John Betteridge

Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial

BACKGROUND Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. METHODS We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. FINDINGS Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. INTERPRETATION Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.

Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study.

Aims To examine the changes in coronary, all-cause, and cancer mortality in patients with heterozygous familial hypercholesterolaemia (FH) before and after lipid-lowering therapy with statins. Methods and results A total of 3382 patients (1650 men) aged <80 years were recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2006 for 46 580 person-years. There were 370 deaths, including 190 from coronary heart disease (CHD) and 90 from cancer. The standardized mortality ratio (compared with the population in England and Wales) was calculated before and from 1 January 1992. In patients aged 20–79 years, CHD mortality fell significantly by 37% (95% CI = 7–56) from 3.4- to 2.1-fold excess. Primary prevention resulted in a 48% reduction in CHD mortality from 2.0-fold excess to none, with a smaller reduction of nearly 25% in patients with established disease. Coronary mortality was reduced more in women than in men. In patients without known CHD at registration, all-cause mortality from 1992 was 33% (21–43), lower than in the general population, mainly due to a 37% (21–50) lower risk of fatal cancer. Conclusion The results emphasize the importance of early identification of FH and treatment with statins.

Residual macrovascular risk in 2013: what have we learned?

Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R3i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R3i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R3i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptorα agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R3i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.

Effect of intensive lipid-lowering therapy on cardiovascular outcome in patients with and those without inflammatory joint disease.

OBJECTIVE To examine the effect of intensive lipid-lowering therapy on a composite cardiovascular outcome (cardiovascular disease [CVD]), consisting of mortality and morbidity end points, in patients with inflammatory joint disease (rheumatoid arthritis [RA], ankylosing spondylitis [AS], or psoriatic arthritis [PsA]) by post hoc analysis of 2 prospective trials of statins with a secondary end point of CVD outcome (the Treating to New Targets [TNT] and Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] studies). METHODS Of the 18,889 patients participating in the 2 trials, 199 had RA, 46 had AS, and 35 had PsA. Lipid-lowering therapy consisted of an intensive regimen of atorvastatin 80 mg or a conventional/low-dose regimen of atorvastatin 10 mg or simvastatin 20-40 mg. The median duration of followup was nearly 5 years. Changes in lipid levels were examined by analyses of covariance. The effect on CVD was examined by Cox regression analyses, and heterogeneity tests were performed. RESULTS Patients with RA and those with AS had lower baseline cholesterol levels than patients without inflammatory joint disease (least squares mean ± SEM 180.7 ± 2.3 mg/dl and 176.5 ± 4.7 mg/dl, respectively, versus 185.6 ± 0.2 mg/dl; P = 0.03 and P = 0.05, respectively). Statin treatment led to a comparable decrease in lipid levels and a 20% reduction in overall risk of CVD in both patients with and those without inflammatory joint disease. CONCLUSION Our findings indicate that patients with and those without inflammatory joint disease experience comparable lipid-lowering effects and CVD risk reduction after intensive treatment with statins.

Familial lipoprotein lipase (LPL) deficiency: a catalogue of LPL gene mutations identified in 20 patients from the UK, Sweden, and Italy.

The aim of this study was to identify mutations in the lipoprotein lipase (LPL) gene in 20 unrelated patients with familial lipoprotein deficiency (FLLD) and to investigate the genotype/phenotype relationship. The previously reported G188E mutation (Monsalve et al., J Clin Invest 86:728–734, 1990) was screened for and found to be present in seven individuals (12/40 alleles). In addition, three patients were heterozygous for the 2.0 kb insertion (Langlois et al., Proc Natl Acad Sci US 86:948–952, 1989). Two approaches were taken for new mutation detection; single‐strand conformation polymorphism and sequencing to identify micro‐mutations in the proximal promoter and exons 1–9 of the LPL gene and Southern blotting to identify gross mutations. Ten different point mutations were found (W86G, A158T, H183Q, G188E, S193R, P207L, L252X, N291S, M301T, L303P). Additionally, a two nucleotide deletion in exon 6 (Δ1006–1007), a six nucleotide deletion in exon 8 (Δ1441–1447), and a silent substitution in the wobble position of codon E118 were identified. In vitro mutagenesis and expression in COS‐B cells suggested that the A158T and S193R substitutions virtually abolished enzyme activity. In analysing the genotype/phenotype relationship, there was no strong association between age at diagnosis, severity of symptoms, lipid levels, and the nature/position of the mutation. Triglyceride levels, however, were higher in compound heterozygotes compared to true homozygotes, possibly reflecting increased instability of heterodimers. Overall, 29 of 40 (72.5%) mutant alleles were identified. Failure to identify the mutation in 11 alleles might reflect the inadequacy of the method or the possibility that mutations lie within regions of the gene not screened in the study because of lack of availability of sequence. Hum Mutat 10:465–473, 1997.

