Featured Commentary

Lifestyle intervention: POWER shows lower cost options can improve adherence

While coronary mortality rates have declined over the last few decades, event rates have merely plateaued. The epidemic of cardiometabolic disease, the major challenge for healthcare providers in the 21^st century, is a major contributing factor. This epidemic is not restricted to industrialised countries. China in particular has been in the spotlight. Despite improved access to better treatment, an increasingly Westernised diet has escalated rates of dyslipidemia (Box 1) and cardiovascular disease.^1,2 It is estimated that cardiovascular disease rates in China will increase by more than 50% over the next 20 years.³

Box 1: Dyslipidemia in China: recent survey2 Survey of 5,761 adults aged 18-79 years (mean 44 years, 58% female)  • 46% of men and 40% of women had LDL cholesterol ≥3.37 mmol/L (130 mg/dL)  • Among men, 20% had low HDL cholesterol (<1.04 mmol/L or 40 mg/dL) and 36% had elevated triglycerides (≥1.7 mmol/L)  • Only 10% of those with dyslipidemia were receiving treatment.

The recent ESC/EAS dyslipidaemia guidelines have emphasised the importance of lifestyle intervention as the fundamental first step in dyslipidemia management.⁴ However, key issues remain in implementation. Not only are there are deficiencies in provision of lifestyle advice to obese/overweight patients, as highlighted by EURIKA (European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice),⁵ but maintaining a healthy lifestyle behaviour in patients in the longer-term is an even greater challenge.

The POWER (Practice-based Opportunities for Weight Reduction) study⁶ has shown that a remote computer-based intervention provides comparable benefits for improved weight control in obese patients. Briefly, POWER was conducted at six primary care practices and included 415 obese adults (mean BMI 36.6 kg/m², mean age 54 years, 64% female). There was a high prevalence of risk factors: 76% had hypertension, 68% had hypercholesterolemia and 23% had diabetes. Patients were randomly allocated to one of three types of intervention:

• Usual care: education about weight management at quarterly visits to the primary care practice. Weight loss was self-directed.
• Remote support only (via telephone, study-specific website and email)
• Face-to-face support (group and individual sessions plus remote support).

The primary endpoint was loss of at least 5% of initial body weight at follow-up. After 6 months, about 50% of patients receiving either remote or face-to-face intervention had achieved the primary endpoint (52.7% vs. 46.0%, respectively). Weight loss was maintained in ca. 40% of patients in each group at 2 years (38.2% vs. 41.4%). Differences between these groups were not statistically significant.

The implications from POWER are clearly relevant in dealing with the obesity epidemic. Sustained weight loss can have important impact in reducing the prevalence of diabetes and metabolic syndrome, and in turn counteracting elevated triglycerides and low HDL cholesterol levels typically observed in these patients. The fact that a remote-based intervention was as effective as the face-to-face intervention runs counter to traditional paradigms. Such an approach also offers the added advantages of improved flexibility, lower cost and fewer barriers to implementation. With the need for financial restraint in healthcare budgets, these data represent an important advance.

After AIM-HIGH where does niacin stand?

The AIM-HIGH (Atherothombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides : Impact on Global Health Outcomes) study⁷ has generated much debate, even leading some to question the role of niacin in the management of cardiometabolic disease.⁸ The study had planned to investigate whether adding niacin (extended release [ER] formulation) to simvastatin therapy reduced cardiovascular events in high-risk patients with controlled LDL cholesterol levels and low HDL cholesterol (<1.03 mmol/L in men and <1.29 mmol/L in women) and elevated triglycerides (1.69-4.52 mmol/L) (Box 2). The previous EAS Consensus Panel statement has highlighted the high risk associated with this dyslipidemic profile despite achievement of LDL cholesterol goal.⁹

Box 2: Baseline characteristics of AIM-HIGH population • 3,414 participants (mean age 64 years, 85% male) with a history of cardiovascular disease • High prevalence of risk factors: 92% had coronary artery disease, 81% had metabolic syndrome, 71% had hypertension and 34% had diabetes • Baseline lipids, median (range or IQR for triglycerides): LDL cholesterol : 74 (59-87) mg/dL  HDL cholesterol: 35 (31-39) mg/dL  Triglycerides: 162 (128-218) mg/dL

