Lipid clinic experience with bempedoic acid in three UK centres.

OBJECTIVE: Novel lipid-lowering therapies are being introduced. Few studies exist of the real-world effectiveness of adenosine-tri-phosphate citrate lyase inhibition with bempedoic acid. METHODS: This study audited bempedoic acid therapy in 216 consecutive patients from three hospital centres - a university hospital (n = 77) and two district general hospitals (n = 106 and 33). Cardiovascular disease (CVD) risk factors, prescription qualification criteria, efficacy and adverse effects were assessed. RESULTS: The population was aged 65.9 ± 11.0 years, 42% were male, 25% had type 2 diabetes, and 31% had familial hypercholesterolaemia. CVD was present in 19% and multibed vascular disease in 8%. Statin intolerance was reported in 92%. Bempedoic acid reduced total cholesterol by 1.58 ± 1.44 mmol/L (20%), LDL-C by 1.37 ± 1.31 mmol/L (27%), triglycerides by 0.22 mmol/L (2%) with an 0.06 mmol/L (1%) increase in HDL-C after 22 ± 9 months follow-up. An LDL-C <2.5 mmol/L was achieved in 40% and <2 mmol/L in 20%. Efficacy (r2 = .33) was predicted by baseline LDL-C (ß = .54; p <.001). No significant changes were seen in transaminases, creatinine, creatine kinase, urate or HbA1c. Treatment was discontinued by 33% of patients and occurred due to myalgia (43%), lack of efficacy (16%) and gastrointestinal adverse effects (15%). No cases of gout were observed. In a logistic regression only the number of previous drug classes not tolerated (ß = 1.60; p = .009) was a contributing factor to discontinuation. CONCLUSION: This audit suggests that bempedoic acid therapy is effective but that adverse effects and discontinuation are common. This suggests nocebo effects might be generalizable to all lipid-lowering drug therapies in susceptible individuals.

Validation of the familial chylomicronaemia syndrome (FCS) score in an ethnically diverse cohort from UK FCS registry: Implications for diagnosis and differentiation from multifactorial chylomicronaemia syndrome (MCS).

BACKGROUND AND AIMS: Prognosis and management differ between familial chylomicronaemia syndrome (FCS), a rare autosomal recessive disorder, and multifactorial chylomicronaemia syndrome (MCS) or severe mixed hyperlipidaemia. A clinical scoring tool to differentiate these conditions has been devised but not been validated in other populations. The objective of this study was to validate this score in the UK population and identify any additional factors that might improve it. METHODS: A retrospective validation study was conducted using data from 151 patients comprising 75 FCS and 76 MCS patients. All participants had undergone genetic testing for genes implicated in FCS. Validation was performed by standard methods. Additional variables were identified from clinical data by logistic regression analysis. RESULTS: At the recommended FCS score threshold ≥10 points, the sensitivity and specificity of the score in the UK population were 96% and 75%, respectively. The receiver operating characteristic (ROC) curve analysis yielded an area under the curve (AUC) of 0.88 (95% CI 0.83-0.94, p < 0.001). This study identified non-European (predominantly South Asian) ethnicity, parental consanguinity, body mass index (BMI) < 25 kg/m2, and recurrent pancreatitis as additional positive predictors, while BMI >30 kg/m2 was found to be a negative predictor for FCS. However, inclusion of additional FCS predictors had no significant impact on performance of standard FCS score. CONCLUSIONS: Our study validates the FCS score in the UK population to distinguish FCS from MCS. While additional FCS predictors were identified, they did not improve further the score diagnostic performance.

Preventive cardiology for the aging population: how can we better design clinical trials of statins?