Pitavastatin – results from phase III & IV

The pitavastatin Phase III and IV studies assessed the efficacy and safety of standard dose pitavastatin vs. comparable doses of alternative statins in a broad range of patients with hypercholesterolaemia. Phase III studies conducted in Europe included five 12-week, randomised, double-blind trials evaluating the non-inferiority of pitavastatin 1-4mg vs. atorvastatin 10-20mg, simvastatin 20-40 mg and/or pravastatin 10-40mg in patients with primary hypercholesterolaemia and combined dyslipidaemia, including patients with high cardiovascular risk, type II diabetes, and age ≥65 years. The primary endpoint was the adjusted mean percent change from baseline in low-density lipoprotein-cholesterol (LDL-C); secondary endpoints included changes from baseline in lipid and lipoprotein profiles, LDL-C-target attainment rates and safety parameters. For each study, treatment was continued in open-label, long-term extension studies. Phase IV Japanese studies included CHIBA - a 12-week, open-label active control, non-inferiority investigator-led trial comparing the efficacy and safety of pitavastatin 2mg and atorvastatin 10 mg in patients with hypercholesterolaemia; PIAT - a 52-week open-label, investigator-led, randomised, parallel-group study comparing the efficacy and tolerability of pitavastatin 2mg and atorvastatin 10 mg in patients with hypercholesterolaemia and glucose intolerance; and LIVES - a 2-year prospective post-marketing surveillance of pitavastatin in 20,279 patients with hypercholesterolaemia. The primary endpoint for the first two studies was the percent change from baseline in non-high-density lipoprotein-C (non-HDL-C) and HDL-C, respectively; secondary endpoints included % changes from baseline in other lipid/lipoprotein parameters, safety and tolerability. Overall, Phase III and IV studies demonstrate that pitavastatin 1-4mg is well tolerated, improves atherogenic lipid profile and increases LDL-C target attainment rates with a similar or greater efficacy to comparable doses of atorvastatin, simvastatin and pravastatin in most patient groups. In each of these studies, improvements in lipid profile were sustained or improved during the long term suggesting benefits for continued treatment with pitavastatin.

Prediction of Cardiovascular Events in Patients with Ankylosing Spondylitis and Psoriatic Arthritis: Role of Lipoproteins in a High-risk Population

Objective. To evaluate lipids and apolipoproteins as predictors of cardiovascular mortality and morbidity (CVD) in patients with spondyloarthritis (SpA). Methods. In the pooled cohort of participants in the IDEAL, TNT, and CARDS trials, 50 had ankylosing spondylitis (AS), 36 had psoriatic arthritis (PsA), and 21,641 did not have AS or PsA (non-SpA). We compared lipid levels at baseline between AS or PsA and non-SpA, and hazard ratios (HR) for CVD were calculated in a Cox proportional hazard model. Results. Atherogenic lipids were lower in samples from AS, but not in PsA, compared to non-SpA. The HR for 1 SD increase in baseline lipids for future CVD was for total cholesterol 1.39 (95% CI 0.82, 2.36) in AS, 1.01 (95% CI 0.44, 2.31) in PsA, and 1.10 (95% CI 1.07, 1.14) in non-SpA. Both high-density lipoprotein (HDL) and apolipoprotein (ApoA-1) were significantly associated with CVD in AS (HR 3.67, 95% CI 1.47, 9.06, and HR 1.89, 95% CI 1.02, 3.54, respectively), in contrast to PsA (HDL: HR 1.03, 95% CI 0.49, 2.15; ApoA-1: HR 0.79, 95% CI 0.34, 1.89) and non-SpA (HDL: HR 0.86, 95% CI 0.84, 0.89; ApoA-1: HR 0.88, 95% CI 0.85, 0.91). Conclusion. HDL and ApoA-1 were surprisingly associated with increased risk of future CVD in patients with AS, whereas these lipids were protective in non-SpA.

Round table discussion: practical issues in the management of dyslipidaemic patients

A male accountant aged 52 years from Bangladesh, who had undergone a coronary artery bypass graft (CABG) at the age of 49 years, was referred to Dr Betteridges clinic. The patients fasting plasma lipid profile was as follows: plasma cholesterol, 5.9 mmol/l; plasma triglycerides (TG), 2.8 mmol/1; and high density lipoprotein (HDL) cholesterol, 0.67 mmol/1. Following his CABG, the patient had attended the clinics standard rehabili, tation course for all myocardial infarction and CABG patients and had, subsequently, reduced his body mass index (BMI) from 29 kg/m 2 to 26 kg/m 2, was undertaking reasonable exercise and had improved his diet considerably. The patient was also receiving concomitant low-dose aspirin treatment.