|
Conference Coverage
NEWS FROM THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS (AACE) 18TH ANNUAL MEETING & CLINICAL CONGRESS
Houston
May 13 to 17, 2009
Guidelines Enhance Safety for Bariatric Surgery Patients
Clinical guidelines illustrating the safest ways to manage a bariatric surgery patient during the periods before and after the procedure were presented at the AACE meeting.The guidelines are a collaborative effort between AACE, The Obesity Society, and the American Society for Metabolic & Bariatric Surgery. The guideline's 166 evidence-based recommendations focus on the metabolic and nutritional aspects of the severely obese patient who plans to undergo the procedure, according to an AACE news release.
"With obesity at epidemic proportions in the United States, bariatric surgery is becoming a much more common procedure," said guidelines coauthor Jeffrey I. Mechanick, MD, FACP, FACE, FACN. Dr. Mechanick is Director of Metabolic Support and Clinical Professor of Medicine in the Division of Endocrinology, Diabetes and Bone Disease at The Mount Sinai Hospital, New York, NY.
The number of severely obese individuals is on the rise, with currently nearly 10 million in the United States affected. This means that for each bariatric surgeon there are approximately 10,000 potential surgical candidates, according to data from AACE.
With more procedures performed every day, considerable concern has been raised regarding the dangers associated with bariatric surgical procedures, such as metabolic bone disease and other nutritional deficiencies. The comprehensive guideline's recommendations address many of these dangers and offer ways to minimize them. The guidelines address the following topics:
- Selecting appropriate patients for bariatric surgery.
- Recommendations regarding the pre- and postoperative evaluation for the patient.
- Ways to recognize and manage postoperative complications.
- Recommendations to select patients for a second bariatric surgical procedure or a revision or reversal of a previous bariatric surgical procedure.
The guidelines can be accessed at www.aace.com/pub/pdf/guidelines/Bariatric.pdf.
Can New Surgery Revolutionize Diabetes Treatment?
Data presented at AACE suggest that metabolic surgery, a surgical approach to metabolic disease, may provide the key to curing diabetes in some patients.
"This goes beyond just weight-loss surgery," Chief of Gastrointestinal Metabolic Surgery at Weill Cornell Medical College Francesco Rubino, MD, said. "For its clinical potential, and maybe even more for its implications for the understanding of diabetes, metabolic surgery is one of the most important research opportunities for the next decade in medicine."
According to Dr. Rubino, a growing body of evidence suggests that the mechanisms of diabetes resolution after surgery involve intestinal signals. "I am confident that we may see important discoveries occur as we direct our attention to the role of the bowel in diabetes."
According to an AACE news release, recent studies have indicated that bariatric surgery can result in normalization of blood glucose levels and other metabolic abnormalities. This results in a reduction of the overall risk of mortality associated with diabetes in severely obese patients.
Dr. Rubino's research showed for the first time that the effects of bariatric surgery on diabetes cannot be entirely explained by weight loss and are intrinsic with the change of intestinal anatomy characteristic of these procedures. (For more on this, see Dr. Rubino's article in the March 2009 issue of Review of Endocrinology, page 29.) As a result, experts have been studying the biological impacts of the surgery on mechanisms of glycemic control and are exploring the possibility to use gastrointestinal surgery to treat diabetes per se.
"It would be premature at this point to argue every diabetes patient is a candidate for gastrointestinal surgery," Dr. Rubino said. "However, there is enough evidence that surgery should be considered as an option to endocrinologists in the treatment of type 2 diabetes."
AACE states that metabolic surgery is the result of a collaborative effort between endocrinologists and surgeons working to optimize the surgery for diabetes patients. Together they can formulate a "tailored intervention," designing procedures that allow them to gain a greater understanding how the disease works.
"Recognizing the need to work as a team across disciplines that include endocrinologists and surgeons is the first critical step to address the issues and opportunities that surgery offers to diabetes care and research," Dr. Rubino said.
Thus far, the results are intriguing. "This collaborative effort is helping us gain a broader, more comprehensive understanding of diabetes," Dr. Rubino said. "In the end, it will pay dividends for patients."
New Clinical Recommendations for Treating Prediabetes
Diabetes experts issued new recommendations for the treatment of prediabetes, a condition affecting 57 million Americans, according to a news release from AACE.