INTRODUCTION: Older adults form a fast-increasing proportion of the world population. However, gains in increasing quantity of life have not been accompanied by similar gains in quality of life. Older people frequently experience frailty, memory problems, and chronic diseases including cardiovascular disease (CVD) and neurodegenerative diseases. Recent trials have demonstrated the efficacy of anti-hypertensive therapy in older populations but failed to show benefits for aspirin. AREA COVERED: Statins clearly reduce CVD events in middle-aged populations. There seems to be evidence that the effect is similar in primary prevention older populations based on meta-analyses mainly from sub-groups in large trials, but this becomes less clear with increasing age. However, given differences in drug metabolism and possibly efficacy, competing co-morbidities, their effects on mortality, disability, and dementia in this age group remain to be determined. EXPERT OPINION: Two large trials are now underway to clarify the role of statin therapy in people aged over 70 years using endpoints of mortality, disability, and neurocognitive endpoints as well as standard cardiovascular disease outcomes. They may provide also provide more evidence on how to approach the over 80 year age group.

Assessment of ethnic inequalities in diagnostic coding of familial hypercholesterolaemia (FH): A cross-sectional database study in Lambeth, South London.

BACKGROUND AND AIMS: Differences in the perceived prevalence of familial hypercholesterolemia (FH) by ethnicity are unclear. In this study, we aimed to assess the prevalence, determinants and management of diagnostically-coded FH in an ethnically diverse population in South London. METHODS: A cross-sectional analysis of 40 practices in 332,357 adult patients in Lambeth was undertaken. Factors affecting a (clinically coded) diagnosis of FH were investigated by multi-level logistic regression adjusted for socio-demographic and lifestyle factors, co-morbidities, and medications. RESULTS: The age-adjusted FH % prevalence rate (OR, 95%CI) ranged from 0.10 to 1.11, 0.00-1.31. Lower rates of FH coding were associated with age (0.96, 0.96-0.97) and male gender (0.75, 0.65-0.87), p < 0.001. Compared to a White British reference group, a higher likelihood of coded FH was noted in Other Asians (1.33, 1.01-1.76), p = 0.05, with lower rates in Black Africans (0.50, 0.37-0.68), p < 0.001, Indians (0.55, 0.34-0.89) p = 0.02, and in Black Caribbeans (0.60, 0.44-0.81), p = 0.001. The overall prevalence using Simon Broome criteria was 0.1%; we were unable to provide ethnic specific estimates due to low numbers. Lower likelihoods of FH coding (OR, 95%CI) were seen in non-native English speakers (0.66, 0.53-0.81), most deprived income quintile (0.68, 0.52-0.88), smokers (0.68,0.55-0.85), hypertension (0.62, 0.52-0.74), chronic kidney disease (0.64, 0.41-0.99), obesity (0.80, 0.67-0.95), diabetes (0.31, 0.25-0.39) and CVD (0.47, 0.36-0.63). 20% of FH coded patients were not prescribed lipid-lowering medications, p < 0.001. CONCLUSIONS: Inequalities in diagnostic coding of FH patients exist. Lower likelihoods of diagnosed FH were seen in Black African, Black Caribbean and Indian ethnic groups, in contrast to higher diagnoses in White and Other Asian ethnic groups. Hypercholesterolaemia requiring statin therapy was associated with FH diagnosis, however, the presence of cardiovascular disease (CVD) risk factors lowered the diagnosis rate for FH.

Determinants of lipid clinic referral and attendance in a multi-ethnic adult population in south London: a cross-sectional study.

