- Email: [email protected]
Insulin resistance, hypertension, and coronary heart disease
A
1997-VOL. 10,JNO. 4, PART 2
H
Saturday May 31, Ballroom B, 9:00 am Theme II: Diabetes, Insutin, and the Heart Insulin Resistance, Hypertension, and Coronary Heart Disease Gerald M. Reaven, M.D. Stanford University School of Medicine, and Shaman Pharmaceuticals, Inc. Anti-hypertensive drug therapy dramatically reduces stroke in patients with high blood pressure (~BP). Unfortunately, treatment of ?BP has had less of a beneficial effect on coronary heart disease (CHD). To account for the discrepancy between blood pressure lowering and the anticipated decrease in CHD, it has been argued that: 1) the discrepancy between blood pressure reduction and decrease in CHD is due to the fact that the trials were not carried on long enough; and 2) tbiazide diuretics and/or beta receptor antagonists had untoward effects on carbohydrate and lipid metabolism that tended to mitigate their beneficial effects on blood pressure. Likely to be of greater relevance is the fact that patients with ~BP, aa a group, tend to be insulin resistant (IR), glucose intolerant, hyperinsulinemic (~1), nnddyslipidemic; cban es that increase risk of CHD. For example, patients with ? BP and electrocardiographic evidence of ischemic heart disease are IR, glucose intolerant, ~1, and dyslipidemic when compared to a matched group of patients with nomral electrocardiograms. In addition, in patients with ?BP and asymptomatic atherosclerosis, intimel-media thickness (fMT) aa assessed by B-mode rdtrasonography of the carotid -V was slgmfwmtly correlated with fR, the height of the plasma glucose and msuhn responses to a glucose challenge, and low HDL-cholesterol concentration. Degree of IRwaa the strongest risk, foRowed by a low HDL-cholesterol concentration, and systolic blood pressure; these tbrce factors accounted for 55% of the differences obsenfed in carotid artery IMT. Finally, the magnitude of the abnurnralities in insulin, glucose and lipoprotein metabolism when present in patients with ~BP is much greater than the untoward effect of any anti-hypsrtensive treatment, and lowering blond pressure with anti-hypertensive treatment dries not return these metabolic abnormalities to normaf. Since no attention waadirectcd toward tbese metabolic abnormalities in any clinical trial, it is not surprising that CHD risk reduction waa less tban anticipated.
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AFACULTY ABSTRACTSP
Saturday May 31, Ballroom A, 9:00 am Theme III: The “Rules” of Evidence in Clinical Medicine: Calcium Antagonists—A Case in Point An Overviewof ResearchMethods: advantages and disadvantages Paul D. Stolley, M.D., M.P.H., Universityof Maryland School of Medicine Reports of a possible association of calcium channel blockers and sudden death resulted in a heated controversy. The issue led to a focus upon the quality and inferential power of various research methods used to address this important clinical question. The research methods that theoretically can be applied to this question are reviewed and the advantages and disadvantages listed and discussed. Criteria usually applied to judge whether an association is likely to be causal are presented. The methods reviewed are: case-repoti series; @se-control; cohort; randomized controlled trial; “ecologic;” meta-analytic;“natural” experiments and “experiments in prevention.”
Key Words:
Hypertension, insulin resistance, hyperirrsulinemia, dyslipidemia, gfrrcose intolerance, coronary heart diseaae.
Key Words:
Researchmethods;causality;caseconfrol;cohort;experimental; non-experimental
Saturday May 31, Ballroom A, 9:00 am Theme III: The “Rules” of Evidence in Clinical Medicine: Calcium Antagonists—A Case in Point
Saturday May 31, Ballroom A, 9:00 am Theme III: The “Rules” of Evidence in Clinical Medicine: Calcium Antagonists—A Case in Point
THE RULES OF EVIDENCE IN CLINICAL MEDICINE: CAMXJM ANTAGONISTS--A CASE IN POINT. OBSERVATIONAL STUDIES. EM_&@, TD Koepsell, DS Siscovick, SR Heckbert, NS Weiss, M Pshor, D Lin, Cardiovsacrdar Health Research Urrit, University of Waahirrgton, Seattfe, WA. ‘Ilre purpose of treating high blood pressure is to reduce the riak of complication such aa stroke and myocardial infarction. In the absence of evidence from clinical trials, obacrvatioml studies have raiaed questiona about the safety arrdefficacy of short-actirrgcalcium arrtagonista. In caae-control and mhort atudies of hypwterraivepatienta, calcium antegonista have been associated increawd riaka of myocardial infarction, congestive heart failure, gaatrointestbral bleeding, cancer and total mortafity. Well-conducted observatioml studies should meet specific criteria that include: (1) complete ascertainment of eventa; (2) a properly choaen cuntrol group; (3) comparable assessment of expoaures and confounders; and (4) appropriate control for confounding. What distinguishes randomized trials from observatioml studies is the proceas by which therapies are assigned, and special forma of confounding by indication are poasible when routine care replacea randomization. Several approaches, including comparisons with therapies having the aame indication, are available to assess and control fur confounding by indication. While the hypothetical effects of putative “unmeasured confounding factors” are often cited as reasons for simply ignoring the findings of observational studies, it is possible to show empirically that these effects are likely to be amall unfess the confounding factor ia at once a major risk factor for the outcome and is, at the same time, strongly associated with the exposure of interest. Obaervatiorral studies are particularly important for aasessirrgrare but serioua side effecta of commonly used therapies. While randomized trials are essential for defining the eftlcacy of dmg therapies, obaervatioml studies are generally adequate to raise.concecrra about aafety.
