PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review.
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ABSTRACT:
SUBMITTER: Handelsman Y
PROVIDER: S-EPMC6064883 | biostudies-literature | 2018 Jun
REPOSITORIES: biostudies-literature
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PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review.
Handelsman Yehuda Y Lepor Norman E NE
Journal of the American Heart Association 20180622 13
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Project description:Type 2 diabetes mellitus (T2DM) is commonly accompanied by other cardiovascular disease (CVD) risk factors, such as hypertension, obesity, and dyslipidemia. Furthermore, CVD is the most common cause of death in people with T2DM. It is therefore of critical importance to minimize the risk of macrovascular complications by carefully managing modifiable CVD risk factors in patients with T2DM. Therapeutic strategies should include lifestyle and pharmacological interventions targeting hyperglycemia, hypertension, dyslipidemia, obesity, cigarette smoking, physical inactivity, and prothrombotic factors. This article discusses the impact of modifying these CVD risk factors in the context of T2DM; the clinical evidence is summarized, and current guidelines are also discussed. The cardiovascular benefits of smoking cessation, increasing physical activity, and reducing low-density lipoprotein cholesterol and blood pressure are well established. For aspirin therapy, any cardiovascular benefits must be balanced against the associated bleeding risk, with current evidence supporting this strategy only in certain patients who are at increased CVD risk. Although overweight, obesity, and hyperglycemia are clearly associated with increased cardiovascular risk, the effect of their modification on this risk is less well defined by available clinical trial evidence. However, for glucose-lowering drugs, further evidence is expected from several ongoing cardiovascular outcome trials. Taken together, the evidence highlights the value of early intervention and targeting multiple risk factors with both lifestyle and pharmacological strategies to give the best chance of reducing macrovascular complications in the long term.
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Project description:Treatment intended to lower cardiovascular (CV) risk in patients with diabetes has always been a primary goal of diabetes treatment. Due to the subdued effects of reducing hemoglobin A1c (HbA1c) on macrovascular complications, controlling other CV risk factors such as hypertension and hyperlipidemia instead of hyperglycemia has been the mainstay treatment to improve CV outcome in patients with type 2 diabetes mellitus (T2DM) until recent years. This review is intended to summarize and compare the results from the available cardiovascular outcome trials (CVOTs) for the two classes of glucose lowering drug: sodium-glucose co-transporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1 RA). The results including the EMPA-REG, CANVAS program and DECLARE-TIMI 58 trials for SGLT2i, and the ELIXA, LEADER, SUSTAIN-6, EXSCEL and HARMONY trials for GLP-1 RA were summarized. The potential mechanisms of these CV beneficial effects and the optimal CV risk reduction treatment in patients with T2DM based on patient risk stratification and evidence from these CVOTs in real-world setting were discussed.
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Project description:INTRODUCTION: To develop and test a diabetes risk score to predict incident diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk. MATERIALS AND METHODS: A diabetes risk score was derived from a subset of 1381 nondiabetic individuals from three centres of the PREDIMED study (derivation sample). Multivariate Cox regression model ß-coefficients were used to weigh each risk factor. PREDIMED-personal Score included body-mass-index, smoking status, family history of type 2 diabetes, alcohol consumption and hypertension as categorical variables; PREDIMED-clinical Score included also high blood glucose. We tested the predictive capability of these scores in the DE-PLAN-CAT cohort (validation sample). The discrimination of Finnish Diabetes Risk Score (FINDRISC), German Diabetes Risk Score (GDRS) and our scores was assessed with the area under curve (AUC). RESULTS: The PREDIMED-clinical Score varied from 0 to 14 points. In the subset of the PREDIMED study, 155 individuals developed diabetes during the 4.75-years follow-up. The PREDIMED-clinical score at a cutoff of ≥6 had sensitivity of 72.2%, and specificity of 72.5%, whereas AUC was 0.78. The AUC of the PREDIMED-clinical Score was 0.66 in the validation sample (sensitivity = 85.4%; specificity = 26.6%), and was significantly higher than the FINDRISC and the GDRS in both the derivation and validation samples. DISCUSSION: We identified classical risk factors for diabetes and developed the PREDIMED-clinical Score to determine those individuals at high risk of developing diabetes in elderly individuals at high cardiovascular risk. The predictive capability of the PREDIMED-clinical Score was significantly higher than the FINDRISC and GDRS, and also used fewer items in the questionnaire.