These clinical recommendations include specific instructions for lifestyle intervention and medication.
The recommendations are a byproduct of the first-ever prediabetes consensus conference, held last July in Washington, DC. At that time, 23 international experts in diabetes and metabolic disorders reviewed all existing scientific data to examine the status of the disease, facts about related complications, what happens to people who progress to diabetes, economic implications of early intervention, and what further studies were needed. An analysis of the available data gave way to recommendations calling for specific guidelines on both lifestyle and pharmaceutical intervention where appropriate.
Some suggested lifestyle modifications for people with prediabetes include:
- Weight reduction. Prediabetes patients should attempt to reduce their weight by 5% to 10%, with long-term maintenance at this level. This modest degree of weight loss may result in decreased fat mass, blood pressure, and glucose.
- A program of moderate to intense physical activity for 30 to 60 minutes daily, at least 5 days a week.
- A diet that includes calorie restriction, increased fiber intake, and possible limitations in carbohydrate intake. Dietary recommendations specifically for blood pressure include lower sodium intake and avoiding excess alcohol.
AACE Vice President Daniel Einhorn, MD, FACP, FACE, suggested a more aggressive approach to treating patients in high-risk groups with medications, including metformin, thiazolidinediones, dipeptidyl peptidase IV, inhibitors, and glucagon-like peptide-1 therapies. Dr. Einhorn is Clinical Professor of Medicine, University of California San Diego and Medical Director, Scripps Whittier Institute for Diabetes.
"These medications illustrate a specific Ôplan of attack' for treating prediabetes," Dr. Einhorn said in the AACE news release. "But it's important that caution is exercised."
Prediabetes enhances patients' risk for developing type 2 diabetes and cardiovascular complications. It is defined by elevated fasting glucose levels or impaired glucose tolerance, although Dr. Einhorn suggested A1C levels should be considered as a diagnostic tool.
"An A1C level of 6.0% to 6.5% indicates treatment for prediabetes with certain caveats," he said. As with diabetes management, the new AACE recommendations focus on early detection and smart lifestyle choices. "Lifestyle intervention should be the cornerstone of treatment for all patients," Dr. Einhorn said. "And it should be reinforced with each visit to the doctor."
A complete copy of the ACE/AACE Consensus Statement, "Diagnosis and Management of Prediabetes in the Continuum of Hyperglycemia—When do the Risks of Diabetes Begin?" is available for download on the AACE Web site at www.aace.com/pub/pdf/guidelines/prediabetesConsensus.pdf.
Type 2 Diabetes: An Epidemic Among America's Youth
With the number of children suffering from type 2 diabetes growing at an alarming rate, physicians at AACE discussed strategies for prevention and treatment of the disease among children and adolescents.
"Type 2 diabetes is extremely complex," said A. Jay Cohen, MD, FACE, pediatric endocrinologist and session moderator. "The rapid rise in obesity, physical inactivity, and the consumption of excessive calories seems to have led to the epidemic of children with type 2 diabetes."
The National Institutes of Health is conducting two clinical trials in order to identify the children at risk for type 2 diabetes and to demonstrate the effectiveness of lifestyle intervention among youth. The first trial, HEALTHY, is following a group of about 6,400 children through middle school, from 6th to 8th grade, to determine if modifications in exercise programs and nutrition in the school environment can reduce the risk of children having the disease. Researchers are tracking the youths' body mass index (BMI), fasting glucose levels, and fasting insulin levels to show the health benefits of lifestyle adjustments. TODAY, the second trial, is exploring the best treatment options for children with type 2 diabetes, an AACE news release stated.
"It is imperative to expose the social, behavioral, and environmental factors, which have led to this epidemic," said Francine R. Kaufman, MD, pediatric endocrinologist and study chair of both trials. Dr. Kaufman is Distinguished Professor of Pediatrics and Communications at the Keck School of Medicine and the Annenberg School of Communications, University of Southern California, and Head of the Center for Endocrinology, Diabetes and Metabolism, Childrens Hospital Los Angeles.
