Lipid management for cardiovascular risk reduction in type 1 diabetes.

PURPOSE OF REVIEW: To review the recent evidence for lipid management in type 1 diabetes (T1D) for cardiovascular risk reduction. RECENT FINDINGS: Individuals with T1D are at increased risk for cardiovascular morbidity and mortality, with atherosclerosis beginning as early as adolescence. Elevated low-density lipoprotein cholesterol (LDL-C), triglycerides, and lipoprotein (a) are associated with increased cardiovascular risk in T1D. Although high-density lipoprotein cholesterol (HDL-C) in T1D is often normal or higher than in nondiabetic controls, HDL in T1D has structural alterations, which make it proatherogenic rather than cardioprotective. Similarly, although LDL-C is not particularly elevated in T1D, LDL still contributes to cardiovascular risk. Studies in individuals with diabetes have primarily included T2D participants, with a much smaller number of T1D participants; such studies have shown that lipid-lowering therapies, such as statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce LDL-C levels and cardiovascular events in both those with and without diabetes. Individuals with T1D have increased cholesterol absorption, suggesting that ezetimibe may be particularly effective in T1D. Results of the REDUCE-IT trial show cardiovascular risk reduction from high-dose omega-3 fatty acid (Icosapent Ethyl) therapy in patients with diabetes (primarily type 2 diabetes), independent of triglyceride lowering, but similar data in T1D are currently lacking. SUMMARY: Individuals with T1D are at high risk of cardiovascular disease, necessitating close lipid monitoring and management from adolescence through adulthood.

PCSK9 Inhibitors: From Nature's Lessons to Clinical Utility.

BACKGROUND: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a novel class of non-statin lipid lowering therapy that reduce LDL-cholesterol by 50 - 60%. PCSK9 inhibitors decrease LDL-cholesterol by preventing intracellular degradation of LDL receptors; subsequently, a greater number of LDL-receptors are available on the cell surface to extract circulating LDL. OBJECTIVE: To describe the origins of PCSK9 inhibitors and their current use in clinical practice. METHODS: We performed a narrative review of the PCSK9 inhibitor class of drugs. RESULTS: Current data indicate that PCSK9 inhibitors effectively reduce LDL-cholesterol and are well tolerated and safe. PCSK9 inhibitors have also been shown to reduce cardiovascular event rates in patients with stable atherosclerotic cardiovascular disease and in patients with a recent (up to one year) acute coronary syndrome. Given the costs, chronicity of the treatment and the potential budget impact, PCSK9 inhibitors are often limited to patients with the highest absolute risk for major adverse cardiovascular events despite optimal treatment with high-intensity statin and ezetimibe. CONCLUSION: PCSK9 inhibitors have a favorable safety, efficacy and tolerability profile. Postmarketing safety surveillance and real-world studies are needed to further support the long-term safety profile of this class of medicine.

What is new in lipid-lowering therapies in diabetes?

Diabetes can lead to a myriad of microvascular and macrovascular complications - with the leading cause of mortality in diabetes being cardiovascular disease. Low-density lipoprotein cholesterol, along with non-high-density lipoprotein cholesterol and triglycerides are proven, modifiable risk factors for cardiovascular disease. This article will focus on lipid-lowering agents in individuals with diabetes. It will summarise relevant changes in the latest guidelines for dyslipidaemia and will also review the mechanisms of action of lipid-lowering agents along with the latest cardiovascular outcomes data specific to individuals with diabetes. Older agents such as statins, ezetimibe, fibrates and nicotinic acid will be reviewed with a focus on new diabetes-specific evidence. Similarly, a relatively novel agent proprotein-convertase subtilisin-kexin type 9 will be reviewed and details around the Pharmaceutical Benefits Scheme criteria governing its usage in Australia will be reported. Finally, this review will touch on agents still on the horizon such as icosapent ethyl, high-density lipoprotein mimetics, bempedoic acid, omega-3 free fatty acids, bromodomain and extra-terminal protein inhibitors and inclisiran - a long-acting ribonucleic acid interference agent. In the appropriately selected population of individuals with diabetes, these agents can assist to improve further lipid profile and reduce cardiovascular events.

