From the ACP Diabetes Care Guide

This tool lists what to consider before providing patients with these medications.

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From the ACP Diabetes Care Guide

Patients with diabetes have accelerated atherosclerosis and an increased incidence of premature cardiovascular events. Epidemiologic studies and major clinical trials have shown that cardiovascular risk factors-including hypercholesterolemia, hypertension, and cigarette smoking-have an increased impact on the incidence and progression of cardiovascular events. These risk factors often coexist as key components of the metabolic syndrome. In particular, patients with type 2 diabetes have an increased prevalence of lipid abnormalities (>80%, based on current goals) and hypertension (>60%). Moreover, patients with type 1 diabetes that is accompanied by renal disease and those with type 2 diabetes that is poorly controlled have additional lipid abnormalities, including high triglyceride levels and low HDL cholesterol levels.

Because of the markedly increased risk of cardiovascular disease in patients with diabetes and the established evidence for improved outcome with optimal management, various clinical practice guidelines (of the American College of Physicians [ACP], the American Diabetes Association [ADA], the American Heart Association [AHA], and others), advocate stricter goals for such patients than for those without diabetes. According to available recent national statistics, however, the control of glycemia, blood pressure, and LDL cholesterol is not being achieved in most patients with diabetes.

NOTE: You may order free copies of the complete ACP Diabetes Care Guide (book and CD-ROM).

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From the ACP Diabetes Care Guide

Persons with diabetes are at increased risk for macrovascular disease; microvascular disease, including retinopathy and nephropathy; peripheral and autonomic neuropathies; and lower extremity disease.

• Diabetic retinopathy is the leading cause of noncongenital blindness among adults.
• Diabetes is the most common cause of endstage kidney disease in the United States, especially among Native American, Hispanic, and African American persons. One quarter to one third of patients with type 1 or type 2 diabetes develop some degree of nephropathy.
• Diabetes doubles the risk for cardiovascular disease in men and triples it in women (data from the Multiple Risk Factor Intervention Trial [MRFIT]).
• Patients with diabetes are several-fold more likely to have peripheral arterial disease than patients without diabetes.
• Peripheral arterial disease and foot ulcers in patients with diabetes account for two thirds of all nontraumatic amputations performed in the United States.

Screening for and prevention of these complications are fundamental to the care of patients with diabetes and are important components of quality of care initiatives for diabetes.

NOTE: You may order free copies of the complete ACP Diabetes Care Guide (book and CD-ROM).

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• What level of creatinine elevation is "significant" as a cardiovascular risk factor?
• Should coronary artery disease and "traditional" cardiovascular risk factors be treated differently in patients with CKD compared with those without?
• Erythropoietin: Leave management to others?
• Does hypokalemia reduce cardiovascular benefit of hypertension care?
• What else do I do besides treating the blood pressure?

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Diabetes imparts a 2- to 4-fold increased risk of major cardiovascular events. The presence of diabetes is now considered a cardiovascular risk equivalent, based on data indicating that patients with diabetes but no history of coronary artery disease are at a similar risk of myocardial infarction as a nondiabetic individual who has survived a previous infarction.

Because of this disproportionate suffering from cardiovascular disease, aggressive risk factor reduction strategies are imperative.

Note: Subscription to MKSAP 14 is required to view this material. For more information, visit www.acponline.org.

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Two meta-analyses released last week add to the growing array of data on the cardiovascular effects of diabetes drugs rosiglitazone and pioglitazone.

The meta-analysis of rosiglitazone included four studies of 14,000 people and concluded that use of the drug for at least 12 months was associated with a significantly increased risk of myocardial infarction (MI) and heart failure, but the study did not find a significantly increased risk of cardiovascular mortality compared with controls.

The second meta-analysis used a database of 19 trials involving 16,000 patients provided by the manufacturer for independent analysis. Researchers found that pioglitazone was associated with a significantly lower risk of death, MI or stroke than controls. The drug did increase serious heart failure, although without an associated increase in mortality.

Authors of both analyses noted that it is unclear why the drugs--both thiazolidinediones--have such different effects on cardiovascular outcomes. The authors of the pioglitazone research concluded that the net clinical benefit of therapy with the drug is favorable. In their view, the reduction in irreversible ischemic events is not attenuated by the risk of more frequent heart failure complications.

The authors of the rosiglitazone analysis said that their research suggests a reversal of the benefit-to-harm balance that led the FDA to approve the drug. They propose that regulatory agencies reevaluate whether the drug belongs on the market. Physicians should not wait for a government decision, the authors advised, and should avoid prescribing the drug for patients who are at risk of cardiovascular events. Both meta-analyses were published in the Sept. 12 Journal of the American Medical Association.