BACKGROUND: Primary dyslipidaemias, including familial hypercholesterolaemia, are underdiagnosed genetic disorders that substantially increase risk for premature coronary artery disease in adults. Early identification of primary dyslipidaemias via lipid clinic referral optimises patient management and enables cascade screening of relatives. Improving the identification of primary dyslipidaemias, and understanding disparities in ascertainment and management, is an NHS priority. We aimed to assess determinants of lipid clinic referral or attendance (LCR) in ethnically diverse adults. METHODS: We did a retrospective cross-sectional study using the Lambeth DataNet containing anonymised data from 41 general practitioner (GP) practices in south London. We looked at referral data for adult patients aged 18 years and older from Jan 1, 1995, until May 14, 2018. LCR was the main outcome. We used sequential multilevel logistic regression models adjusted for practice effects to estimate the odds of LCR assessed across six ethnic groups (reference group White) and patient-level factors (demographic, socioeconomic, lifestyle, comorbidities, total cholesterol [TC] >7·5mmol/L, statin prescription, and practice factors). The study was approved by NHS South East London Clinical Commissioning Group (CCG) and NHS Lambeth CCG. FINDINGS: 780 (0·23%) of 332 357 adult patients were coded as referred (n=538) or seen (n=252) in a lipid clinic. 164 487 (46·49%) were women (appendix). The fully adjusted model for odds of LCR showed the following significant associations for age (odds ratio [OR] 0·96, 95% CI 0·96-0·97, p<0·001); Black, African, Caribbean, or Black-British ethnicity (0·67, 0·53-0·84, p=0·001); ex-smoker status (1·29, 1·05-1·57, p=0·014); TC higher than 7·5 mmol/L (12·18, 9·60-15·45, p<0·001); statin prescription (14·01, 10·85-18·10, p<0·001); diabetes (0·72, 0·58-0·91, p=0·005); high-frequency GP attendance at seven or more GP consultations in the past year (1·49, 1·21-1·84, p<0·001); high GP-density (0·5-0·99 full-time equivalent GPs per 1000 patients; 2·70, 1·23-5·92, p=0·013). Sensitivity analyses for LCR restricted to familial hypercholesterolaemia-coded patients (n=581) found associations with TC higher than 7·5 mmol/L (4·26, 1·89-9·62, p<0·001), statin prescription (16·96, 2·19-131·36, p=0·007), and high GP-density (5·73, 1·27-25·93, p=0·023), with no significant associations with ethnicity. The relative contribution of GP practices to LCR was 6·32% of the total variance. There were no significant interactions between ethnicity and deprivation, age, or obesity. INTERPRETATION: While interpretation is limited by the accuracy and completeness of coded records, the study showed factors associated with a higher likelihood of LCR included individuals recorded as having TC higher than 7·5 mmol/L, statin prescription, ex-smoker status, high-frequency GP attendance, and registration at a GP practice with 0·5-0·99 GP density. Patients with increasing age; Black, African, Caribbean, or Black-British ethnicity patients; and patients with diabetes had lower odds of LCR. Finally, the difference in odds of LCR between Black and White patients highlights potential health inequalities. FUNDING: NHS Race & Health Observatory.

Severe Hypertriglyceridaemia and Chylomicronaemia Syndrome-Causes, Clinical Presentation, and Therapeutic Options.

We have reviewed the genetic basis of chylomicronaemia, the difference between monogenic and polygenic hypertriglyceridaemia, its effects on pancreatic, cardiovascular, and microvascular complications, and current and potential future pharmacotherapies. Severe hypertriglyceridaemia (TG > 10 mmol/L or 1000 mg/dL) is rare with a prevalence of <1%. It has a complex genetic basis. In some individuals, the inheritance of a single rare variant with a large effect size leads to severe hypertriglyceridaemia and fasting chylomicronaemia of monogenic origin, termed as familial chylomicronaemia syndrome (FCS). Alternatively, the accumulation of multiple low-effect variants causes polygenic hypertriglyceridaemia, which increases the tendency to develop fasting chylomicronaemia in presence of acquired factors, termed as multifactorial chylomicronaemia syndrome (MCS). FCS is an autosomal recessive disease characterized by a pathogenic variant of the lipoprotein lipase (LPL) gene or one of its regulators. The risk of pancreatic complications and associated morbidity and mortality are higher in FCS than in MCS. FCS has a more favourable cardiometabolic profile and a low prevalence of atherosclerotic cardiovascular disease (ASCVD) compared to MCS. The cornerstone of the management of severe hypertriglyceridaemia is a very-low-fat diet. FCS does not respond to traditional lipid-lowering therapies. Several novel pharmacotherapeutic agents are in various phases of development. Data on the correlation between genotype and phenotype in FCS are scarce. Further research to investigate the impact of individual gene variants on the natural history of the disease, and its link with ASCVD, microvascular disease, and acute or recurrent pancreatitis, is warranted. Volanesorsen reduces triglyceride concentration and frequency of pancreatitis effectively in patients with FCS and MCS. Several other therapeutic agents are in development. Understanding the natural history of FCS and MCS is necessary to rationalise healthcare resources and decide when to deploy these high-cost low-volume therapeutic agents.

