Volume 01, Issue 04
May 7, 2010
Cardiometabolic Risk: Focus on Clinical Trials
ACCORD, ADVANCE, and VADT: What Do the Subanalyses Suggest?
Commentary by:
Peter Reaven, MD, Professor of Clinical Medicine and Director, Diabetes Program, Carl T. Hayden Veterans Administration Medical Center, Phoenix, AZ
Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial
In February, 2008, the glycemic control study of ACCORD was stopped early because of the finding of increased mortality in the group undergoing intensive glycemic control, compared to the standard-therapy group. One of the factors thought to contribute to the excess mortality is severe hypoglycemia (which was more common with intensive therapy).
Prespecified subanalyses of the ACCORD data identified two groups that seemed to benefit from intensive therapy: individuals who had no history of cardiovascular events at study entry and those who entered the study with a hemoglobin A1C <8%.
Veterans Affairs Diabetes Trial (VADT)
There was some association of intensive treatment with increased mortality in this trial, but the difference was not statistically significant. Furthermore, subanalyses show that duration of diabetes affected response to treatment: Individuals who had diabetes for £15 years seemed to benefit from intensive therapy, whereas those with longer duration of disease seemed to be at increased risk with intensive therapy.
Retrospective cohort study from the United Kingdom
This study assessed survival as a function of A1C in individuals ³50 yr of age with type 2 diabetes. Researchers created two cohorts (one treated with oral agents only; the other treated with insulin therapy), using data from the UK General Practice Research Database. In both groups, survival was greatest at an average A1C of »7.5%; survival rates decreased as average A1C increased or decreased.
VADT substudy: atherosclerosis
Computed tomography was used to assess baseline coronary calcium as a marker of atherosclerosis. Participants were then randomized to standard or intensive management of blood glucose and followed for cardiovascular outcomes. Patients with low baseline levels (Agatston score of 0-10) of coronary calcium seemed to benefit from intensive management, but the benefit decreased with increasing Agatston score.
Relationship with comorbidities
A study by Greenfield and colleagues looked at the relationship between comorbidities (scored using the total illness burden index [TIBI]) and response to antihyperglycemic therapy. Participants with a TIBI score <12 seemed to benefit (in terms of cardiovascular events) from having low A1C levels. However, those with higher TIBI scores did not seem to benefit from having low A1C.
Take-home messages
• Other cardiovascular risk factors (lipids; BP; smoking; overweight) should be treated aggressively.
• Aggressive glycemic control may not be indicated for all patients (eg, those who are older, have a long history of diabetes, or have CVD).
• Other subsets of patients benefit from intensive efforts to control blood glucose, but this needs to be done safely to avoid hypoglycemia.
• If the findings from the VADT substudy are confirmed, there may be a role for coronary imaging for assessing vascular risk and making decisions about therapy.
The ACCORD Lipid Trial: Results and Implications
Interview with:
Henry Ginsberg, MD, Irving Professor of Medicine and Director, Irving Institute for Clinical and Translational Research, Columbia University, New York, NY
Overview
Question: Is combination therapy of a statin (simvastatin) and fibrate (fenofibrate) associated with greater protection from cardiovascular events than is statin monotherapy?
Design: Randomized, double-blind, placebo-controlled substudy, which enrolled »5500 participants (from the ACCORD glycemic control study). Half the patients were randomized to simvastatin monotherapy (40 mg/day); the other half to simvastatin plus fenofibrate.
Primary outcome: Composite of cardiovascular death, nonfatal MI, and nonfatal stroke.
Results: Combination therapy was associated with a risk reduction of 8%, compared to monotherapy, but this difference was not statistically significant.
Subgroup analyses
Women vs men: There was a significant sex-based difference in response to therapy. Combination therapy seemed to increase risk in women but decrease risk in men. The researchers are continuing to investigate these associations.
Lipid profile: Combination therapy was associated with benefit (just short of statistical significance) in participants with high levels of triglycerides (>204 mg/dL) and low levels of HDL-cholesterol (<34 mg/dL).
Adverse effects
Myalgias: Previous studies found that gemfibrozil interfered with statin metabolism, resulting in elevated blood levels of the drug and increased risk for myalgias. No such effect was found with fenofibrate. In ACCORD, rates of myalgias and myositis were low, and no differences were seen between treatment groups. It should be noted that in ACCORD the statin dose was 40 mg of simvastatin. Myalgias may be more common with higher doses or with more potent statins.