Body mass index impacts the choice of lipid-lowering treatment with no correlation to blood cholesterol - Findings from 52 916 patients in the Dyslipidemia International Study (DYSIS).

A high body mass index (BMI) is associated with increased cardiovascular risk. We sought to identify whether BMI influences the choice of lipid-lowering treatment in a large, real-world cohort of 52 916 patients treated with statins. The Dyslipidemia International Study (DYSIS) is a cross-sectional, observational, multicentre study in statin-treated patients ≥45 years of age from 30 countries; 1.1% were underweight (BMI < 18.5 kg/m2 ), 33.1% had normal weight (BMI 18.5-24.9 kg/m2 ), 41.5% were overweight (BMI 25-29.9 kg/m2 ), 17.1% had class I obesity (BMI 30.0-34.9 kg/m2 ), 5.0% had class II obesity (BMI 35-39.9 kg/m2 ), and 2.1% had class III obesity (≥40 kg/m2 ). BMI correlated with high-density lipoprotein cholesterol (HDL-C) and triglycerides (Spearman's ρ: -0.147 and 0.170, respectively; P < 0.0001 for both); however, there was no correlation with low-density lipoprotein cholesterol (LDL-C; ρ: 0.003; P = 0.51). Statin intensity increased with increasing BMI (ρ: 0.13; P < 0.001), an association that held after adjustment for comorbidities (OR: 2.4; 95% CI: 2.0-3.0) on BMI ≥ 30 kg/m2 for atorvastatin equivalent ≥40 mg/d.

New treatment options for lipid-lowering therapy in subjects with type 2 diabetes.

Dyslipidemias represent a variety of quantitative and/or qualitative lipoprotein abnormalities. According to etiology, we distinguish primary dyslipidemias with strictly genetic background and secondary ones with their origin in other disease or pathological states. Diabetic dyslipidemia is a type of secondary dyslipidemia and plays an important role in determining the cardiovascular risk of subjects with type 2 diabetes. In these patients, insulin resistance is responsible for overproduction and secretion of atherogenic very low density lipoprotein. In addition, insulin resistance promotes the production of small dense low-density lipoprotein (LDL) and reduces high-density lipoprotein (HDL) production. Cardiovascular disease remains a leading cause of morbidity and mortality in diabetic patients. Previous results support the role for small, dense LDL particles in the etiology of atherosclerosis and their association with coronary artery disease. Moreover, lowering LDL cholesterol reduces the risk of cardiovascular death. Therefore, the European guidelines for the management of dyslipidemias recommend an LDL cholesterol goal < 100 mg/dL in diabetic subjects without cardiovascular events. Moreover, if triglycerides (TG) are elevated (> 400 mg/dL), they recommend a non-HDL cholesterol goal < 130 mg/dL in diabetic individuals without cardiovascular events. Statins are the first line of LDL-lowering therapy in diabetic patients and combined therapy with ezetimibe and statins could be useful in very high cardiovascular risk diabetic subjects. Furthermore, the effect of a fibrate as an add-on treatment to a statin could improve the lipid profile in diabetic individuals with high TG and low HDL cholesterol. Regarding new therapies, recent data from phase III trials show that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors considerably decrease LDL cholesterol. Thus, they may be useful in diabetic patients with concomitant diseases such as familial dyslipidemia, recurrent cardiovascular events, and elevated LDL cholesterol after second drug administration in addition to maximal statin dose or statin intolerance.

Familial Hypercholesterolemia: Advances in Recognition and Therapy.