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Thiazolidinediones, primarily rosiglitazone (Avandia), increase the risk of congestive heart failure, acute myocardial infarction and death for older patients with diabetes, a new study found.

The retrospective cohort study used health care databases in Ontario to examine 159,026 diabetes patients age 66 years and older who had been treated with at least one hypoglycemic agent between 2002 and 2005. Follow up was for a median of 3.8 years. The study was published in the Dec. 12 Journal of the American Medical Association.

Patients treated with thiazolidinedione monotherapy had a 60% higher risk of congestive heart failure, a 40% higher risk of acute myocardial infarction and a 29% higher risk of death compared with people taking other hypoglycemic agent combination therapies. Patients treated with thiazolidinedione combination therapy had a 31% higher risk of congestive heart failure, and a 24% higher risk of death, but no higher risk of heart attack, compared with those taking other therapies. The association between thiazolidinedione treatment and cardiac events appears limited to rosiglitazone, the authors said.

Past research has indicated that rosiglitazone and pioglitazone may increase the risk of congestive heart failure, while two meta-analyses have suggested rosiglitazone may increase the risk of acute myocardial infarction. The FDA recently added boxed warnings to the drugs' labels to reflect these risks, but has stopped short of recommending that the drugs be pulled from the market.

"These findings provide evidence from a real-world setting and support data from clinical trials that the harms of thiazolidinediones may outweigh their benefits," though further studies are needed, the authors said. For now, clinicians need to weigh the potential benefits and harms of treatment on an individual basis, especially with high-risk elderly populations, they said.

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A large government trial of diabetes treatments was halted last week after it was found that intensive efforts to lower patients? blood sugar were associated with higher mortality rates.

The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial included more than 10,000 patients who had diabetes and at least two other risk factors for heart disease. The patients were randomized to either intensively low blood sugar goals (A1c of less than 6%) or standard goals and treatment (A1c between 7% and 7.9%). Over the almost four-year study period, 257 patients in the intensive group had died, compared with 203 patients in the standard group, NIH officials announced last week. Based on that survival difference (which works out to 3 deaths per 1,000 participants per year), officials decided to halt the intensive treatment arm of the trial.

The researchers have not uncovered an explanation for the difference in survival, although an investigation is ongoing. Overall, death rates in both groups were lower than in similar populations in other studies. Because of recent concerns, the researchers specifically looked at rosiglitazone for a link to the increased deaths, but they found no association. The standard treatment arm of the ACCORD study, as well as related trials of blood pressure and lipid treatment, will continue until the planned conclusion date of June 2009.

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SAN FRANCISCO - Diabetes and testosterone studies topped the news at ENDO 08, the Endocrine Society's 90th annual meeting held last week. Among the research of interest to internists:

• Women with type 2 diabetes and heart disease get less intensive medical treatment for, and have poorer control of, these two conditions than men. In a study of nearly 45,000 diabetics, the comorbid women were 44% more likely than the comorbid men to have high LDL, but 15% less likely to get lipid-lowering medication. The women were also 19% more likely to have uncontrolled hypertension, and 15% more likely to have poor long-term control of their blood glucose levels. The findings may explain why death from heart disease has decreased among diabetic men in the past 25 years, but hasn't decreased for diabetic women, the study's lead author said.
• For obese and overweight men with type 2 diabetes, moderate fitness levels lowered the risk of all-cause death by 40%-50% during an average follow-up of seven years. By measuring peak metabolic rate during a standard treadmill exercise tolerance test, researchers classified fitness levels as low, moderate or high. Moderate fitness reduced death risk by 40% in healthy-weight and overweight men, and 52% in obese men, while high fitness level reduced death risk by 60% in healthy-weight men, and 65% in overweight men. The results suggest all diabetics, regardless of weight, should achieve and maintain at least a moderate fitness level, a study co-author said.

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A recent large study found that poor glucose control was associated with a fourfold increase in mortality and major complications following cardiac surgery, regardless of whether patients had been diagnosed with diabetes.

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Question
In older patients with type 2 diabetes, do thiazolidinediones (TZDs) increase risk for heart failure (HF), myocardial infarction (MI), and mortality more than other oral hypoglycemic agents?

Conclusion
In older patients with type 2 diabetes, thiazolidinediones (in particular, rosiglitazone) were associated with higher risks for heart failure, myocardial infarction, and mortality than other oral hypoglycemic agents.