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Project description:BackgroundThere have been scarce data comparing cardiovascular outcomes between individual sodium-glucose cotransporter-2 (SGLT2) inhibitors. We aimed to compare the subsequent cardiovascular risk between individual SGLT2 inhibitors.MethodsWe analyzed 25,315 patients with diabetes mellitus (DM) newly taking SGLT2 inhibitors (empagliflozin: 5302, dapagliflozin: 4681, canagliflozin: 4411, other SGLT2 inhibitors: 10,921). We compared the risks of developing heart failure (HF), myocardial infarction (MI), angina pectoris (AP), stroke, and atrial fibrillation (AF) between individual SGLT2 inhibitors.ResultsMedian age was 52 years, and 82.5% were men. The median fasting plasma glucose and HbA1c levels were 149 (Q1-Q3:127-182) mg/dL and 7.5 (Q1-Q3:6.9-8.6) %. During a mean follow-up of 814 ± 591 days, 855 HF, 143 MI, 815 AP, 340 stroke, and 139 AF events were recorded. Compared with empagliflozin, the risk of developing HF, MI, AP, stroke, and AF was not significantly different in dapagliflozin, canagliflozin, and other SGLT inhibitors. For developing HF, compared with empagliflozin, hazard ratios of dapagliflozin, canagliflozin, and other SGLT2 inhibitors were 1.02 (95% confidence interval [CI] 0.81-1.27), 1.08 (95% CI 0.87-1.35), and 0.88 (95% CI 0.73-1.07), respectively. Wald tests showed that there was no significant difference in the risk of developing HF, MI, AP, stroke, and AF among individual SGLT2 inhibitors. We confirmed the robustness of these results through a multitude of sensitivity analyses.ConclusionThe risks for subsequent development of HF, MI, AP, stroke, and AF were comparable between individual SGLT2 inhibitors. This is the first study comparing the wide-range cardiovascular outcomes of patients with DM treated with individual SGLT2 inhibitors using large-scale real-world data.
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Project description:Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) remains the cornerstone in the primary and secondary prevention of cardiovascular disease. However, lack of efficacy and adverse effects mean that a substantial proportion of patients fail to achieve acceptable LDL-C levels with currently available lipid-lowering drugs. Over the last decade, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic strategy to reduce residual cardiovascular disease risk. Binding of PCSK9 to the LDL receptor targets the receptor for lysosomal degradation. The recognition that inhibition of PCSK9 increases LDL receptor activity has led to the development of a number of approaches to directly target PCSK9. Numerous monoclonal antibodies against PCSK9 are currently being evaluated in phase 3 trials, involving various patient categories on different background lipid-lowering therapies. Current evidence shows reductions in LDL-C levels of up to 70 % may be achieved with PCSK9 inhibition, independent of background statin therapy. This review examines the most recent evidence and future prospects for the use of PCSK9 inhibitors in the prevention of cardiovascular disease.
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Project description:The purpose of this study is to describe lipid-lowering therapy (LLT) prescriptions and low-density lipoprotein cholesterol (LDL-C) monitoring in patients with diabetes mellitus (DM) with or without concomitant cardiovascular disease (CVD). Olmsted County, Minnesota residents with a first-ever diagnosis of DM or CVD (ischemic stroke/transient ischemic attack, myocardial infarction, unstable angina pectoris, or revascularization procedure) between 2005 and 2012 were classified as having DM only, CVD only, or CVD + DM. All LLT prescriptions and LDL-C measurements were obtained for 2 years after diagnosis. A total of 4,186, 2,368, and 724 patients had DM, CVD, and CVD + DM, respectively. Rates of LDL-C measurement were 1.31, 1.66, and 1.88 per person-year and 14%, 32%, and 42% of LDL-C measurements were <70 mg/dl in those with DM, CVD, and CVD + DM. Within 3 months after diagnosis, 47%, 71%, and 78% of patients with DM, CVD, and CVD + DM were prescribed LLT. Most prescriptions were for moderate-intensity statins. Under one-fifth of patients with CVD and CVD + DM were prescribed high-intensity statins. Predictors of high-intensity statin prescriptions included male sex, having CVD or CVD + DM, increasing LDL-C, and LDL-C measured more recently (2012 to 2014 vs before 2012). In conclusion, a large proportion of patients at high CVD risk are not adequately treated with LLT. Despite often being considered a risk equivalent, patients with DM have substantially lower rates of LLT prescriptions and lesser controlled LDL-C than those with CVD or CVD + DM.
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