Patients were randomly allocated to either high-dose ER niacin (titrated to 1.5-2 g/day, n=1,718) or placebo treatment (n=1,696), against a background of simvastatin therapy. This event-driven trial was designed to have an 85% power to detect a 25% reduction in cardiovascular events. It was planned that a sample size of 3,400 participants followed for 2.5 - 7 years would generate the required 800 primary events. However, the study was terminated 18 months earlier than planned due to futility, with no statistically significant differences between the groups for any of the key outcomes (Table 1).

Table 1. Key outcomes from AIM-HIGH

Endpoint	Niacin (%)	Placebo (%)	Hazard ratio (95% CI) with niacin	p-value
Primary*	16.4	16.2	1.02 (0.87-1.21)	0.80
CHD death/ nonfatal MI/ ischaemic stroke/ high-risk ACS	10.0	9.3	1.08 (0.87-1.34)	0.49
CHD death/ nonfatal MI/ ischaemic stroke	8.1	9.1	1.13 (0.90-1.42)	0.30

*composite of coronary heart disease (CHD) death, nonfatal myocardial infarction (MI), ischaemic stroke, hospitalisation for acute coronary syndrome (ACS) or symptom-driven coronary or cerebral revascularisation

Further analysis revealed several reasons for the trial’s failings.
• First, the planned event rates for this trial were overly ambitious for the study population. While treatment with niacin increased HDL cholesterol levels by 25% to 42 mg/dL, there was also a substantial increase in HDL cholesterol in the placebo group (by 12% to 38 mg/dL). Based on population studies, the difference between the two groups - 4 mg/dL – would have predicted at most a 10% difference in CV events, less than half the predicted 25% reduction on which the power calculations were based.
• Second, the vast majority (ca. 90%) of patients had already been treated with statin therapy for more than 1 year before the study. In addition, ca. 20% of patients had previously received niacin (treatment was discontinued for 30 days before entry to the study).
• Third, the placebo was supplemented with a low dose of immediate-release niacin (50mg per 0.5 or 1.0 g niacin tablet) to maintain study blinding. This may have impacted the study findings given uncertainties regarding the dose-benefit curve for niacin.
• Fourth, there was considerable use of additional lipid-modifying therapy in the placebo group. 75% of patients in this group were receiving simvastatin doses of 40 mg/day or higher, and 21% were also receiving add-in ezetimibe.
Thus AIM-HIGH was not powered to test the potential benefits of adding niacin to statin-treated patients. For answers to this question, we need to wait for the very much larger HPS2-THRIVE study that has randomised 25,000 participants.

Niacin: new evidence for mechanism of antiinflammatory effects

Niacin is a conundrum. Despite being in clinical use for over 50 years, the mechanism(s) of niacin are only now being elucidated. Data from the Coronary Drug Project showed a cardioprotective effect with niacin.^10,11 Recent experimental studies have shown beneficial vasoprotective and anti-inflammatory activities,^12,13 which appear to be independent of lipid effects. Most recently, a study in Circulation¹⁴ has shown that induction of heme oxygenase-1 (HO-1) by niacin may contribute to its anti-inflammatory effects.

Heme oxygenases (HOs) catalyse the oxidation of heme into carbon monoxide (CO), iron, and biliverdin, which is then converted to bilirubin by biliverdin reductase.¹⁵ In man, there are two isoforms: HO-1 and HO-2. There is growing evidence implicating HO-1 in the atheroprotective effects of niacin, as well as cardioprotective effects in animal models of cardiac ischemia/reperfusion injury, pulmonary hypertension, and in cardiac transplant arteriosclerosis.¹⁶

The researchers hypothesed that these cardioprotective effects are attributed to the products of HO-1 metabolism, i.e. bilirubin, CO and iron. Previous studies have shown anti-oxidant and anti-inflammatory properties associated with bilirubin, cardioprotective effects in experimental models associated with CO, and that iron is involved in the generation of endothelial progenitor cells in vivo.^17-19