Long-term effects of volanesorsen on triglycerides and pancreatitis in patients with familial chylomicronaemia syndrome (FCS) in the UK Early Access to Medicines Scheme (EAMS).

BACKGROUND AND AIMS: The VOL4002 study assessed the efficacy and safety of volanesorsen in 22 adults with genetically confirmed familial chylomicronaemia syndrome (FCS) treated in the UK Early Access to Medicines Scheme (EAMS), with ("prior exposure") or without ("treatment naive") previous treatment in the APPROACH and/or APPROACH-OLE volanesorsen phase 3 studies. METHODS: Data collection focused on triglyceride (TG) levels, platelet counts and pancreatitis events. Pancreatitis incidence during volanesorsen treatment was compared against the 5-year period preceding volanesorsen exposure. Volanesorsen 285 mg was self-administered subcutaneously once every 2 weeks. RESULTS: Individual patient volanesorsen exposure ranged from 6 to 51 months (total cumulative exposure, 589 months). Among treatment-naive patients (n = 12), volanesorsen treatment resulted in an averaged median 52% reduction (-10.6 mmol/L) from baseline (26.4 mmol/L) in TG levels at 3 months, which were maintained through time points over 15 months of treatment (47%-55% reductions). Similarly, prior-exposure patients (n = 10) experienced a 51% reduction (-17.8 mmol/L) from pre-treatment baseline (28.0 mmol/L), with reductions of 10%-38% over 21 months of treatment. A comparison of pancreatitis event rates found a 74% reduction from the 5-year period before (one event/2.8 years) and during (one event/11.0 years) volanesorsen treatment. Platelet declines were consistent with observations in phase 3 clinical trials. No patient recorded a platelet count <50 × 109/L. CONCLUSIONS: This longitudinal study supports the efficacy of volanesorsen in patients with FCS for lowering TG levels over treatment periods up to 51 months with no apparent safety signals related to increased duration of exposure.

Colesevelam - a bile acid sequestrant for treating hypercholesterolemia and improving hyperglycemia.

INTRODUCTION: Low density Lipoprotein cholesterol)LDL-C) levels show a clear relationship with cardiovascular disease (CVD). Statins are first line agents to reduce LDL-C and CVD risk. However, combination lipid-lowering therapy is often required to achieve large reductions in LDL-C. AREA COVERED: Colesevelam HCl is a bile acid sequestrant (BAS), which reduces LDL-C by 16-22% in monotherapy and adds a further 12-14% reduction in LDL-C when combined with other lipid-lowering drugs. Like statins, colesevelam reduces C-reactive protein levels by 16% in monotherapy and additional 6% when added to statins. Colesevelam also reduced HbA1c by 4 mmol/mol (0.5%) when used alone and added to other hypoglycemic drugs in studies of patients with diabetes . EXPERT OPINION: Bile acid sequestrants reduce LDL-C and HbA1c and have some CVD outcome evidence. The uses of these agents are limited in patients with gastrointestinal disease or high triglycerides due to adverse effects on gut function and raising triglycerides and they interfere with the absorption of lipid-soluble drugs. Colesevelam has a higher bile acid binding capacity, and fewer adverse effects than other BAS. Colesevelam may be useful as a third line agent for treatment of hypercholesterolemia with some additional specific benefits on glycemic control.