Children with type 2 diabetes may be afflicted with other associated conditions, including obesity, hypertension, hyperlipidemia, and potential risks of infertility such as polycystic ovarian syndrome, Dr. Kaufman said. These youth also have an increased risk of developing long-term complications, including heart disease, stroke, kidney disease, and nerve damage, according to an AACE news release.
With results from the HEALTHY trial anticipated to be released this fall, Dr. Kaufman remains optimistic. "The research from these trials will allow us to identify and implement the necessary lifestyle changes that will ultimately foster the health and well-being of not only those at risk but generations of children to come."
Taking a Hard-Line Approach to Cardiovascular Risks in the Diabetes Patient
When treating the patient with diabetes, doctors discussed how a "one-size-fits-all" approach to testing is not enough to determine an individual's risk for cardiovascular disease (CVD).
"We need to be more aggressive in treating our patients," Howard S. Weintraub, MD, a cardiologist and Clinical Associate Professor of Medicine at NYU Medical School, said in an AACE news release. "This requires individualized testing and early intervention."
Dr. Weintraub suggested that while gathering a patient's blood sugar data is important, assessing his or her results on an individual basis is crucial. Doing so may help to proactively identify the "constellation of issues" present in many patients. This means placing more emphasis on the "diabetic state." By assessing factors like hypertension, low-density lipoprotein cholesterol (LDL-C), blood glucose, triglycerides, and weight, doctors can better predict the multiple cardiovascular risks likely to prey upon a patient.
"It's the physician's job to interpret all the risk factors and see the big picture," Dr. Weintraub said. "And appropriate action should be taken before it's too late."
For more information about preventive health measures and diabetes, download the American College of Endocrinology's (ACE) Power of Prevention magazine at www.powerofprevention.com. The magazine features medical information on type 1 and type 2 diabetes, diabetes complications, and tips on how diabetes patients can best prepare for disaster.
Recommended Daily Dosage for Vitamin D Is "Grossly Inadequate"
During AACe, current recommendations for vitamin D were called "grossly inadequate."
"National recommendations from the Food and Nutrition Board are 400 to 600 International Units (IU) a day," Neil Binkley, MD, Associate Professor in Geriatrics and Endocrinology at the University of Wisconsin said in a news release. "That's simply not enough. Experts recommend somewhere between 1,500 to 2,600 IU daily. It's considered a very safe vitamin. One would need daily doses of 40,000 IU or higher before seeing negative side effects."
Vitamin D is essential for bone health, however Dr. Binkley discussed its role in improving muscle function.
"One of the primary killers among older adults is falls," Dr. Binkley said. "A sufficient amount of vitamin D not only enhances bone strength but also improves muscle function thereby reducing the risk of fractures."
The ubiquitous effects of the "sunshine vitamin" are demonstrated by research studies associating lower circulating vitamin D levels with cancer, type 1 diabetes, and CVD, according to the news release.
Although young people produce vitamin D in their skin after brief exposure to sunlight (10–15 minutes of UVB ray exposure per day), Americans often avoid sun exposure or use sunscreen. Additionally, older adults have less ability to produce vitamin D in the skin and generally require vitamin D supplementation, Dr. Binkley said.
"Nearly 40% of our endocrinology clinic patients over the age of 50 [years] have inadequate vitamin D levels," R. Mack Harrell, MD, with Broward Health in Ft. Lauderdale, Fla., said. "We used to think that sunscreen utilization was the main cause, but the problem is clearly more complicated than that."
As vitamin D's importance comes into focus, questions and confusion remain about different versions of the vitamin, according to AACE. There are two types of vitamin D: D2 (ergocalciferol) and D3 (cholecalciferol). D2 comes from plant life, whereas D3 is derived from animals. Dr. Binkley recommends checking the labels when buying vitamin D, because existing data indicate that D3 may be more effective.
Colesevelam Had Positive Effects on Blood Glucose, LDL-C in Diabetes Patients
A study presented at AACE found that colesevelam HCl (Welchol, Daiichi Sankyo, Inc.) added to metformin significantly reduced A1C and LDL-C in patients with type 2 diabetes. Additionally, an open-label extension study demonstrated the safety and durability of colesevelam for up to 78 weeks, according to a news release from Daiichi Sankyo.
