Re: Lower LDL = reduced IMT

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Hi All, pdfs of the papers are availed. BV, Roman MJ, Devereux RB, Fleg JL, Galloway JM, JA, WJ, Lee ET, Mete M, Poolaw B, Ratner RE, M, Silverman A, Stylianou M, Umans JG, Wang W, Weir MR, Weissman NJ, C, Yeh F, Zhu J.Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial.JAMA. 2008 Apr 9;299(14):1678-89. PMID: 18398080 http://tinyurl.com/4tz6e9 ED, Wang TY.The great debate of 2008--how low to go in preventive cardiology?JAMA. 2008 Apr 9;299(14):1718-20. No abstract available. PMID: 18398086 The debates of 2008 have already been quite intense. During this election year, politicians and pundits alike, reviewing the same set of information, have

formulated remarkably different conclusions and recommendations for national policy. The field of preventive cardiology has likewise been witness to its own debate. Spurred by a series of important yet somewhat unexpected clinical trial results, the question of "how low to go" in cardiovascular risk-factor modification has been hotly disputed. This debate is not new and traditionally has been waged between the "true believers," those with a strong a priori conviction that more aggressive pharmacological treatment will reduce future events, and the "therapeutic nihilists," those who require unequivocal proof before acceptance. In recent years, the true believers have had the upper hand. Epidemiologic data have consistently concluded that lower levels of lipids, blood pressure, and glucose all correlate with less cardiovascular disease. Similarly, among patients with established cardiovascular disease, intensive lipid lowering with statins has

been demonstrated to reduce future cardiac events.1 Thus, national treatment guidelines have progressively lowered their thresholds for initiation of drug therapy as well as the target levels to be achieved.2-3 Yet the benefit of aggressive pharmacological therapy for primary prevention is less clear, even among high-risk subgroups.4-5 Additionally, while statin therapy appears beneficial for hypertensive patients,6 the ideal targets for low-density lipoprotein cholesterol (LDL-C) or blood pressure lowering in these patients have not been defined. Here lies the doubt of the nihilists: "Where is the evidence that intensive lowering is necessarily better or even safe?" In this issue of JAMA, and colleagues7 report the results of the Stop Atherosclerosis in Native Diabetics Study (SANDS), which compared aggressive therapy of systolic blood pressure and LDL-C lowering to standard therapy among American Indian patients with type 2 diabetes

mellitus. This is one of the first studies to assess the role of aggressive risk factor modification in a high-risk primary prevention setting. The study was well-designed and rigorously conducted with patient follow-up every 3 months for up to 3 years. The authors also examined these questions in a traditionally understudied population. The results showed that patients receiving intensive management had significant regression of carotid intimal medial thickness (IMT) and reduced left ventricular mass compared with patients treated with standard strategies. In contrast to the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT),8 there appeared to be no synergistic effect between lipid and blood pressure lowering on these separate surrogates—aggressive LDL-C lowering was associated with IMT regression, but was not a predictor of left ventricular mass reduction; conversely, aggressive systolic blood pressure lowering was associated with left ventricular mass reduction, but not

with IMT regression. Importantly, while the study was not powered to address clinical outcomes, intensively managed patients had no significant reduction in cardiovascular events after 3 years of follow-up relative to patients receiving standard treatment. In fact, more adverse effects (hypotension, hyperkalemia) were observed in the group receiving aggressive blood pressure treatment. Some of the obstacles facing primary prevention trials are highlighted in SANDS. Given low annual event rates, primary prevention trials often require large sample sizes and long-term follow-up to assess hard clinical outcomes. Comparing event differences becomes particularly challenging when the question moves from a placebo-based comparison to one that assesses the incremental effect of more aggressive vs standard therapy. In an attempt to expedite evidence development, many have turned to surrogate markers, intermediate end points in the biological pathway,

as more readily measurable alternatives to clinical outcomes. However, surrogate end points often fail if they are not in the direct causal pathway of the effect of the intervention or if the intervention causes harm independent of the disease process. Even though surrogate end points such as IMT and left ventricular hypertrophy have evidence associating them with both cardiovascular risk factors and outcomes,9-10 there is a paucity of evidence showing that changes in these markers will accurately predict future cardiovascular events.11 For example, the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study found that vitamin supplementation delayed carotid IMT progression, but had no effect on reducing clinical events.12 Similarly, while cholesterol lowering has been well associated with carotid IMT regression, the ENHANCE trial recently reported that aggressive lipid lowering may not necessarily correlate with IMT