The researchers first investigated effects on HO-1 in an in vivo model. Rabbits were fed a chow diet (with or without niacin supplementation, equivalent to a daily dose of 1 g niacin) for 2 weeks before placement of a non-occlusive carotid collar. After 24 h, there were greater increases in HO-1 mRNA expression, HO-1 activity and serum bilirubin levels with niacin compared with controls. Vascular inflammation was also reduced by dietary niacin, compared with controls. These effects were abolished by treatment with tin protoporphyrin-IX, a global inhibitor of HO. However, specific inhibition of HO-1 in carotid arteries (by transfection with HO-1 siRNA) only partially blocked the inhibitory effect of niacin on vascular inflammation.

In vitro cell culture studies using human coronary artery endothelial cells were used to investigate the mechanisms underlying this effect. The studies showed that niacin increased HO-1 expression by activating the nuclear transcription factor Nrf2/ p38 mitogen activated protein kinase (MAPK) signalling pathway and inhibiting endothelial inflammation induced by tumour necrosis factor-alpha. Similar effects were reported with incubation with bilirubin. However, incubation with tin protoporphyrin-IX or knockdown of Nrf2 expression abolished the anti-inflammatory effects of niacin. 
 

Key points about this study • There is growing evidence implicating HO-1 in the vasculoprotective effects of niacin. • In an in vivo model, dietary niacin supplementation increased HO-1 expression and activity and reduced vascular inflammation, compared with controls. • In vitro cell culture studies showed that niacin increased HO-1 expression by activating the nuclear transcription factor Nrf2/ p38 MAPK signalling pathway and inhibiting endothelial inflammation induced by tumour necrosis factor-alpha.

Another CETP inhibitor enters the race

The potential of inhibitors of cholesteryl ester transfer protein (CETP) has been discussed in an earlier newsletter (see CETP inhibition in perspective, September newsletter). Data from a Phase II trial with evacetrapib shows that this is a promising addition to the range of CETP inhibitors currently in development.²⁰

The trial included 398 dyslipidemic patients (mean age 58 years, 56% women) with mean baseline LDL cholesterol of 3.73 mmol/L (144 mg/dL) and HDL cholesterol 1.42 mmol/L (55 mg/dL). Patients were randomly allocated to evacetrapib as monotherapy (doses 30 mg/d, 100 mg/d, or 500 mg/d) or combined with the usual therapeutic dose of three commonly used statins (evacetrapib 100 mg/d plus simvastatin 40 mg/d; atorvastatin 20 mg/d; or rosuvastatin 10 mg/d), or statin alone. The duration of treatment was 12 weeks. The key outcomes were the percent changes from baseline in HDL and LDL cholesterol levels to 12 weeks, and the safety of treatment.

As monotherapy, evacetrapib resulted in dose-dependent:

• Increases in HDL-cholesterol levels ranging from 53.6% to 128.8% vs. a decrease of 3% on placebo. Increases in HDL cholesterol were higher in patients with lower levels of HDL cholesterol (p<0.001) or elevated triglycerides (p=0.005) at baseline.
• Decreases in LDL cholesterol levels ranging from 13.6% to -35.9% vs. a decrease of 3.9% on placebo.

Evacetrapib combined with a statin significantly raised HDL cholesterol (p<0.001) and produced greater decreases in LDL cholesterol (p<0.001) than statin monotherapy (Fig. 1).

Evacetrapib showed a favourable safety profile with no adverse effects on blood pressure, aldosterone or cortisol levels, or renal, liver or muscle safety parameters.

Figure 1. Percent change from baseline in HDL and LDL cholesterol with statin plus evacetrapib 100 mg/day (red) or statin alone (blue). The relative percent change between the two groups is indicated.