Data from the 16-week, randomized, open-label pilot study showed that colesevelam significantly improved glycemic control and reduced mean LDL-C when added to metformin monotherapy in patients with type 2 diabetes. In this study, sitagliptin (Januvia, Merck & Co.) and rosiglitazone (Avandia, GlaxoSmithKline) also significantly improved glycemic control, but LDL-C increased in patients on both of these treatment regimens. In total, 169 patients were randomized to receive either colesevelam (n=57), sitagliptin, (n=56) or rosiglitazone (n=56).
"Seventy percent of patients with type 2 diabetes have elevated LDL-C and are not at the recommended goal of <100 mg/dL, which greatly increases their risk for [CVD]," said Yehuda Handelsman, MD, FACP, FACE, Medical Director of the Metabolic Institute of America in Tarzana, Calif. and principal investigator of the study. "These new data further support that [colesevelam] reduces these two risk factors for CVD in patients with type 2 diabetes by significantly lowering A1C and LDL, thereby offering physicians a unique therapeutic option."
Data derived from a separate post-hoc analysis of the metformin arm of a 52-week open-label extension study (n=146) were also presented. The results demonstrated that colesevelam was well-tolerated and effective for up to 78 weeks when added to metformin-based therapy, which is important considering the chronic and progressive nature of type 2 diabetes, according to the news release.
"The safety of colesevelam has been established through an extensive clinical trial program and more than 9 years as an approved treatment option for patients with high LDL-C," said Harold E. Bays, MD, Medical Director of Louisville Metabolic and Atherosclerosis Research Center Inc., Louisville, and principal investigator of the open-label extension study. "I'm encouraged to see that the safety and durability of [colesevelam] also extends to patients with type 2 diabetes, which is a significant finding given that patients with type 2 diabetes need sustained control of both blood glucose and LDL-C, two important metabolic parameters."
NEWS FROM THE AMERICAN SOCIETY OF HYPERTENSION (ASH) 24TH ANNUAL SCIENTIFIC MEETING AND EXPOSITION
San Francisco
May 6 to 9, 2009
Ongoing ROADMAP Study Found Significant Improvement in Blood Pressure Control at One Year
Blinded 1-year blood pressure (BP) reduction data from the ongoing landmark study ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention), were presented at ASH.
According to a news release from Daiichi Sankyo Co., Ltd, ROADMAP is the first-ever large-scale clinical trial being conducted in 19 European countries to evaluate whether the angiotensin II receptor blocker (ARB) olmesartan medoxomil (Benicar) can prevent the onset of microalbuminuria in patients with type 2 diabetes. Microalbuminuria, an early sign of kidney disease, is also an important risk factor of CVD. The secondary objective of the ROADMAP trial includes incidence of cardiovascular and renal morbidity and mortality. A qualitative parameter in the secondary objective was to measure cuff BP.
The double-blinded 1-year data presented at ASH 2009 showed that a strict BP control (<130/80 mm Hg) regimen in the ROADMAP trial improved BP compared to baseline in type 2 diabetes patients. The data presented represent the blinded total patient population, which includes patients randomized either to olmesartan or placebo in addition to standard antihypertensive treatment (excluding renin-angiotensin system inhibition).
After 1 year of treatment, 61% of patients in ROADMAP achieved the recommended BP goal of <130/80 mm Hg, a significant increase from a baseline of 28% controlled. The prevalence of stage 1 and stage 2 hypertension decreased from 32% to 11% and from 9% to 2%, respectively. ROADMAP was designed to allow analysis of BP responses and potential renal and CVD risk benefits across a wide range of patients with diabetes classified from normotension to hypertension and to test whether this extensive subgrouping might provide additional insight for practicing physicians.
"It is essential to manage [BP] very aggressively in diabetics because their [myocardial infarction {MI}] and stroke rates are more closely related to their [BP] levels than to their blood [glucose] levels," said Joseph L. Izzo, Jr, MD, Professor of Medicine and Pharmacology at SUNY-Buffalo and Director of Medicine at the Erie County Medical Center in Buffalo. "In ROADMAP, to date, we have achieved some of the lowest BP levels ever in a clinical trial."