The “Rules” of Evidence in Clinical Medicine: Calcium Antagonista - A Case in Point. Clinical Trials Curt D. Furberg, Buwman Gray School of Medicine The randomized clinical trial (RCT) is the gold standard method for the evaluation of treatment effects in clinical medicine. Critical design decisions involve the selection of the study population, the primary outcome, the intervention and the comparison groups. In hypertension trials, the most fundamental question includes selection of the outcome, since this dramatically influences the trial size, duration arrd cost. The selection of morbidity and mortelity outcomes (to reflect health benefits) is critical to the proper evaluation of newer antihypertensives. Reliance on blood pressure- lowering potential, a surrogate outcome, is based on several faulty assumptions, including the one that drugs have a single mechanism of action. The sum of all drug actions, good and bad, determines the health benefit to patients. Positive contrri’1 trials are proper designs for trials of newer agents, since they can provide documentation of relative etlcacy, safety and cost-effectiveness. Proper trial documentation of Iong-term eftlcacy and safety is not always available. Diuretics, especially in low doses, and beta-blockers have been shown in large, long-term placebo-controlled RCTS to convey overall health benefits to patients with hypertension. Such documentation is lacking for the newer and more expensive classes of antihypertensive agents. Clinical trials of calcium antagonists and other newer agents are underway and they will eventually determine the appropriate role of these agents in the treatment of hypertension. Key Words:
225A
1997-VOL. 10,JNO. 4, PART 2
H
Saturday May 31, Ballroom B, 9:00 am Theme II: Diabetes, Insutin, and the Heart Insulin Resistance, Hypertension, and Coronary Heart Disease Gerald M. Reaven, M.D. Stanford University School of Medicine, and Shaman Pharmaceuticals, Inc. Anti-hypertensive drug therapy dramatically reduces stroke in patients with high blood pressure (~BP). Unfortunately, treatment of ?BP has had less of a beneficial effect on coronary heart disease (CHD). To account for the discrepancy between blood pressure lowering and the anticipated decrease in CHD, it has been argued that: 1) the discrepancy between blood pressure reduction and decrease in CHD is due to the fact that the trials were not carried on long enough; and 2) tbiazide diuretics and/or beta receptor antagonists had untoward effects on carbohydrate and lipid metabolism that tended to mitigate their beneficial effects on blood pressure. Likely to be of greater relevance is the fact that patients with ~BP, aa a group, tend to be insulin resistant (IR), glucose intolerant, hyperinsulinemic (~1), nnddyslipidemic; cban es that increase risk of CHD. For example, patients with ? BP and electrocardiographic evidence of ischemic heart disease are IR, glucose intolerant, ~1, and dyslipidemic when compared to a matched group of patients with nomral electrocardiograms. In addition, in patients with ?BP and asymptomatic atherosclerosis, intimel-media thickness (fMT) aa assessed by B-mode rdtrasonography of the carotid -V was slgmfwmtly correlated with fR, the height of the plasma glucose and msuhn responses to a glucose challenge, and low HDL-cholesterol concentration. Degree of IRwaa the strongest risk, foRowed by a low HDL-cholesterol concentration, and systolic blood pressure; these tbrce factors accounted for 55% of the differences obsenfed in carotid artery IMT. Finally, the magnitude of the abnurnralities in insulin, glucose and lipoprotein metabolism when present in patients with ~BP is much greater than the untoward effect of any anti-hypsrtensive treatment, and lowering blond pressure with anti-hypertensive treatment dries not return these metabolic abnormalities to normaf. Since no attention waadirectcd toward tbese metabolic abnormalities in any clinical trial, it is not surprising that CHD risk reduction waa less tban anticipated.