The profile of lipid-modifying effects with evacetrapib plus statin was more similar to anacetrapib than dalcetrapib. Dalcetrapib has been shown to consistently raise HDL cholesterol by ca. 30% at doses of 600 mg/day (against a background of statin therapy), without any significant effects on LDL cholesterol.^21,22 In contrast, ancetrapib 100 mg/day plus statin raised HDL cholesterol by 138% and lowered LDL cholesterol by 40% vs. statin alone in the DEFINE trial.²³

However, whether these agents have therapeutic application, or indeed whether the extent of HDL cholesterol raising is relevant, cannot be answered at this stage. The Emerging Risk Factors Collaboration had previously shown that there was no further reduction in cardiovascular event rates associated with raising HDL cholesterol levels beyond ca. 1.5 mmol/L.²⁴ These uncertainties can only be addressed after the results of large ongoing outcomes studies with dalcetrapib and anacetrapib are available.

SATURN: head-to-head comparison of potent statins

In the largest intravascular ultrasound study (IVUS) to date, high dose rosuvastatin and atorvastatin were similarly effective in promoting regression of atherosclerosis, as assessed by the percent change in atheroma volume (PAV).²⁵

SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin) enrolled 1,385 patients (mean age 58 years, 74% male) with angiographic evidence of coronary artery disease and LDL cholesterol levels >2.6 mmol/L (100 mg/dL) if not treated with a statin in the last 4 weeks or >2.1 mmol/L (80 mg/dL) if already on a statin at study entry. Patients were randomised to treatment with rosuvastatin 40 mg/d or atorvastatin 80 mg/d for 104 weeks. The primary endpoint was the percent atheroma volume (PAV) and the secondary endpoint was the normalised total atheroma volume (TAV), from IVUS measurements performed at baseline and end of study.

In total, 1,039 patients completed the study. While LDL and HDL cholesterol changes were significantly greater with rosuvastatin than atorvastatin (Table 2), there was no difference between the groups for the change in PAV (-1.22% [95% CI -1.52 to -0.90], vs. -0.99% [95% CI -1.19 to -0.63], p=0.17).

Table 2. SATURN: Mean on-treatment lipid values. Data are given as mmol/L (mg/dL).

	Rosuvastatin (n=520)	Atorvastatin (n=519)
LDL cholesterol	1.62 (62.6)**	1.82 (70.2)
HDL cholesterol	1.30 (50.4)*	1.26 (48.6)
Non-HDL cholesterol	2.30 (88.9)**	2.45 (95.4)
*p=0.01, **p<0.001

There was, however, a statistically significant effect in favour of rosuvastatin for the change in TAV (-6.39 mm³ [95% CI -7.52 to -5.12] vs. 4.42 mm³ [95% CI-5.98 to 3.26], p=0.01). Additionally, a significantly greater proportion of patients had atheroma regression (as assessed by the change in TAV) on rosuvastatin than atorvastatin (71.3% vs. 64.7%, p=0.02).

SATURN clearly shows that intensive statin therapy results in achievement of LDL cholesterol goals and regression of atheroma. These benefits are seen across a range of different patient populations.

Furthermore, the findings from SATURN add to recently published long-term data from the Heart Protection Study (HPS).²⁶ In this report, the absolute benefits of simvastatin (40 mg/day) accrued as treatment continued during 5 years. There was a proportional reduction in major vascular events of 23% (95% CI 19-28%, p<0.0001) after 5 years.

The study population was followed-up for a further 6 years. The clinical benefits observed in patients previously allocated simvastatin persisted largely unchanged during the post-trial period, despite similar use of statins among the surviving study population (59% at 1 year rising to 84% at 6 years) and similar LDL cholesterol levels (2.6 mmol/L at 3.2 years).

The other important finding from these data was that statin treatment for up to 11 years was safe with no evidence of any increase in cancer incidence or non-vascular mortality.

Thus, the HPS follow-up data provide important evidence confirming the role of statins as the cornerstone of lipid-modifying therapy for prevention of premature cardiovascular events.