Hypertriglyceridaemia: an update.

Triglycerides (TGs) form part of the standard lipid profile. Elevations in TGs are associated with increased cardiovascular disease risk through triglyceride-rich lipoprotein particles found as part of non-HDL cholesterol. Many elevations of TGs are secondary to other causes, but primary hypertriglyceridaemia syndromes need to be identified. The genetic causes of hypertriglyceridaemia range from familial combined hyperlipidaemia through the autosomal recessive remnant hyperlipidaemia (related to apolipoprotein E variants) and familial chylomicronaemia syndromes. Patients with primary hypertriglyceridaemia >10 mmol/L require characterisation and specific intervention. Simple lipid profiles do not provide adequate information for detailed diagnosis and additional assays such as apolipoprotein (apo)B100, apoE genotype and next-generation sequencing may be useful. Management of raised TGs includes optimising diet, reducing exacerbating factors as well as lipid-lowering medications such as statins, fibrates, niacin and omega-3 fatty acids. Novel medications for orphan disease indications such as familial chylomicronaemia syndrome include volanesorsen, evinacumab and other antisense therapeutics. Extreme hypertriglyceridaemia syndromes, especially chylomicronaemia syndromes, which can be exposed by pregnancy or other factors are a medical emergency and require admission and specialist management sometimes including plasma exchange.

Lipidomics in diabetes.

PURPOSE OF REVIEW: Multiple studies have shown a strong association between lipids and diabetes. These are usually described through the effects of cholesterol content of lipid particles and in particular low-density lipoprotein. However, lipoprotein particles contain other components, such as phospholipids and more complex lipid species, such as ceramides and sphingolipids. Ceramides, such as sphingolipids are also produced intracellularly and have signalling actions in regulating cell metabolism including effects on inflammation, and potentially have a mechanistic role in the development of insulin resistance. RECENT FINDINGS: Recently, techniques have been developed to analyse detailed molecular profiles of lipid particles - lipidomics. Proteomics has confirmed the different proteins associated with different particles but far less is known about the relationship of individual lipid species with diabetes and cardiovascular risk. A number of studies have now shown that the plasma lipidome, and in particular, ceramides and sphingolipids may predict the development of diabetes. SUMMARY: Lipidomics had identified ceramides and sphingolipids as potential mediators of cellular dysfunction in diabetes. Further work is required to ascertain whether they have clinical utility.

Elevated Lipoprotein(a): Background, Current Insights and Future Potential Therapies.

Lipoprotein(a) forms a subfraction of the lipid profile and is characterized by the addition of apolipprotein(a) (apo(a)) to apoB100 derived particles. Its levels are mostly genetically determined inversely related to the number of protein domain (kringle) repeats in apo(a). In epidemiological studies, it shows consistent association with cardiovascular disease (CVD) and most recently with extent of aortic stenosis. Issues with standardizing the measurement of Lp(a) are being resolved and consensus statements favor its measurement in patients at high risk of, or with family histories of CVD events. Major lipid-lowering therapies such as statin, fibrates, and ezetimibe have little effect on Lp(a) levels. Therapies such as niacin or cholesterol ester transfer protein (CETP) inhibitors lower Lp(a) as well as reducing other lipid-related risk factors but have failed to clearly reduce CVD events. Proprotein convertase subtilisin kexin-9 (PCSK9) inhibitors reduce cholesterol and Lp(a) as well as reducing CVD events. New antisense therapies specifically targeting apo(a) and hence Lp(a) have greater and more specific effects and will help clarify the extent to which intervention in Lp(a) levels will reduce CVD events.

Screening for patients with Gaucher's disease using routine pathology results: PATHFINDER (ferritin, alkaline phosphatase, platelets) study.