-
AFACULTY ABSTRACTSP
Saturday May 31, Ballroom A, 9:00 am Theme III: The “Rules” of Evidence in Clinical Medicine: Calcium Antagonists—A Case in Point An Overviewof ResearchMethods: advantages and disadvantages Paul D. Stolley, M.D., M.P.H., Universityof Maryland School of Medicine Reports of a possible association of calcium channel blockers and sudden death resulted in a heated controversy. The issue led to a focus upon the quality and inferential power of various research methods used to address this important clinical question. The research methods that theoretically can be applied to this question are reviewed and the advantages and disadvantages listed and discussed. Criteria usually applied to judge whether an association is likely to be causal are presented. The methods reviewed are: case-repoti series; @se-control; cohort; randomized controlled trial; “ecologic;” meta-analytic;“natural” experiments and “experiments in prevention.”
Key Words:
Hypertension, insulin resistance, hyperirrsulinemia, dyslipidemia, gfrrcose intolerance, coronary heart diseaae.
Key Words:
Researchmethods;causality;caseconfrol;cohort;experimental; non-experimental
Saturday May 31, Ballroom A, 9:00 am Theme III: The “Rules” of Evidence in Clinical Medicine: Calcium Antagonists—A Case in Point
Saturday May 31, Ballroom A, 9:00 am Theme III: The “Rules” of Evidence in Clinical Medicine: Calcium Antagonists—A Case in Point
THE RULES OF EVIDENCE IN CLINICAL MEDICINE: CAMXJM ANTAGONISTS--A CASE IN POINT. OBSERVATIONAL STUDIES. EM_&@, TD Koepsell, DS Siscovick, SR Heckbert, NS Weiss, M Pshor, D Lin, Cardiovsacrdar Health Research Urrit, University of Waahirrgton, Seattfe, WA. ‘Ilre purpose of treating high blood pressure is to reduce the riak of complication such aa stroke and myocardial infarction. In the absence of evidence from clinical trials, obacrvatioml studies have raiaed questiona about the safety arrdefficacy of short-actirrgcalcium arrtagonista. In caae-control and mhort atudies of hypwterraivepatienta, calcium antegonista have been associated increawd riaka of myocardial infarction, congestive heart failure, gaatrointestbral bleeding, cancer and total mortafity. Well-conducted observatioml studies should meet specific criteria that include: (1) complete ascertainment of eventa; (2) a properly choaen cuntrol group; (3) comparable assessment of expoaures and confounders; and (4) appropriate control for confounding. What distinguishes randomized trials from observatioml studies is the proceas by which therapies are assigned, and special forma of confounding by indication are poasible when routine care replacea randomization. Several approaches, including comparisons with therapies having the aame indication, are available to assess and control fur confounding by indication. While the hypothetical effects of putative “unmeasured confounding factors” are often cited as reasons for simply ignoring the findings of observational studies, it is possible to show empirically that these effects are likely to be amall unfess the confounding factor ia at once a major risk factor for the outcome and is, at the same time, strongly associated with the exposure of interest. Obaervatiorral studies are particularly important for aasessirrgrare but serioua side effecta of commonly used therapies. While randomized trials are essential for defining the eftlcacy of dmg therapies, obaervatioml studies are generally adequate to raise.concecrra about aafety.
The “Rules” of Evidence in Clinical Medicine: Calcium Antagonista - A Case in Point. Clinical Trials Curt D. Furberg, Buwman Gray School of Medicine The randomized clinical trial (RCT) is the gold standard method for the evaluation of treatment effects in clinical medicine. Critical design decisions involve the selection of the study population, the primary outcome, the intervention and the comparison groups. In hypertension trials, the most fundamental question includes selection of the outcome, since this dramatically influences the trial size, duration arrd cost. The selection of morbidity and mortelity outcomes (to reflect health benefits) is critical to the proper evaluation of newer antihypertensives. Reliance on blood pressure- lowering potential, a surrogate outcome, is based on several faulty assumptions, including the one that drugs have a single mechanism of action. The sum of all drug actions, good and bad, determines the health benefit to patients. Positive contrri’1 trials are proper designs for trials of newer agents, since they can provide documentation of relative etlcacy, safety and cost-effectiveness. Proper trial documentation of Iong-term eftlcacy and safety is not always available. Diuretics, especially in low doses, and beta-blockers have been shown in large, long-term placebo-controlled RCTS to convey overall health benefits to patients with hypertension. Such documentation is lacking for the newer and more expensive classes of antihypertensive agents. Clinical trials of calcium antagonists and other newer agents are underway and they will eventually determine the appropriate role of these agents in the treatment of hypertension. Key Words:
225A