reduction, at least in a small short-term evaluation.13 In addition, tighter blood glucose control has been associated with delayed IMT progression, yet the ACCORD trial found that more aggressive glycemic control led to an excess of deaths relative to standard management.14 Without doubt, these trials underscore the need to look not just at surrogate markers, but at the ultimate clinical expression of the intervention—patient outcomes. However, there are no easy solutions for improving the throughput of trials with hard clinical end points. Enriching the study population with high-risk populations can increase event rates, but this is not always predictable (as evidenced by the unexpectedly low event rates in SANDS), and doing so can limit study generalizability. Longer and larger studies are ideal, yet using current trial methodologies, can be quite costly. SANDS,7 with only 500 patients, cost approximately $12 million, whereas a 10

000-patient clinical end point–driven trial may cost in excess of $200 million. Thus, methods to improve trial efficiency with better tools to identify eligible patients, quicker site activation, streamlined electronic data collection, and remote monitoring are needed to make trials more practical and affordable. What are the take-home messages from SANDS? For the true believers, the study confirms that aggressive lipid and hypertension treatment has a favorable effect on proven "early markers" of disease. Thus, with longer duration of follow-up (which will hopefully be the case), the study would most assuredly demonstrate improved patient outcomes. For the therapeutic nihilists, however, SANDS took high-risk patients with type 2 diabetes, studied them under idealized circumstances, and still found no clinical benefit after 3 years of follow-up. In fact, an aggressive approach involved greater polypharmacy and costs and had a higher risk of

adverse effects. In contrast to these extremes and while awaiting longer-term data, a practical middle-of-the-road approach might be to support intensive lipid lowering with statin therapy in patients with diabetes, because this is supported by prior large, randomized, clinical, end point–driven trials,15 and has relatively few adverse effects or patient risks. For intensive blood pressure management, however, more data are needed because the benefits are not assured and there are modest, but measurement-negative effects on patients' finances and well-being. The blood pressure lowering group of the ACCORD trial,16 comparing a goal of lower than 120 mm Hg vs lower than 140 mm Hg, as well as the recently announced National Heart, Lung, and Blood Institute's Systolic Blood Pressure Intervention Trial (SPRINT), comparing aggressive vs standard blood pressure management in a large end point–driven trial, should provide these much needed data.

Finally, believers or not, all clinicians can support the pressing need to better assist patients in effectively modifying their risk factors to whatever goal deemed appropriate. Even in the rigorous National Heart, Lung, and Blood Institute's protocol-driven study environment of SANDS, with concomitant patient education and dedicated study physician and nursing care, blood pressure and lipid targets were reached in fewer than half of all patients. Now in community practice, only a third of patients with hypertension and hyperlipidemia are meeting standard treatment goals.17 This problem would only be magnified if future evidence mandates more stringent goals. Thus, novel strategies to facilitate patient engagement in their disease management are needed.18-19 In conclusion, SANDS is an important step forward in discovering whether lower goals are truly better for primary prevention. While the study results can

be interpreted to support both viewpoints on the ideal target of therapy, such debates are healthy and will ultimately drive physicians to search for more definitive evidence as well as to seek system-wide strategies to effectively reach therapeutic goals in community practice.bill4cr <bill4cr@...> wrote: Effect of Lower Targets for Blood Pressure and LDL Cholesterol onAtherosclerosis in DiabetesThe SANDS Randomized TrialBarbara V. , PhD; J. Roman, MD; B. Devereux, MD;Jerome L. Fleg,