AIMS: Lysosomal ß-glucocerebrosidase A (GBA) deficiency causes Gaucher disease (GD), a recessive disorder caused by bi-allelic mutations in GBA. The prevalence of GD is associated with ethnicity but largely unknown and potentially underestimated in many countries. GD may manifest with organomegaly, bone involvement, and neurological symptoms as well as abnormal laboratory biomarkers. This study attempted to screen for GD in patients using abnormal platelet, alkaline phosphatase (ALP), and ferritin results from laboratory databases. METHODS: Electronic laboratory databases were interrogated using a 2- to 4-year time interval to identify from clinical biochemistry records patients with a phenotype of reduced platelets (<150 × 109 /L) and either elevated ALP (>130 iu/L) or ferritin [>150 (female) or >250 µg/L (male)]. The mean value over the screening window was used to reduce variability in results. A dried blood spot sample was collected for the determination of GBA activity in patients meeting these criteria. If low GBA activity was found, then the concentration of the GD-specific biomarker glucosyl-sphingosine (lyso-GB1) was assayed, and the GBA gene sequenced. RESULTS: Samples were obtained from 1058 patients; 232 patients had low GBA activity triggering further analysis. No new cases of GD with homozygosity for pathogenic variants were identified, but 12 patients (1%) were identified to be carriers of a pathogenic variant in GBA. CONCLUSIONS: Pathology databases hold routine information that can be used to screen for patients with inherited errors of metabolism. However, biochemical screening using mean platelets, ALP, and ferritin has a low yield for unidentified cases of GD.

Triglycerides and cardiovascular disease.

PURPOSE OF REVIEW: Triglycerides (TGs) are measured as part of routine lipid profiles but their relationship to cardiovascular disease (CVD) risk has been controversial and overshadowed by high-density lipoprotein cholesterol (HDL-C). RECENT FINDINGS: Epidemiological studies show a clear relationship of TG-containing lipoproteins including remnant particles with CVD risk with the effect being most clearly demonstrated through the excess risk captured by non-HDL-C compared with low-density lipoprotein-cholesterol (LDL-C). Mendelian randomisation studies show a consistent relationship of gene variants linked to TG metabolism with rates of CVD. Furthermore, meta-analyses of intervention trials with statins and other nonstatin drugs also suggest that reducing TGs is associated with benefits on rates of CVD events. Historical subgroup data from fibrate trials suggest benefits in patients with high TG:HDL ratios but seem to add little to optimized statin therapy. Recent trials with omega-3 fatty acids (specifically eicosapentaenoic acid) have suggested that high-dose formulations in contrast to low dose formulations have benefits on CVD outcomes. SUMMARY: Further studies with newer agents are required to determine the place of TG-lowering drugs in therapeutic pathways. Trials with agents such as pemafibrate and vupanorsen may finally answer these questions.

Impact of Therapeutic Inertia on Long-Term Blood Pressure Control: A Monte Carlo Simulation Study.

[Figure: see text].

Identification of patients with Fabry disease using routine pathology results: PATHFINDER (eGFR) study.

AIMS: Lysosomal α-galactosidase A deficiency (Fabry disease (FD)) was considered an X-linked recessive disorder but is now viewed as a variable penetrance dominant trait. The prevalence of FD is 1 in 40 000-117 000 but the ascertainment of late-onset cases and degree of female penetrance makes this unclear. Its prevalence in the general population, especially in patients with abnormal renal function is unclear. This study attempted to identify the prevalence of FD in patients with abnormal renal function results from laboratory databases. METHODS: Electronic laboratory databases were interrogated to identify from clinical biochemistry records patients with a phenotype of reduced estimated glomerular filtration rate categorised by age on one occasion or more over a 3-year time interval. Patients were recalled and a dried blood spot sample was collected for the determination of α-galactosidase A activity by fluorimetric enzyme assay in men and mass spectrometry assays of α-galactosidase A and lyso-globotriaosylceramide (lyso-GL-3) concentrations in women. RESULTS: Samples were obtained from 1084 patients identified with reduced renal function. No cases of FD were identified in 505 men. From 579 women, one subject with reduced α-galactosidase activity (1.5 µmol/L/h) and increased Lyso-GL-3 (5.5 ng/mL) was identified and shown to be heterozygous for a likely FD pathogenic variant (GLA c.898C>T; p.L300F; Leu300Phe). It was later confirmed that she was a relative of a known affected patient. CONCLUSIONS: Pathology databases hold routine information that can be used to identify patients with inherited errors of metabolism. Biochemical screening using reduced eGFR alone has a low yield for unidentified cases of Fabry Disease.

