Jupiter was a trial of individuals without hyperlipidemia, but with elevated high-sensitivity C Reactive protein (CRP) levels. Rosuvastatin treatment significantly reduced the incidence of major cardiovascular events. The results suggest that elevated CRP may be a risk factor for cardiovascular events. A statin drug which lowers levels of CRP as well as cholesterol may have a favorable effect when given to people with elevated C-reactive protein levels but without hyperlipidemia or previous history of atherosclerotic cardiovascular disease.
In JUPITER, 17.802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels 2.0 mg per liter or higher were randomly assigned to rosuvastatin, 20 mg daily, or placebo and followed for the occurrence of primary cardiovascular end points.
Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein
levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95%.
Consistent beneficial cardiovascular events rate were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.
Introduction
Jupiter was an excellently designed and controlled clinical trial with a population of patients chosen at the latest decades of life(thus more likely to have ASCVD consequences in a shorter period of time); that age group selection was likely responsible for the early benefit of the therapeutic intervention (mean duration of less than 2 years).
Different Potency among statins.
It is pertinent to point out that rosuvastatin (the statin used in Jupiter) is by all accounts -based on extended comparative efficacy studies- the statin with the widest spectrum and greatest efficacy to improve abnormal serum lipoprotein levels.
The lipid regulating capacity of 20 mg/ day of rosuvastatin shows lowering of serum LDL-C (low density lipoprotein cholesterol) to a greater extent than the other two most potent statins, simvastatin and atorvastatin at their maximal approved doses (80 mg/d). And it is also of even greater efficacy than most other marketed statins at their maximal approved doses (lovastatin and pravastatin) .
The difference between rosuvastatin and atorvastatin is most remarkable in regards to raising HDL cholesterol and Apo A1 levels. Extensive studies comparing their efficacy have consistently demonstrated a inverse dose correlation effect of atorvastatin on HDL and Apo A1. The higher the dose of atorvastatin the lesser the increase of serum HDL cholesterol and Apo A1. This paradoxical, inverse dose related effect of atorvastatin was clearly corroborated by multiple comparative studies.
Because of all that reasons the results of Jupiter may not justify the use of just any statin in individuals (not yet patients) presenting with CRP levels of = or > than 2 mg/ dl. The results can only justify the use of rosuvastin, which was the statin that provided the beneficial effects in Jupiter.
ASCVD benefis of serum CRP levels reduction
As it can be deduced from the above stated facts, if the Jupiter study were to have been performed using any of the other currently available statins, the serum lipid regulating effects would have most likely been of lesser magnitude. It is then logical to believe that even if all other statins have the same extent of serum CRP lowering, the ASCVD endpoint’s benefits of rosuvastatin seen in Jupiter, would most likely not had been matched by any one of them because of their lower potency on serum lipoprotein abnormalities.
The recent trials with simvastatin and atorvastatin (HPS,TN and Prove It, did not result in the magnitude and rapid onset of benefits shown in Jupiter. This may support the important effect of lowering elevated CRP, but calls for caution in the interpretation of the role of CRP lowering when occurring concomitantly with the most potent lipoprotein level regulating effects of the most potent available statin, rosuvastatin .
Do Jupiter results confirm CRP level as an independent ASCVD riskfactor ?
Probably not, to have done so we would have needed subjects in whom the effect of the therapeutic intervention was only the reduction of CRP levels. Jupiter patients had also some of the greatest reduction in LDLC levels ever achieved, in addition to Triglyceride reductions and slight increase in HDLC levels.
Jupiter results help to confirm what was already shown by post hoc analysis of results of AFCAPS, TEXCAPS studies, that utilized statins; in that elevated CRP levels are an important additive factor for ASCVD risk and that the presence or absence of CRP levels elevations have different benefit impact at the same extent of LDL cholesterol lowering.
Side Effects from rosuvastatin seen in Jupiter
It was most encouraging, the almost absolute absence of muscle toxicity. However the most common cause of alleged statin induced miotoxicity with elevated CPK levels, is the spurious elevation seen in patients undertaking vigourous physical activity or trauma.