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Question
In patients with prediabetes or type 2 diabetes, do thiazolidinediones (TZDs) increase the risk for congestive heart failure (CHF) and cardiovascular death?

Conclusion
In patients with prediabetes or type 2 diabetes, thiazolidinediones increase the risk for congestive heart failure but not cardiovascular death.

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Question
In patients with heart failure (HF) and diabetes, what is the relation between antidiabetic therapy and morbidity and mortality?

Conclusion
Metformin and thiazolidinediones are associated with reduced risk but insulin is associated with increased risk for all-cause mortality in patients with heart failure and diabetes.

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Question
In patients with type 2 diabetes, what is the risk for heart failure (HF) associated with thiazolidinediones (TZDs)?

Conclusion
Thiazolidinediones increase risk for heart failure in patients with type 2 diabetes.

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Question
In patients with type 2 diabetes, does pioglitazone reduce cardiovascular events, other adverse events, and mortality or improve health-related quality of life?

Conclusions
Based on 1 randomized trial, pioglitazone does not reduce risk for mortality or cardiovascular events in patients with type 2 diabetes. Some evidence exists that pioglitazone increases risk for such adverse events as weight gain, decrease in hemoglobin level, and edema.

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Question
In patients with type 2 diabetes, is atorvastatin more effective than placebo for preventing cardiovascular (CV) events?

Conclusions
In low-risk patients with type 2 diabetes, atorvastatin did not prevent cardiovascular events.

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Question
In patients with vascular disease, does lowering plasma homocysteine levels with folic acid and B vitamins reduce risk for major vascular events?

Conclusion
In patients with vascular disease, lowering plasma homocysteine levels with folic acid and B vitamins did not reduce risk for the composite endpoint of myocardial infarction, stroke, or death from cardiovascular causes more than placebo.

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Question
In patients with type 1 diabetes, does long-term intensive insulin therapy (IIT) reduce cardiovascular disease (CVD) events?

Conclusion
In patients with type 1 diabetes, long-term intensive insulin therapy reduced cardiovascular disease events.

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Question
In patients with type 2 diabetes mellitus, what is the effect of long-term fenofibrate therapy on coronary heart disease (CHD) events?

Conclusion
In patients with type 2 diabetes mellitus, long-term fenofibrate therapy did not reduce major coronary events but may reduce total cardiovascular disease events.

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Question
In patients with type 2 diabetes and evidence of macrovascular disease, does pioglitazone reduce all-cause mortality and macrovascular complications?

Conclusions
In patients with type 2 diabetes and evidence of macrovascular disease, pioglitazone did not reduce the primary or preplanned secondary composite endpoints. Pioglitazone use reduced a “main secondary” composite endpoint of all-cause mortality, nonfatal MI, and stroke, but increased the incidence of heart failure.

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Question
In patients with type 2 diabetes mellitus receiving hemodialysis, does atorvastatin reduce the composite risk for nonfatal myocardial infarction (MI), stroke, and death from cardiac causes?

Conclusion
In patients with type 2 diabetes receiving hemodialysis, atorvastatin did not reduce the composite risk for cardiovascular events or death from cardiac causes more than placebo.

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Question
In black or nonblack patients with hypertension, is amlodipine or lisinopril better than chlorthalidone for reducing cardiovascular disease (CVD)?

Conclusions
In black or nonblack patients with hypertension, amlodipine or lisinopril was not better than chlorthalidone for reducing cardiovascular disease. Chlorthalidone was associated with a lower risk for heart failure than amlodipine or linisopril in either racial subgroup.

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Question
In patients with vascular disease or diabetes mellitus, what is the cost-effectiveness of simvastatin compared with placebo for reducing major vascular events (MVEs)?

Conclusions
In patients with vascular disease or diabetes, simvastatin was cost-effective for reducing major vascular events and reduced hospitalization costs. Cost-effectiveness varied according to underlying risk for vascular events.

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Question
In patients with type 2 diabetes and acute myocardial infarction (MI), does an insulin-glucose regimen followed by insulin-based therapy reduce mortality and morbidity (group 1) more than an insulin-glucose infusion followed by standard care (group 2) or standard care alone (group 3)?

Conclusion
In patients with type 2 diabetes and acute myocardial infarction, an insulin-glucose regimen with long-term insulin control was not better than an insulin regimen with standard glucose control for improving survival.

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Question
In patients with type 2 diabetes mellitus and peripheral arterial disease (PAD), is picotamide better than aspirin for preventing all-cause mortality and major cardiovascular (CV) events?