Familial hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein cholesterol levels and increased risk for premature cardiovascular disease. It is under-diagnosed, yet early detection and treatment are critical to limit premature atherosclerotic disease. High-intensity statins are the mainstay of treatment, which should be started as early as possible in homozygous FH and as soon as the diagnosis of heterozygous FH is made in adults. Combination therapy is often necessary in FH patients and can include the addition of ezetimibe and bile acid sequestrants. Lipoprotein apheresis is used when pharmacotherapy is inadequate, especially for those with homozygous FH and some patients with severe heterozygous FH. Mipomersen and lomitapide are also indicated for patients with homozygous FH. The recently approved PCSK9 inhibitors, alirocumab and evolocumab, are a promising treatment and outcome studies are ongoing. This article reviews the pathophysiology, diagnosis, and management of FH.

Dyslipidemia treatment and cardiovascular disease in the renal patient.

Cardiovascular disease is the most prevalent cause of death in patients with chronic kidney disease (CKD), even at an early stage of the disease and is considered a coronary heart disease risk equivalent. Therefore, therapeutic efforts to control modifiable additional cardiovascular risk factors such as dyslipidemia in this population seems reasonable. Indeed, abnormalities of lipid metabolism are often encountered in patients with CKD, end stage renal disease or after kidney transplantation. In this review we will summarize the currently available data on etiology, epidemiology, and impact on cardiovascular morbidity in patients with CKD, renal pathologies like the nephrotic syndrome and after kidney transplantation and give a brief overview of the existing guidelines on treating dyslipidemia.

Prevention of atherosclerosis and drug treatment of high-risk lipid abnormalities in children and adolescents.

OBJECTIVE: To discuss risk factors of atherosclerosis in pediatrics, dietary and physical activity guidelines, and, mainly, drug treatment of high-risk lipid abnormalities. SOURCES: Data were obtained from articles indexed in MEDLINE, published over the last 5 years. SUMMARY OF THE FINDINGS: Children with severe dyslipidemia or additional risk factors such as family history of early cardiovascular disease or other signs of metabolic syndrome may need treatment with hypolipidemic drugs. New recommendations from the U.S. guidelines indicate drug treatment before the age of 10 years according to the magnitude of the additional risk factors for cardiovascular disease. Pediatricians should know when to diagnose dyslipidemia, when to indicate drug treatment and which medication can be used in children and adolescents with the least risk or harm to their development. CONCLUSIONS: The first-line treatment of dyslipidemia consists of lifestyle changes, focusing on prevention. Children with high-risk lipid abnormalities should be considered for drug treatment. Decisions to be made together with the parents must be evaluated taking into consideration risks and benefits of the medication to the patient.

Prevenção da aterosclerose e tratamento medicamentoso de anormalidades lipídicas de alto risco em crianças e adolescentes: [revisão] / Prevention of atherosclerosis and drug treatment of high-risk lipid abnormalities in children and adolescents: [review]

OBJETIVO: Discutir os fatores de risco da aterosclerose na pediatria e as recomendações de dieta e exercício físico e, principalmente, o tratamento medicamentoso de anormalidades lipídicas de alto risco. FONTES DOS DADOS: Os dados foram obtidos por meio de artigos indexados na MEDLINE, publicados nos últimos 5 anos. SÍNTESE DOS DADOS: Crianças com dislipidemia grave ou outros fatores de risco, como história familiar de doença cardiovascular precoce ou outros sinais de síndrome metabólica, podem necessitar de tratamento com drogas hipolipemiantes. Novas recomendações do consenso americano indicam tratamento medicamentoso antes dos 10 anos de idade, dependendo da magnitude de outros fatores de risco para doença cardiovascular. Cabe aos pediatras saber quando diagnosticar dislipidemia, quando indicar o tratamento medicamentoso e quais as drogas que podem ser utilizadas em crianças e adolescentes com menor risco e prejuízo ao seu desenvolvimento. CONCLUSÕES: O tratamento da dislipidemia deve ser inicialmente realizado sempre por meio de mudanças nos hábitos de vida, dando-se ênfase à prevenção. Crianças com anormalidades lipídicas de alto risco merecem tratamento medicamentoso. A decisão a ser tomada junto com os pais sempre deve respeitar os riscos e os benefícios que o tratamento acarretará ao paciente.