Creatinine elevation: Although some elevations were seen with fenofibrate therapy, levels returned to normal once the agent was stopped. Despite the elevations in creatinine, there were fewer cases of microalbuminuria and macroalbuminuria. Therefore, the researchers consider the elevations to be benign.
“The last thing that anybody should take away from [the ACCORD trial] is that statins don’t work… Every diabetic should be placed on a statin.”
Options for patients
who can’t tolerate statins
• Bile acid binding resins (eg, colesevelam) can lower LDL cholesterol by 15% to 20%.
• Ezetimibe can lower LDL cholesterol by 15% to 20%.
• Combination therapy with colesevelam and ezetimibe is associated with 30% to 35% reduction in LDL cholesterol.
• Niacin therapy is associated with 10% to 15% reduction (note, however, that niacin therapy may result in elevated blood glucose and A1C).
The ACCORD Blood Pressure Trial: Results and Implications
Interview with:
William Cushman, MD, Chief, Preventive Medicine, Memphis Veterans Administration Medical Center, Memphis, TN
Overview
Question: Does a therapeutic strategy targeting a systolic BP <120 mm Hg reduce cardiovascular events, compared to a strategy targeting a systolic BP <140 mm Hg?
BP control: Intensive group — Therapy was initiated with two agents. Treatment was adjusted on a monthly basis to achieve a systolic BP <120 mm Hg (or until investigators determined that further increases in medication would be unsafe or unlikely to result in further reductions in BP). Standard group — Medication was uptitrated if systolic BP was ³160 mm Hg on a single visit or ³140 mm Hg on two consecutive visits. Doses could be decreased if BP dropped below 130 mm Hg.
Mean systolic BP achieved: 134 mm Hg in the standard therapy group; 119 mm Hg in the intensive therapy group.
Primary outcome: Composite of cardiovascular death, nonfatal MI, and nonfatal stroke.
Results: No significant differences were seen in the composite outcome. However, intensive therapy was associated with a 40% reduction in risk for stroke (secondary outcome).
Other clinical trials
A number of clinical trials have shown benefit of lowering BP in patients with diabetes. Studies such as the United Kingdom Prospective Diabetes Study (UKPDS), the Hypertension Optimal Treatment (HOT) study, and the Systolic Hypertension in the Elderly Program (SHEP) showed that reducing BP (to levels around 140-150 mm Hg) was associated with improvements in morbidity and mortality.
Effect on stroke risk
The finding of reduced risk for stroke with lower BP is consistent with previous trials: A 10- to 15-mm Hg reduction in systolic BP has been associated with a risk reduction similar to that seen in ACCORD.
The number needed to treat (NNT) to prevent one stroke in ACCORD was 89. However, because stroke was not a primary outcome of ACCORD, this finding needs to be confirmed. More research is needed to better understand the relationship between BP control and stroke risk and to identify which patients may benefit most from intensive therapy.
Adverse events
Compared to standard therapy, intensive therapy was associated with increased risk for:
• Hypotension
• Elevations in creatinine
• Elevations in potassium
However, the rate of adverse events was low, and they were typically manageable and reversible.
The future of BP goals
The American Diabetes Association (ADA) and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) currently recommend a systolic BP target of 130 mm Hg.
To date, there have been no randomized clinical trials using this level of BP as a target. So far, most evidence supports a systolic BP of 140 mm Hg. However, there may be benefit associated with lower BP, in terms of reducing risk for stoke in some patients.
The importance of lifestyle
Lifestyle changes (ie, diet and physical activity) appear safe and effective for improving BP, glycemic control, and cardiovascular risk.
“It’s not bad news that we don’t have to add a few more drugs.”
Cardiometabolic Risk Management: Where Do We Stand?
Interview with:
Robert Eckel, MD, Professor, Departments of Medicine, Physiology, and Biophysics, University of Colorado Health Science Center, Denver, CO
Comments on ACCORD
Lipid trial: Findings are consistent with those of other clinical trials (eg, Fenofibrate Intervention and Event Lowering in Diabetes [FIELD]; Veterans Affairs High-Density Lipoprotein Intervention Trial [VA-HIT]). Individuals who seem to benefit from the addition of fibrate therapy are those with high levels of triglycerides (>200 mg/dL).
BP trial: Although increasing intensity of therapy resulted in lower BP, it was not associated with reduced overall cardiovascular risk. In addition, adverse effects were more common with intensive therapy. Therefore, the current recommendation of a target BP of 130/80 mm Hg is sufficient; most people are unlikely to benefit from lower BP.
