. There may be shared pathophysiology linking the two disorders, including hypothalamic-pituitary-adrenal and mitochondrial dysfunction, common genetic links, and epigenetic interactions. Life-style, phenomenology of bipolar symptoms, and adverse effects of pharmacotherapy may be contributing factors. Patients with BD and T2DM have a more severe course of illness and are more refractory to treatment. Control of their diabetes is poorer when compared to diabetics without BD, and an existing disparity in medical care may be partly responsible. Glucose abnormalities in bipolar patients need to be screened for and treated. Metformin appears to have the best benefit/risk ratio, and the dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists and analogues also appear promising, although these agents have not been specifically studied in populations with mood disorders. Physicians need to be aware of the increased risk for T2DM and cardiovascular disease in bipolar patients, and appropriate prevention, screening, case finding, and treatment is recommended.

Type 2 diabetes mellitus management in Canada: is it improving?

OBJECTIVE: To gain insight into the current management of patients with type 2 diabetes mellitus by Canadian primary care physicians. METHOD: A total of 479 primary care physicians from across Canada submitted data on 5123 type 2 diabetes patients whom they had seen on a single day on or around World Diabetes Day, November 14, 2012. RESULTS: Mean glycated hemoglobin (A1C) was 7.4%, low-density lipoprotein (LDL-C) was 2.1 mmol/L and blood pressure (BP) was 128/75 mm Hg. A1C ≤7.0% was met by 50%, LDL-C ≤2.0 mmol/L by 57%, BP <130/80 mm Hg by 36% and the composite triple target by 13% of patients. Diet counselling had been offered to 38% of patients. Of the 87% prescribed antihyperglycemic agents, 18% were on 1 non-insulin antihyperglycemic agent (NIAHA) (85% of which was metformin), 15% were on 2 NIAHAs, 6% were on ≥3 NIAHAs, 19% were on insulin only and 42% were on insulin + ≥1 NIAHA(s). Amongst the 81% prescribed lipid-lowering therapy, 88% were on monotherapy (97% of which was a statin). Among the 83% prescribed antihypertensive agents, 39%, 34%, 21% and 6% received 1, 2, 3 and >3 drugs, respectively, with 59% prescribed angiotensin-converting enzyme inhibitors and 35% angiotensin II receptor blockers. CONCLUSIONS: The Diabetes Mellitus Status in Canada survey highlights the persistent treatment gap associated with the treatment of type 2 diabetes and the challenges faced by primary care physicians to gain glycemic control and global vascular protection in these patients. It also reveals a higher use of insulin therapy in primary care practices relative to previous surveys. Practical strategies aimed at more effectively managing type 2 diabetes patients are urgently needed.

Impact of admission serum glucose level on in-hospital outcomes following coronary artery bypass grafting surgery.

OBJECTIVE: The impact of admission serum glucose (SG) level on outcomes in coronary artery bypass grafting (CABG) surgery is unknown. The present study sought to determine whether elevated admission SG level is associated with adverse outcomes following CABG surgery. METHODS: Patients undergoing CABG surgery between January 2000 and December 2005 at a single centre were identified (n=2856). Admission SG levels of less than 9.2 mmol/L and 9.2 mmol/L or greater were chosen to divide patients into two groups based on the 75th percentile of SG distribution. A logistic regression model was generated to determine the impact of admission SG level on a composite outcome of any one or more of in-hospital mortality, stroke, perioperative myocardial infarction, sepsis, deep sternal wound infection, renal failure, requirement for postoperative inotropes and prolonged ventilation. RESULTS: In total, 76.3% of patients had an admission SG level of less than 9.2 mmol/L (group A) and 23.7% had an admission SG level of 9.2 mmol/L or greater (group B). Group B patients were more likely to be female, have diabetes, have preoperative renal failure, have an ejection fraction of less than 40%, experience myocardial infarction within 21 days before surgery, and have triple vessel or left main disease (P<0.05). Univariate analysis revealed no difference in in-hospital mortality between group A (2.2%) and group B (3.2%) (P=0.12); however, the composite outcome was more likely to occur in group B (40.8%) versus group A (27.9%) (P=0.0001). After multivariable adjustment, admission SG level of 9.2 mmol/L or greater remained an independent predictor of composite outcome (OR=1.3, 95% CI 1.0 to 1.7, P=0.02, receiver operating characteristic = 78%). CONCLUSION: Admission SG level of 9.2 mmol/L or greater is associated with significant morbidity in patients undergoing CABG surgery.