MD; M. Galloway, MD; A. , MD,MPH; Wm. , MD; T. Lee, PhD; Mihriye Mete, PhD; BrycePoolaw, MD; E. Ratner, MD; Marie , MD; Silverman,MSN, CANP; Stylianou, PhD; G. Umans, MD, PhD; Wenyu Wang,PhD; R. Weir, MD; Neil J. Weissman, MD; Charlton , MD;Fawn Yeh, PhD; Jianhui Zhu, MDJAMA. 2008;299(14):1678-1689.Context Individuals with diabetes are at increased risk forcardiovascular disease (CVD), but more aggressive targets for riskfactor control have not been tested.Objective To compare progression of subclinical atherosclerosis inadults with type 2 diabetes treated to reach aggressive targets oflow-density lipoprotein cholesterol (LDL-C) of 70 mg/dL or lower andsystolic blood pressure (SBP) of 115 mm Hg or lower vs standardtargets of LDL-C of 100 mg/dL or lower and SBP of 130 mm Hg or lower.Design, Setting, and

Participants A randomized, open-label,blinded-to-end point, 3-year trial from April 2003-July 2007 at 4clinical centers in Oklahoma, Arizona, and South Dakota. Participantswere 499 American Indian men and women aged 40 years or older withtype 2 diabetes and no prior CVD events.Interventions Participants were randomized to aggressive (n=252) vsstandard (n=247) treatment groups with stepped treatment algorithmsdefined for both.Main Outcome Measures Primary end point was progression ofatherosclerosis measured by common carotid artery intimal medialthickness (IMT). Secondary end points were other carotid and cardiacultrasonographic measures and clinical events.Results Mean target LDL-C and SBP levels for both groups were reachedand maintained. Mean (95% confidence interval) levels for LDL-C in thelast 12 months were 72 (69-75) and 104 (101-106) mg/dL and SBP levelswere 117 (115-118) and 129 (128-130) mm Hg

in the aggressive vsstandard groups, respectively. Compared with baseline, IMT regressedin the aggressive group and progressed in the standard group (–0.012mm vs 0.038 mm; P < .001); carotid arterial cross-sectional area alsoregressed (–0.02 mm2 vs 1.05 mm2; P < .001); and there was greaterdecrease in left ventricular mass index (–2.4 g/m2.7 vs –1.2 g/m2.7; P= .03) in the aggressive group. Rates of adverse events (38.5% and26.7%; P = .005) and serious adverse events (n = 4 vs 1; P = .18)related to blood pressure medications were higher in the aggressivegroup. Clinical CVD events (1.6/100 and 1.5/100 person-years; P = .87)did not differ significantly between groups.Conclusions Reducing LDL-C and SBP to lower targets resulted inregression of carotid IMT and greater decrease in left ventricularmass in individuals with type 2 diabetes. Clinical events were lowerthan expected and did not differ significantly

between groups. Furtherfollow-up is needed to determine whether these improvements willresult in lower long-term CVD event rates and costs and favorablerisk-benefit outcomes.Trial Registration clinicaltrials.gov Identifier: NCT00047424Author Affiliations: MedStar Research Institute, Hyattsville, land(Drs B. V. , Mete, Ratner, Umans, Weissman, and Zhu, and MsSilverman); Weill Cornell Medical College, New York, New York (DrsRoman and Devereux); National Heart, Lung, and Blood Institute,Bethesda, land (Drs Fleg and Stylianou); University of ArizonaHealth Science Center, Tucson (Dr Galloway); Black Hills Center forAmerican Indian Health, Rapid City, South Dakota (Dr );Washington Hospital Center, Washington, DC (Dr W. J. );University of Oklahoma Health Sciences Center, Oklahoma City (Drs Lee,Wang, and Yeh); Lawton Indian Hospital, Lawton, Oklahoma (Dr Poolaw);Phoenix Indian

Medical Center, Phoenix, Arizona (Drs and); and University of land School of Medicine, Baltimore (DrWeir).

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[Guest guest]

Hi folks:

All this fuss. All this expense. When all they really need to do is eat 25% to 40% fewer calories. And that doesn't cost anything. It SAVES 25% to 40% on food bills. Sigh.

Rodney.