International FH Foundation launched InterChol has been re-launched as the International FH Foundation to emphasise its focus specifically on familial hypercholesterolaemia (FH). This global Foundation aims to raise awareness of FH across public, clinical and government domains. It is notable that the ESC/EAS guidelines on dyslipidemia management was the first guidelines group to specifically address the diagnosis and management of genetic dyslipidemias, including FH.4 For further information contact: http://www.fh-foundation.org/

References

1. Critchley J, Liu J, Zhao D, Wei W, Capewell S., Explaining the increase in coronary heart disease mortality in Beijing between 1984 and 1999, Circulation, 2004;110:1236-44.

2. Cai L, Zhang L, Liu A et al. Prevalence, awareness, treatment and control of dyslipidemia among adults in Beijing, China. J Atheroscler Thromb 2011 [Epub ahead of print].

3. Moran A, Gu D, Zhao D et al. Future cardiovascular disease in China: Markov model and risk factor scenario projections from the coronary heart disease policy model-china. Circ Cardiovasc Qual Outcomes 2010;3:243-52.

4. The Task Force on the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS); Reiner Z, Catapano A, de Backer G et al. ESC/EAS guidelines for the management of dyslipidaemias. European Heart Journal 2011; 32:1769-818.

5. Banegas JR, Lopez-Garcia E. Dallongeville J et al. Achievement of treatment goals for primary prevention of cardiovascular disease in clinical practice across Europe. Eur Heart J 2011; 32:2143-52.

6. Appel LJ, Clark JM, Yeh H-C et al. Comparative effectiveness of weight-loss interventions in clinical practice. NEJM 2011;365:1959-68.

7. The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. New Engl J Med 2011;[Epub ahead of print].

8. Giugliano RP. Niacin at 56 years of age – time for an early retirement? [editorial]. NEJM 2011; [Epub ahead of print].

9. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.

10. The Coronary Drug Project Group. Clofibrate and niacin in coronary heart disease. JAMA 1975; 231:360-81.

11. Canner PL, Berge KG, Wenger NK et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245-55.

12. Chapman MJ, Redfern JS, McGovern ME, Giral P. Niacin and fibrates in atherogenic dyslipidemia: Pharmacotherapy to reduce cardiovascular risk. Pharmacol Ther 2010;126:314–45.

13. Wu BJ, Yan L, Charlton F, Witting P, Barter PJ, Rye KA. Evidence that niacin inhibits acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids. Arterioscler Thromb Vasc Biol 2010;30:968-75.

14. Wu BJ, Chen K, Barter PJ, Rye KA. Niacin inhibits vascular inflammation via the induction of heme oxygenase-1. Circulation 2011; [Epub ahead of print].

15. Li C, Hossieny P, Wu BJ, Qawasmeh A, Beck K, Stocker R. Pharmacologic induction of heme oxygenase-1. Antioxid Redox Signal 2007;9:2227-39.

16. Otterbein LE, Soares MP, Yamashita K, Bach FH. Heme oxygenase-1: Unleashing the protective properties of heme. Trends Immunol 2003;24:449-55.

17. Stocker R. Antioxidant activities of bile pigments. Antioxid. Redox Signal 2004;6:841-9.

18. Ryter SW, Alam J, Choi AM. Heme oxygenase-1/carbon monoxide: From basic science to therapeutic applications. Physiol Rev 2006;86:583-650.

19. Wu BJ, Midwinter RG, Cassano C et al. Heme oxygenase-1 increases endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2009;29:1537-42.

20. Nicholls SJ, Brewer B, Kastelein JJP et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol. JAMA 2011;306:2099-109.

21. Fayad ZA, Mani V, Woodward M et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised trial. Lancet 2011;378:1547-59.

22. Stein EA, Stroes ES, Steiner G et al. Safety and tolerability of dalcetrapib. Am J Cardiol 2009;104:82-91.

23. Cannon CP, Shah S, Dansky HM et al. The DEFINE Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406-15.

24. The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993-2000.

25. Nicholls SJ, Ballantyne CM, Barter PJ et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 20111; [Epub ahead of print].

26. Heart Protection Study Collaborative Group. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20 536 high-risk individuals: a randomised controlled trial. Lancet 2011. [Epub ahead of print].