ZACBLM NATIONAL SYMPOSIUM 3
Cardiovascular Disease in Evidence Based, P4 (Personalised, Preventative, Predictive and
Participatory) Medicine:
RESOLUTIONS
1. Clinicians need to work with laboratory staff in order for the scientists to
gain access to clinical data
of patients and conduct relevant research in cardiovascular diseases
2. More research needs to be done on statins as these predispose patients to diabetes and renal failure
3. The use of novel markers (apolipoproteins, cytokines) is strongly recommended in cardiovascular disease
investigations to complement current laboratory tests.
4. Evidence based medicine is needed by doing research and producing results to convince policy makers
and enable release of funds from government to do research
5. Standardization of methods is necessary as well as promoting mass spectroscopy in diagnosis
6. There is need to explore research in non-communicable diseases which are on the increase. Noncommunicable disease department needs to work together with medical school
7. Diabetes is on the rise as such there is need to validate HB1c because of genetic and haemoglobin
variations
8. Departmental collaborations are needed to share research findings and possibly sell it
9. There is knowledge gap on metabolic syndrome especially on simpler screening tools for BMI and lipid
profiles
10. Drug control is need in treatment of CVDs particularly on assessing statin drugs. A joint committee
including pharmacy, medical school and clinicians is needed
11. More information on inflammation is required as this can complement risk factors of CVDs in HIV
12. There is need for appropriate data collection tools as proper knowledge dissemination is unavailable
13. More ward rounds needed for clinical scientists to establish a research base
Commentary on Statins and the Disease
Associate Professor Dr Beste Ozben, Marmara University, Medical Faculty,,Department of Cardiology
Istanbul, Turkey
The search for a cholesterol-lowering drug has begun since the early 1970s. As circulating cholesterol is
mostly produced by the body in the liver rather than obtained from the diet, researches have been focused on the
drugs that inhibit HMG-CoA reductase, the rate limiting step in the cholesterol synthesis. Statins act
by competitively inhibiting HMG-CoA reductase and reduce the rate by which HMG-CoA reductase is able to
produce mevalonate, the next molecule in the cascade that eventually produces cholesterol in the liver. By
inhibiting the HMG CoA reductase pathway, statins inhibit the production of, not only cholesterol, but also certain
prenylated proteins, which may explain statins pleiotropic cardiovascular benefits including improvement of
endothelial function, modulation of immune function and inflammatory responses, maintenance of plaque stability
and prevention of thrombus formation (1-3).
The major use of statins is in the primary and secondary prevention of cardiovascular disease (CVD). Statins
have been shown to reduce cardiovascular (CV) events and all-cause mortality in patients with known CVD who
are at high risk for CV events. Intensive statin therapy reduces mortality in patients with an acute coronary
syndrome and is recommended as initial therapy. The absolute benefits of statins are smaller in primary prevention.
However, randomized trials of statins have demonstrated similar relative risk reductions for CV events and
coronary heart disease mortality across a wide range of baseline lipid levels in patients treated for primary and
secondary prevention.
Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. Serial
angiographic studies have shown that cholesterol lowering can retard the progression, and in some cases, induce
regression
of
coronary
atherosclerosis
The ASTEROID
trial showed
direct ultrasound evidence
of atheroma regression during statin therapy (4). Levels of C-reactive protein (CRP) appear to be associated with
clinical outcomes. In 2008, the JUPITER study showed benefit in those who had no history of high cholesterol or
heart disease, but only elevated CRP levels (5). In contrast, patients with heart failure do not appear to gain
significant benefits from statins, even when they have ischemic causes of heart failure and interestingly, a low
serum cholesterol in patients with heart failure is associated with higher mortality (6,7).
In patients with hyperlipidaemia, statins decrease the risk of major cerebrovascular events (fatal and
nonfatal strokes and transient ischemic attacks) and in patients with stroke, statin treatment is considered as
secondary prevention. The SPARCL trial was the first to show that statin treatment decreased the risk of recurrent
ischemic stroke among patients with a history of stroke or transient ischemic attack (8). Long-term treatment with
statins reduces the risk of ischemic stroke, even though hypercholesterolemia is not a strong risk factor for stroke
as the protective effects of statins are not mediated by only cholesterol lowering, but also by their antiatherothrombotic properties such as improving endothelial function, reducing inflammation, plaque stabilization,
and slowing carotid arterial disease progression. Even patients with "average" serum cholesterol concentrations
appear to benefit from statin therapy in terms of stroke reduction (8).
Vascular stiffness is one of the important predictors of mortality in haemodialysis and renal transplant
patients. Despite beneficial effects of statins on vessel stiffening and endothelial function in patients with chronic
kidney disease (CKD), there are conflicting data concerning the effect of statins on progression of CKD. Current
data suggest that statins do not prevent the loss of renal function and statin therapy is not recommended solely for
renal protection. On the other hand, a meta-analysis showed that statins could reduce the risk of contrast-induced
nephropathy by 53% in people undergoing coronary angiography/percutaneous interventions. The effect was found
to be stronger among those with pre-existing kidney dysfunction or diabetes mellitus (9).
Statin therapy should be given to patients with CKD for cardiovascular protection. Even mild-to-moderate
CKD is associated with increased cardiovascular risk and statin therapy is associated with reduced cardiovascular
and all-cause mortality in patients with CKD (10,11). However, patients with end stage renal disease and patients
on dialysis do not appear to gain significant benefits from statin therapy.
The most commonly seen side effects of statins are muscle problems (mostly muscle pain, but myositis and
rhabdomyolysis may also be seen), an increased risk of diabetes, and increased blood liver enzymes due to liver
damage (12,13). These may be related to the inhibition of protein prenylation and to other processes of the HMGCoA reductase enzyme, such as CoQ10 production, which is important for muscle cells and in blood sugar regulation
(14-16). Statins are associated with a slightly increased risk of diabetes (2–17%) (17). Higher doses have a greater
effect, but the decrease in cardiovascular disease outweighs the risk of developing diabetes (18). Hypothyroidism
is a potential cause of dyslipidaemia and hypothyroidism may predispose patients to statin-induced myopathy
Combining statin treatment with fibrate or niacin increases the risk of rhabdomyolysis. Monitoring liver enzymes
and creatine kinase is especially necessary in those on high-dose statins or on statin/fibrate combinations, and in
the case of muscle cramps or of deterioration of kidney function.
Several meta-analyses have found no increased risk of cancer, and some meta-analyses have found a
reduced risk (19,20). Statins may reduce the risk of oesophageal cancer, colorectal cancer, gastric
cancer, hepatocellular carcinoma, and possibly prostate cancer. They appear to have no effect on the risk of lung
cancer, kidney cancer, breast cancer, pancreatic cancer, or bladder cancer (21-30).
Other possible adverse effects include cognitive and memory loss, cataract, peripheral neuropathy, lupus,
pancreatic and hepatic dysfunction, and sexual dysfunction (31). Statins may cause proteinuria through tubular
inhibition of active transport of small molecular weight proteins. However, it is believed that proteinuria with
statins is a benign finding (32,33). Research continues into other areas where specific statins also appear to have a
favourable effect, including dementia, lung cancer, nuclear cataracts, hypertension, and prostate cancer (34-38).
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