OBJECTIVE: To discuss risk factors of atherosclerosis in pediatrics, dietary and physical activity guidelines, and, mainly, drug treatment of high-risk lipid abnormalities. SOURCES: Data were obtained from articles indexed in MEDLINE, published over the last 5 years. SUMMARY OF THE FINDINGS: Children with severe dyslipidemia or additional risk factors such as family history of early cardiovascular disease or other signs of metabolic syndrome may need treatment with hypolipidemic drugs. New recommendations from the U.S. guidelines indicate drug treatment before the age of 10 years according to the magnitude of the additional risk factors for cardiovascular disease. Pediatricians should know when to diagnose dyslipidemia, when to indicate drug treatment and which medication can be used in children and adolescents with the least risk or harm to their development. CONCLUSIONS: The first-line treatment of dyslipidemia consists of lifestyle changes, focusing on prevention. Children with high-risk lipid abnormalities should be considered for drug treatment. Decisions to be made together with the parents must be evaluated taking into consideration risks and benefits of the medication to the patient.

Omega-(2-Naphthyloxy) amino alkanes as a novel class of anti-hyperglycemic and lipid lowering agents.

omega-(2-Naphthyloxy) amino alkanes, obtained as major by-product during course of synthesis of carbamate esters from omega-(2-naphthyloxy) alkyl halides and amines, showed significant anti-hyperglycemic and lipid lowering activities in various test models as a novel class of compounds. Compounds were tested in rat GLM, SLM, STZ, and STZ-S models at 100mg/kg dose. Of these compound 13 was found to be the most active which caused lowering of sugar by 33.6%, 31.0%, 28.5%, and 73.8% in GLM, SLM, STZ, STZ-S, and db/db mice models, respectively. It also significantly effected lowering of LDL in rat model and also in Hamster model without reducing HDL. Most of the compounds showing anti-diabetic and lipid lowering activity have shown promising PPAR-alpha/gamma/delta-activity. Compounds 6, 13, and 19 have shown very good PPAR-alpha/gamma/delta activity.

Cholesterol, cholesterol-lowering agents/statins, and urologic disease: Part III--A rapid review of FDA-approved cholesterol-lowering agents.

There are a variety of agents, dosages, and mechanisms involved in reducing cholesterol. Statins are the most well-known class and three of the six currently available agents have now lost patent protection. Thus, large reductions in price are expected in 2006-2007 across the entire class. The other classes of cholesterol-lowering agents include targeted triglyceride reducers and high-density lipoprotein boosters; two other classes include primarily cholesterol absorption inhibitors. A recent addition to the cholesterol-lowering prescriptions include prescription omega-3 products, which are highly concentrated, have excellent quality control, and are used to reduce abnormally high levels of triglycerides. All of these agents can be used in some restricted combination, or individually to significantly impact the various forms of lipids in the bloodstream. The bottom line is that practitioners have a large diversity of medications available for cholesterol lowering, and this is enormously exciting at a time when these agents have such profound effects in a variety of disciplines.

Antihiperlipemiantes de origen vegetal / No disponible

Las hiperlipidemias constituyen uno de los principales factores de riesgo para la salud cardiovascular en las sociedades desarrolladas. La necesidad de disponer de agentes activos frente a las alteraciones del perfil lipídico, ha conducido a que la búsqueda de los mismos, se haya extendido a la investigación de productos naturales con actividad en las hiperlipidemias. Gracias a estos estudios, se ha podido establecer la actividad antihiperlipemiante de varias plantas medicinales (Camellia thea, Glyeine max, Plantago spp, Gareinia cambogia, entre otras) y constituyentes vegetales (derivados azufrados del ajo, lecitina de soja, fitosteroles, berberina, distintos derivados polifenólicos, etc.). A la vista del interés de estos productos naturales, es fácil concluir que el mundo vegetal es una fuente de remedios en el tratamiento y prevención de las hiperlipidemias y sus graves secuelas