Conclusions
In patients with type 2 diabetes mellitus and peripheral arterial disease, picotamide was more effective than aspirin for preventing all-cause mortality. Picotamide did not reduce nonfatal cardiovascular events.

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Question
In older patients with isolated systolic hypertension (ISH) with or without diabetes, what is the long-term effectiveness of a diuretic-based, stepped-care antihypertensive therapy compared with placebo?

Conclusions
In older patients with isolated systolic hypertension, diuretic-based, stepped-care antihypertensive therapy reduced long-term cardiovascular mortality. Patients who had diabetes at baseline or who developed diabetes during follow-up and received stepped care had lower mortality rates than did those who received placebo.

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Question
In patients with type 2 diabetes mellitus, is atorvastatin better than placebo for primary prevention of major cardiovascular disease (CVD) events?

Conclusion
In patients with type 2 diabetes mellitus, atorvastatin was more effective than placebo for reducing the rate of major cardiovascular disease events.

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Question
In patients with type 2 diabetes mellitus, do lipid-lowering agents reduce cardiovascular disease (CVD) events?

Conclusion
In patients with type 2 diabetes mellitus (with or without coronary artery disease), lipid-lowering agents reduce cardiovascular disease events.

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Question
In patients with abnormal fasting glucose (AFG) (diabetes and impaired fasting glucose [IFG]) and a history of myocardial infarction (MI) or unstable angina, is pravastatin better than placebo for reducing major coronary heart disease (CHD) events?

Conclusion
In patients with abnormal fasting glucose (diabetes and impaired fasting glucose) and a history of myocardial infarction or unstable angina, pravastatin reduced major coronary heart disease events.

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Question
In patients with diabetes mellitus, does simvastatin reduce vascular events?

Conclusion
In adults with diabetes mellitus, simvastatin therapy at 40 mg daily reduced vascular events.

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Question
In patients with type 2 diabetes and microalbuminuria, is a targeted intensive multifactorial intervention more effective than conventional treatment?

Conclusion
In patients with type 2 diabetes and microalbuminuria, a targeted, long-term, intensified, multifactorial intervention using behavioral modification and polypharmacologic therapy was more effective than conventional treatment for reducing cardiovascular and microvascular events.

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Question
In elderly persons with or at risk for vascular disease, what is the effectiveness and safety of pravastatin?

Conclusion
In elderly persons with or at risk for vascular disease, pravastatin lowered the risk for coronary disease events.

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Question
In patients with type 2 diabetes mellitus, hypertension, and persistent microalbuminuria, what is the effectiveness of the angiotensin-II–receptor antagonist (ARA) irbesartan for delaying or preventing the development of nephropathy?

Conclusion
In patients with type 2 diabetes mellitus, hypertension, and persistent microalbuminuria, irbesartan delayed progression to nephropathy independent of its effect on blood pressure.

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Question
In patients with type 2 diabetes mellitus, diabetic nephropathy, and hypertension, what effect does the angiotensin-II–receptor antagonist (ARA) irbesartan and the calcium-channel blocker amlodipine have on renal disease?

Conclusion
In patients with type 2 diabetes, nephropathy, and hypertension, irbesartan was more effective in reducing progression of nephropathy independent of the effect on blood pressure than was amlodipine or placebo.

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Question
In patients with type 2 diabetes mellitus and nephropathy, what is the renoprotective effect of the angiotensin-II–receptor antagonist (ARA) losartan?

Conclusions
Losartan was renoprotective in patients with type 2 diabetes mellitus and nephropathy. This effect was beyond that attributable to blood pressure control.

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Question
Is stress hyperglycemia associated with an increased risk for in-hospital death and congestive heart failure (CHF) after myocardial infarction (MI) in patients with and without diabetes mellitus?

Conclusions
Stress hyperglycemia after myocardial infarction is associated with an increased risk for in-hospital death in patients with and without diabetes; an increased risk for congestive heart failure or cardiogenic shock is also seen in patients without diabetes.

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Background:

Coronary heart disease is the leading cause of morbidity and mortality in the United States. Exercise tolerance testing has been proposed as a means of better identifying asymptomatic patients at high risk for coronary heart disease events.

Purpose:

To review the evidence on the use of exercise tolerance testing to screen adults with no history of cardiovascular disease for coronary heart disease.

Data Sources:

The MEDLINE database from 1966 through February 2003, hand-searching of bibliographies, and expert input.

Study Selection:

Eligible studies evaluated the benefits or harms of exercise tolerance testing when added to traditional risk assessment for adults with no known history of cardiovascular events.