The population of Jupiter was uniquely different from most previous trials in that the qualifying ages were equal or greater than 50 years for men and 60 for women, Subjects at such age ranges are the least likely to undertake high levels of physical activity or traumas. This selected population might have played a role in the absence of myopathy or elevated CPK levels in Jupiter.
The explanation for a statistically significant higher doctor’s reported onset of diabetes mellitus in rosuvastatin treated subjects is difficult to ascertain, but may also be related to the population’s age. It can be speculated that a population older than 50 to 60 years of age, 41% of whom have diagnosis of metabolic syndrome will be be having the greatest chance of developing mature onset diabetes mellitus.
More so when the majority of them most likely were overweight and possibly glucose intolerant as expected in patients who met the criteria for metabolic syndrome in the presence of low serum triglycerides an relatively high HDLC levels at baseline. This fact leaves obesity and glucose intolerance playing a more preponderant role in the diagnosis of metabolic syndrome in Jupiter subjects.
Jupiter results and current treatment guidelines.
The Jupiter study treated wih rosuvastatin these individuals with a mean baseline LDL level of 108 mg /dl. The first guidelines recommended pharmacotherapy in patients with LDL above 160 mg/dl. The last guidelines indicated a level of 130 md/dl or greater to justify pharmacotherapy.
In Jupiter LDL lowering was a maximum ever achieved, and the reduction of some of the ASCVD endpoints was the greatest ever accomplished, and at the earliest average time ever in a statin vs placebo clinical trial on a study (less than 2 years average treatment duration).
Humans as well as all other animal species are born with LDL cholesterol levels of 40 to 60 mg/dl. All animal species remain at that level for their entire life except humans. The large majority of people reach levels of 100 mg/dl of LDL by early adulthood. More than 50 % of them go to levels of LDL of 130 mg or greater thereon. This phenomenon is probably due to their lifestyles, most of which are not designed to mantain the same the cholesterol levels at birth.
The choice of subjects (not yet patients) with parameters which made them not eligible for pharmacotherapy intervention under current guidelines, gives convincing evidence to the belief that our current guidelines with their suggested ideal levels of LDL of 100 mg/dl for low risk patients may not represent a criteria that meets ideal goals.
What statins to use in Clinical Practice based on Jupiter results
For the above mentioned reasons the results of Jupiter may not justify the use just of any statin in individuals (not yet patients) like those who qualified for the Jupiter study presenting with CRP levels of = or > than 2 mg/ dl. The Jupiter’s results can only justify the use of rosuvasttin, which was the statin that has shown to provide all the beneficial prevention of mortality and ASCVD disease morbidity in the results of that study.
There is only one lipid regulating pharmacological intervention documented to have similar or greater serum lipoprotein regulating capacity and CRP level reduction,that is the combination of Ezetimibe and Simvastatin. Only a controlled clinical trial using that combination therapy in the same type of population than Jupiter can prove that possibility.
In summary Jupiter results may prove the validity of preventive reduction of elevated CRP level regardless of presence of dyslipidemia or ASCVD risk. The question remains on which is the most practical and safest mode of intervention for that purpose. We must remember that elevated CRP levels have been shown to be effectively reduced by weight loss in the obese, exercise in the sedentary and smoking cessation in the smokers.
It is then rational to have those lifestyle interventions be the initial approach to people like those in the Jupiter study who presented no immediate ASCVD risk and in whom pharmacological intervention is not yet suggested by current guidelines.
Why are the endpoints from jupiter better than other trials ?
A decrease in 44 % was observed between the groups in Jupiter, and speculation has arose about the difference with regard to other trials. We chose to compare this results with other trials using statins at mid to high dose range.
Patients started with levels of 108, 49 and 118 mg/dl of LDL, HDL and TG and levels changed to 55, 50 and 99 respectively. In the TNT study the baseline levels were 98, 47 and 151 mg/dl respectively and changed to 77 and HDL did not change. The primary endpoint of the trial had a 22% risk reduction between the 80 and the 10 mg atorvastatin arms in patients with stable coronary disease.