Hyperlipidemias constitute one of the main risk factors for the cardiovascular diseases at the developed societies. The need of active agents against the alterations of the lipid profile, has lead to the search of natural products with activity on elevated lipid levels. Thanks to these studies, the antihyperlipidemic activity of several medicinal plants (Camelia thea, Glycine maz, Plantago spp, Garcinia cambogia, among others) and plant constituents (i.e: sulphur containing derivates of garlic, soybean lecitine, phytoesterols, berberine, several polyphenol derivates, etc., has been well stablished. By regarding the interest of this natural products, it is easy to conclude that the plant kingdom is a useful source of therapeutic agent for the treatment and prevention of hypercholesterolemia and its serious sequelae consequences

[Guidelines of lipid therapy translation into clinical practice]. / Leitlinien der Lipidtherapie Umsetzung im Praxisalltag.

Alterations in lipid metabolism play a major role in the pathogenesis of atherosclerosis and are an important risk factor for cardiovascular events. Lowering of LDL cholesterol by statins reduces morbidity and mortality in patients with coronary artery disease (CAD), both in primary and secondary prevention. The results of large controlled trials that included more than 50,000 patients are the basis for target values promoted by current guidelines. According to the NCEP-ATP III guidelines LDL cholesterol should be lowered to less than 100 mg/dl in high risk patients (CAD or CAD equivalent) and in very high risk patients optional to less than 70 mg/dl. Up to now even in high risk patients the recommended goals are not sufficiently achieved: Up to 80% of high risk patients do not receive a statin and only a minority of those being treated with a statin have a LDL cholesterol below 100 mg/dl. Furthermore, after a major event (e.g. myocardial infarction) the quality of lipid reduction decreases over time. Further efforts are required to improve this situation as a guide-line oriented approach may help to prevent up to 100,000 myocardial infarctions and deaths alone in high risk patients in Germany.

[Optimization of cholesterol reduction principles and clinical results of dual inhibition]. / Optimierte Cholesterinsenkung. Prinzip und klinische Resultate der dualen Hemmung.

Ezetimibe is a recently developed compound, which inhibits intestinal cholesterol absorption. Because there are hints for an increase of cholesterol absorption during statin therapy, the combination of Ezetimibe with a statin seems to be appropriate. This dual approach -- inhibition of intestinal cholesterol absorption and hepatic cholesterol synthesis -- offers a very potent reduction of cholesterol. The combination of statins with Ezetimibe leads to a further reduction of LDL-cholesterol up to 12-21%. The dual inhibition causes a more effective reduction of LDL-cholesterol than a statin monotherapy. LDL treatment goals can be reached more easily, and possible side effects of otherwise necessary high doses of statins can be avoided. Clinical endpoint studies with Ezetimibe are underway.

Theoretical exposure of chronically treated patients to lipid lowering agents.

PURPOSE: The objective was to analyse the exposure to lipid lowering agents (LLA) using the databases of health insurance companies and to appraise its concordance with the findings of evidence based medicine. METHODS: Three health insurance companies' prescription based databases were analysed in the years 1997-2000. All inhabitants in the Czech Republic (CR) have to be insured. The insured person with a recorded prescription for LLA in the year of interest was defined as a patient, the insured person with a recorded prescription for LLA in the years bordering the year of interest was defined as a chronically treated patient. In the year of interest the percentage of chronically treated patients without LLA medication, with 'very low' (<122 defined daily doses (DDD)/year), 'low' (122-243 DDD/year) and 'adequate' (>243 DDD/year) consumption was determined. RESULTS: During the observed period the total consumption of LLA increased among 450 000 inhabitants twice (by 109.6%) to 24.8 DDD/1000 inhabitants/day. In 2000 the rate of the consumption of statins and fibrates represented 34.2 and 65.6% respectively. In 1998 33.5% and in 1999 41.0% of the chronically treated patients occurred in the 'adequate' consumption group. CONCLUSIONS: The signals of inappropriate drug treatment such as the preferred use of fibrates and low doses of LLA prescribed to the Czech population were identified. Conversely, the increasing proportion of the chronically treated patients belonging to the group with the 'adequate' consumption could be considered as a positive signal.