Data Extraction:

One reviewer extracted information from eligible articles into evidence tables, and another reviewer checked the tables. Disagreements were resolved by consensus.

Data Synthesis:

No study has directly examined the effect of screening asymptomatic patients with exercise tolerance testing on coronary heart disease outcomes or risk-reducing behaviors or therapies. Multiple cohort studies demonstrate that screening exercise tolerance testing identifies a small proportion of asymptomatic persons (up to 2.7% of those screened) with severe coronary artery obstruction who may benefit from revascularization. Several large prospective cohort studies, conducted principally in middle-aged men, suggest that exercise tolerance testing can provide independent prognostic information about the risk for future coronary heart disease events (relative risk with abnormal exercise tolerance testing, 2.0 to 5.0). However, when the risk for coronary heart disease events is low, most positive findings will be false and may result in unnecessary further testing or worry. The risk level at which the benefits of additional prognostic information outweigh the harms of false-positive results is unclear and requires further study.

Conclusions:

Although screening exercise tolerance testing detects severe coronary artery obstruction in a small proportion of persons screened and can provide independent prognostic information about the risk for coronary heart disease events, the effect of this information on clinical management and disease outcomes in asymptomatic patients is unclear.

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In an effort to provide internists and other primary care physicians with effective management strategies for diabetes care, the Clinical Efficacy Assessment Subcommittee (CEAS) of the American College of Physicians (ACP) decided to develop guidelines on the management of dyslipidemia, particularly hypercholesterolemia, in people with type 2 diabetes mellitus. The CEAS commissioned a systematic review of the currently available evidence on the management of lipids in type 2 diabetes mellitus. The evidence review is presented in a background paper in this issue. On the basis of this systematic review, the CEAS developed recommendations that the ACP Board of Regents then approved as policy.

The target audience for this guideline is all clinicians who care for patients with type 2 diabetes. The target patient population is all persons with type 2 diabetes, including those who already have some form of microvascular complication and, of particular importance, premenopausal women. The recommendations are as follows.

Recommendation 1: Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients (both men and women) with known coronary artery disease and type 2 diabetes.

Recommendation 2: Statins should be used for primary prevention against macrovascular complications in patients (both men and women) with type 2 diabetes and other cardiovascular risk factors.

Recommendation 3: Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be taking at least moderate doses of a statin.

Recommendation 4: For those patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.

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Background:

Cardiovascular disease is the primary complication and cause of death in patients with type 2 diabetes mellitus. Modification of cardiovascular risk factors may improve patient outcomes.

Purpose:

To evaluate the effectiveness of pharmacologic lipid-lowering therapy on outcomes in type 2 diabetes mellitus.

Data Sources:

Review of the literature.

Study Selection:

Randomized trials evaluating clinical outcomes of lipid-lowering treatment in patients with diabetes.

Data Extraction:

Studies were identified by searching the Cochrane Library, MEDLINE, meta-analyses, review articles, and inquiries to experts. The Cochrane Library and MEDLINE searches were done in September 2002. Data were abstracted onto standardized forms by a single reviewer and were confirmed by a second reviewer.

Data Synthesis:

Meta-analysis of 6 primary prevention studies showed that lipid-lowering medications reduced risks for cardiovascular outcomes (relative risk, 0.78 [95% CI, 0.67 to 0.89]; absolute risk reduction, 0.03 [CI, 0.01 to 0.04] in 4.3 years of treatment); 1 major cardiovascular event was prevented by treating 34 to 35 patients. Meta-analysis of 8 studies of secondary prevention showed a similar relative risk (0.76 [CI, 0.59 to 0.93]) but more than twice the absolute risk reduction (0.07 [CI, 0.03 to 0.12] in 4.9 years of treatment) and a number needed to treat for benefit of 13 to 14. Most studies compared a lipid-lowering drug with placebo but did not evaluate the effect of reaching specific cholesterol levels. The benefit of lipid lowering with a fixed dose of a statin appeared to be similar regardless of starting cholesterol levels.

Limitations:

Target cholesterol levels and the effectiveness of dose titration (or the use of multiple agents) have not been rigorously examined.

Conclusions:

In patients with type 2 diabetes, treatment with lipid-lowering agents reduces cardiovascular risk. Most patients, including those whose baseline low-density lipoprotein cholesterol levels are below 2.97 mmol/L (<115 mg/dL), and possibly below 2.59 mmol/L (<100 mg/dL), benefit from statins. Moderate doses of these drugs suffice in most patients with diabetes.

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