After ACS studied in the Prove It study the baseline values were 106, 39 and 156 mg/ dl and decreased to 95 and 62 mg/dl in the atorvastatin and pravastatin arms respectively. HDL levens increased by 6.5 and 8.1% respectively in the arms, producing a 16% relative risk reduction between arms.
In the HPS patients with CAD, other occlusive arterial disease and diabetes were randomized to 40 mg of simvastatin or placebo. Their baseline lipid levels were 5.9, 1,06 and 2.1mmol/L of LDL, HDL and TG respectively. These values were changed to 4.9, 1.03 and 1.8 as post treatment averages producing a 24% reduction in the first occurrence of major vascular events.
Summary
The results of JUPITER suggested but not proved that elevated CRP levels may be an independent risk factor,because Rosuvastatin exerted the greatest ever reduction of LDL cholesterol as well as reducing CRP levels.
The definition of "independent" risk factor is that changes of only that factor,without changes in any other/s will be enough to change endpoints. One possibility of enhancing the chances for CRP levels to be acceptable as an independent risk factor, would be to find in further analysis of the data of Jupiter, a correlation between CRP levels’changes and ASCVD endpoints highly and statistically significantly stronger than between LDLC levels and those same endpoints.
References
- Paul M Ridker, M.D., Eleanor Danielson, M.I.A., Francisco A.H. Fonseca, M.D., Jacques Genest, M.D., Antonio M. Gotto, Jr., M.D., John J.P. Kastelein, M.D., Wolfgang Koenig, M.D., Peter Libby, M.D., Alberto J. 2. Lorenzatti, M.D., Jean G. MacFadyen, B.A., Børge G. Nordestgaard, M.D., James Shepherd, M.D., James T. Willerson, M.D., Robert J. Glynn, Sc.D., for the JUPITER Study Group. Rosuvastatin to Prevent Vascular 3. Events in Men and Women with Elevated C-Reactive Protein N Eng J Med 2008; 350: 2195-2207
- Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto JW; STELLAR Study Group.Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003 Jul 15;92(2):152-60.
- Schneck DW, Knopp RH, Ballantyne CM, McPherson R, Chitra RR, Simonson SG. Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. Am J Cardiol 2003; 91: 33-41
- Kastelein JJ, Isaacsohn JL, Ose L, Hunninghake DB, Frohlich J, Davidson MH, Habib R, Dujovne CA, Crouse JR, Liu M, Melino MR, O'Grady L, Mercuri M, Mitchel YB. Comparison of effects of simvastatin versus atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I levels. Am J Card, 2000;86(2): 221-223
- Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet,2002; 360: 7-22,
- Christopher P. Cannon, M.D., Eugene Braunwald, M.D., Carolyn H. McCabe, B.S., Daniel J. Rader, M.D., Jean L. Rouleau, M.D., Rene Belder, M.D., Steven V. Joyal, M.D., Karen A. Hill, B.A., Marc A. Pfeffer, M.D., Ph.D., Allan M. Skene, Ph.D., for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes N Eng J Med 2004; 350: 1495-504.
- John C. LaRosa, M.D., Scott M. Grundy, M.D., Ph.D., David D. Waters, M.D., Charles Shear, Ph.D., Philip Barter, M.D., Ph.D., Jean-Charles Fruchart, Pharm.D., Ph.D., Antonio M. Gotto, M.D., D.Phil., Heiner
- Greten, M.D., John J.P. Kastelein, M.D., James Shepherd, M.D., Nanette K. Wenger, M.D., for the Treating to New Targets (TNT) Investigators. Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease N Eng J Med 2005; 352: 1425-35, Dujovne CA. Side effects of statins: hepatitis versus "transaminitis"-myositis versus "CPKitis". .Am J Cardiol 2002; 89, 1411-1413
- Schneck DW, Knopp RH, Ballantyne CM, McPherson R, Chitra RR, Simonson SG. Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. Am J Cardiol. 2003 Jan 1;91(1):33-41.
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