Options for the diagnosis of high blood pressure in primary care: a systematic review and economic model.

The 2011 NICE hypertension guideline (CG127) undertook a systematic review of the diagnostic accuracy of different blood pressure (BP) assessment methods to confirm the diagnosis of hypertension. The guideline also undertook a cost-utility analysis exploring the cost-effectiveness of the monitoring methods. A new systematic review was undertaken as part of the 2019 NICE hypertension guideline update (NG136). BP monitoring methods compared included Ambulatory BP, Clinic BP and Home BP. Ambulatory BP was the reference standard. The economic model from the 2011 guideline was updated with this new accuracy data. Home BP was more sensitive and specific than Clinic BP. Specificity improved more than sensitivity since the 2011 review. A higher specificity translates into fewer people requiring unnecessary treatment. A key interest was to compare Home BP and Ambulatory BP, and whether any improvement in Home BP accuracy would change the model results. Ambulatory BP remained the most cost-effective option in all age and sex subgroups. In all subgroups, Ambulatory BP was associated with lower costs than Clinic BP and Home BP. In all except one subgroup (females aged 40), Ambulatory BP was dominant. However, Ambulatory BP remained the most cost-effective option in 40-year-old females as the incremental cost-effectiveness ratio for Home BP versus Ambulatory BP was above the NICE £20,000 threshold. The new systematic review showed that the accuracy of both Clinic BP and Home BP has increased. However, Ambulatory BP remains the most cost-effective option to confirm a diagnosis of hypertension in all subgroups evaluated.

Cost-Effectiveness of Initiating Pharmacological Treatment in Stage One Hypertension Based on 10-Year Cardiovascular Disease Risk: A Markov Modeling Study.

Antihypertensive drug treatment is cost-effective for adults at high risk of developing cardiovascular disease (CVD). However, the cost-effectiveness in people with stage 1 hypertension (140-159 mm Hg systolic blood pressure) at lower CVD risk remains unclear. The objective was to establish the 10-year CVD risk threshold where initiating antihypertensive drug treatment for primary prevention in adults, with stage 1 hypertension, becomes cost-effective. A lifetime horizon Markov model compared antihypertensive drug versus no treatment, using a UK National Health Service perspective. Analyses were conducted for groups ranging between 5% and 20% 10-year CVD risk. Health states included no CVD event, CVD and non-CVD death, and 6 nonfatal CVD morbidities. Interventions were compared using cost-per-quality-adjusted life-years. The base-case age was 60, with analyses repeated between ages 40 and 75. The model was run separately for men and women, and threshold CVD risk assessed against the minimum plausible risk for each group. Treatment was cost-effective at 10% CVD risk for both sexes (incremental cost-effectiveness ratio £10 017/quality-adjusted life-year [$14 542] men, £8635/QALY [$12 536] women) in the base-case. The result was robust in probabilistic and deterministic sensitivity analyses but was sensitive to treatment effects. Treatment was cost-effective for men regardless of age and women aged >60. Initiating treatment in stage 1 hypertension for people aged 60 is cost-effective regardless of 10-year CVD risk. For other age groups, it is also cost-effective to treat regardless of risk, except in younger women.