> Effect of Lower Targets for Blood Pressure and LDL Cholesterol on> Atherosclerosis in Diabetes> > The SANDS Randomized Trial> > Barbara V. , PhD; J. Roman, MD; B. Devereux, MD;> Jerome L. Fleg, MD; M. Galloway, MD; A. , MD,> MPH; Wm. , MD; T. Lee, PhD; Mihriye Mete, PhD; Bryce> Poolaw, MD; E. Ratner, MD; Marie , MD; Silverman,> MSN, CANP; Stylianou, PhD; G. Umans, MD, PhD; Wenyu Wang,> PhD; R. Weir, MD; Neil J. Weissman, MD; Charlton , MD;> Fawn Yeh, PhD; Jianhui Zhu, MD> > JAMA. 2008;299(14):1678-1689.> > Context Individuals with diabetes are at increased risk for> cardiovascular disease (CVD), but more aggressive targets for risk> factor control have not been tested.> > Objective To compare progression of subclinical atherosclerosis in> adults with type 2 diabetes treated to reach aggressive targets of> low-density lipoprotein cholesterol (LDL-C) of 70 mg/dL or lower and> systolic blood pressure (SBP) of 115 mm Hg or lower vs standard> targets of LDL-C of 100 mg/dL or lower and SBP of 130 mm Hg or lower.> > Design, Setting, and Participants A randomized, open-label,> blinded-to-end point, 3-year trial from April 2003-July 2007 at 4> clinical centers in Oklahoma, Arizona, and South Dakota. Participants> were 499 American Indian men and women aged 40 years or older with> type 2 diabetes and no prior CVD events.> > Interventions Participants were randomized to aggressive (n=252) vs> standard (n=247) treatment groups with stepped treatment algorithms> defined for both.> > Main Outcome Measures Primary end point was progression of> atherosclerosis measured by common carotid artery intimal medial> thickness (IMT). Secondary end points were other carotid and cardiac> ultrasonographic measures and clinical events.> > Results Mean target LDL-C and SBP levels for both groups were reached> and maintained. Mean (95% confidence interval) levels for LDL-C in the> last 12 months were 72 (69-75) and 104 (101-106) mg/dL and SBP levels> were 117 (115-118) and 129 (128-130) mm Hg in the aggressive vs> standard groups, respectively. Compared with baseline, IMT regressed> in the aggressive group and progressed in the standard group (–0.012> mm vs 0.038 mm; P < .001); carotid arterial cross-sectional area also> regressed (–0.02 mm2 vs 1.05 mm2; P < .001); and there was greater> decrease in left ventricular mass index (–2.4 g/m2.7 vs –1.2 g/m2.7; P> = .03) in the aggressive group. Rates of adverse events (38.5% and> 26.7%; P = .005) and serious adverse events (n = 4 vs 1; P = .18)> related to blood pressure medications were higher in the aggressive> group. Clinical CVD events (1.6/100 and 1.5/100 person-years; P = .87)> did not differ significantly between groups.> > Conclusions Reducing LDL-C and SBP to lower targets resulted in> regression of carotid IMT and greater decrease in left ventricular> mass in individuals with type 2 diabetes. Clinical events were lower> than expected and did not differ significantly between groups. Further> follow-up is needed to determine whether these improvements will> result in lower long-term CVD event rates and costs and favorable> risk-benefit outcomes.> > Trial Registration clinicaltrials.gov Identifier: NCT00047424> > Author Affiliations: MedStar Research Institute, Hyattsville, land> (Drs B. V. , Mete, Ratner, Umans, Weissman, and Zhu, and Ms> Silverman); Weill Cornell Medical College, New York, New York (Drs> Roman and Devereux); National Heart, Lung, and Blood Institute,> Bethesda, land (Drs Fleg and Stylianou); University of Arizona> Health Science Center, Tucson (Dr Galloway); Black Hills Center for> American Indian Health, Rapid City, South Dakota (Dr );> Washington Hospital Center, Washington, DC (Dr W. J. );> University of Oklahoma Health Sciences Center, Oklahoma City (Drs Lee,> Wang, and Yeh); Lawton Indian Hospital, Lawton, Oklahoma (Dr Poolaw);> Phoenix Indian Medical Center, Phoenix, Arizona (Drs and> ); and University of land School of Medicine, Baltimore (Dr> Weir).> > > > > > > ---------------------------------> Be a better friend, newshound, and know-it-all with Mobile. Try it now.>