Thiazolidinediones (TZDs)
The American Heart Association and American College of Cardiology Foundation recently released a science advisory on the use of thiazolidinediones. The advisory states:
• TZDs should not be used with an expectation of benefit with respect to ischemic heart disease events.
• Insufficient data exist to support the choice of pioglitazone over rosiglitazone.
• TZDs increase the risk of heart failure and should not be initiated in patients with class III/IV heart failure.
Approach to management
Glycemic control
• An A1C target <7% is appropriate for most patients.
• For individuals with type 2 diabetes, metformin is recommended as first-line medical therapy.
• Many options exist for second-line therapy, including sulfonylureas (but these may cause hypoglycemia), incretin therapies, TZDs, and insulin.
Lipid control
• All patients with type 2 diabetes should be on statin therapy, if tolerated.
• The current target for LDL cholesterol is <100 mg/dL, with an optional target of <70 mg/dL for patients at high risk for CVD.
• Triglyceride-lowering therapy should be considered for patients with triglyceride levels >200 mg/dL.
BP control
The current recommendation is £130/80 mm Hg.
Coming next month…
Diabetes Self-Management and Patient Empowerment
New Technologies in Diabetes Education and Management
American Diabetes Association’s 70th Scientific Sessions
June 25 - 29, 2010, Orlando, Florida
Orange County Convention Center
If you are involved in diabetes research or the delivery of diabetes care and services — don't miss this chance to join your colleagues at the world's largest and most prestigious diabetes meeting. The comprehensive programming of the 70th Scientific Sessions provides cutting-edge education and information for all members of the diabetes community — physicians, scientists, nurses, nurse practitioners, dietitians, pharmacists, podiatrists, psychologists and other health care professionals.
Registration Deadlines
May 13, 2010 ¾ Advance Registration Deadline
June 4, 2010 ¾ Deadline to Register by Mail
June 17, 2010 ¾ Deadline to Register Online
For more information, go to http://professional.diabetes.org
Suggested Reading
The ACCORD Study Group: Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med Mar 14, 2010 [Epub ahead of print]; The ACCORD Study Group: Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med Mar 18, 2010 [Epub ahead of print]; Aizawa K et al: Longitudinal changes in central artery stiffness with lifestyle modification, washout, and drug treatment in individuals at risk for cardiovascular disease. Metab Syndr Relat Disord Apr 1, 2010 [Epub ahead of print]; Albu JB et al: Metabolic changes following a 1-year diet and exercise intervention in patients with type 2 diabetes. Diabetes 59:627, 2010; American Diabetes Association: Standards of medical care in diabetes – 2010. Diabetes Care 33 (Suppl 1):S11, 2010; Bergenstal RM et al: Type 2 diabetes: assessing the relative risks and benefits of glucose-lowering medications. Am J Med 123:374, 2010; Currie CH et al: Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet 375:481, 2010; Greenfield S et al: Comorbidity affects the relationship between glycemic control and cardiovascular outcomes in diabetes: a cohort study. Ann Intern Med 151:854, 2009; Homko CJ et al: Gender differences in cardiovascular risk factors and risk perception among individuals with diabetes. Diabetes Educ Apr 1, 2010; Kaul S et al: Thiazolidinedione drugs and cardiovascular risks. A science advisory from the American Heart Association and American College of Cardiology Foundation. Circulation Feb 23, 2010 [Epub ahead of print]; Qasim AN et al: Lipoprotein(a) is strongly associated with coronary artery calcification in type 2 diabetes women. Int J Cardiol Mar 18, 2010 [Epub ahead of print]; Reaven PD et al: Intensive glucose-lowering therapy reduces cardiovascular disease events in Veterans Affairs Diabetes Trial participants with lower calcified coronary atherosclerosis. Diabetes 58:2642, 2009; Rizvi AA: Hypertension, obesity, and inflammation: the complex designs of a deadly trio. Metab Syndr Relat Disord Apr 1, 2010 [Epub ahead of print]; Rutter MK, Nesto RW: The BARI 2D study: a randomised trial of therapies for type 2 diabetes and coronary artery disease. Diab Vasc Dis Res 7:69, 2010; Scheede-Bergdahl C et al: Cardiovascular disease markers in type 2 diabetes: the effects of a moderate home-based exercise training programme. Diab Vasc Dis Res 6:291, 2009; Sharma M et al: Systematic review: comparative effectiveness and harms of combination therapy and monotherapy for dyslipidemia. Ann Intern Med 151:622, 2009; Skyler JS et al: Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials: a position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol 53:298, 2009.
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