BP Reduction With Olmesartan, Olmesartan HCT Helped Elderly Patients Achieve Target BP
Daiichi Sankyo, Inc. also announced other trial results of olmesartan presented at ASH. The BeniSILVER study found that olmesartan and olmesartan hydrochlorothiazide (HCT) provided a mean reduction in 24-hour ambulatory systolic BP (SBP) of 25.7 mm Hg among patients with an average age of 72 years, demonstrating efficacy without compromising safety. Patients aged ≥65 years also saw their 24-hour ambulatory diastolic BP (DBP) drop a mean of 12.3 mm Hg. The BeniSILVER study was designed to investigate the safety and BP-lowering efficacy of olmesartan and olmesartan HCT in patients aged ≥65 years with mild-to-moderate (stage 1) or challenging (stage 2) hypertension.
Studies have found that both the prevalence and severity of hypertension increase as people age, making it critical to achieve strict BP control in elderly populations, according to the news release. In fact, in 2008, HYVET (Hypertension in the Very Elderly Trial) demonstrated that decreasing BP in the elderly can have significant benefits in reducing the incidence of heart failure, MI, and stroke. Olmesartan and olmesartan HCT are indicated for the treatment of hypertension. There are no studies with either treatment showing a reduction in cardiovascular events.
In the BeniSILVER study, researchers evaluated the percentage of elderly patients achieving mean 24-hour ambulatory BP (ABPM) targets of <135/85, <130/80, and <120/80 mm Hg. ABPM is generally considered a better indicator of target organ injury than cuff measurement, since it provides a 24-hour measurement of patient BP. Olmesartan and olmesartan HCT were able to safely and effectively achieve a 24-hour ABPM target BP of <135/85 mm Hg in 83% of elderly patients (aged ≥65 years). In addition, 73% and 44% reached the ambulatory targets of <130/80 mm Hg and <120/80 mm Hg, respectively.
"The ability of olmesartan to bring elderly patients to BP targets is very important, because attaining BP targets can be so challenging in this group," said Joel M. Neutel, MD, director, Orange County Heart Institute and Research Center. "Although some physicians may be reluctant to use aggressive treatments for fear of an increased risk of adverse events, the findings show hypertension treatment can be accomplished safely and effectively in the elderly."
Amlodipine and Olmesartan Medoxomil Significantly Improved 24-Hour AMBP
Data presented at ASH from AZTEC (Azor Trial Evaluating Blood Pressure Reductions and Control) demonstrated that a stepwise amlodipine and olmesartan medoxomil-based (Azor, Daiichi Sankyo) titration regimen provided mean 24-hour AMBP reductions in SBP of 21.4 mm Hg and DBP of 12.7 mm Hg.
In addition, 71% of patients in the study were able to safely and effectively achieve a 24-hour AMBP target of <130/80 mm Hg, a news release from Daiichi Sankyo stated. The study also showed large mean 24-hour AMBP reductions in patients with hypertension from two groups with elevated risk for developing hypertension, black patients (20.7/11 mm Hg) and patients with type 2 diabetes (21.5/12.6 mm Hg).
AZTEC was the first time researchers have analyzed the effect of amlodipine and olmesartan combination on 24-hour ABPM, the company said. JNC 7 (Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure) states that ABPM patients whose 24-hour BP is >135/85 mm Hg are nearly twice as likely to have a cardiovascular event as those with BP <135/85 mm Hg.There are no studies with amlodipine and olmesartan demonstrating a reduction in cardiovascular events, according to the company.
"Analyzing AMBP gives physicians a clear picture of how well a patient's BP is controlled through a full 24-hour dosing period," said Dr. Neutel. "Most patients require treatment with at least two antihypertensive agents to achieve their recommended goal BP. The results of this study demonstrated the ability of a stepwise amlodipine and olmesartan medoxomil-based titration regimen to maintain BP reductions over 24 hours. This study also showed that an amlodipine and olmesartan medoxomil-based titration regimen can be an effective tool for treating hypertension in more challenging patient populations, such as patients with type 2 diabetes and [black patients]."
During the study, amlodipine and olmesartan demonstrated significant reductions in seated blood pressure (SeBP) or cuff BP. Unlike ABPM, SeBP is only recorded once during the course of a day. Amlodipine and olmesartan 10/40 mg provided a mean reduction in seated SBP (SeSBP) of 24.6 mm Hg and the SeDBP reading of 12.3 mm Hg.
ACE Inhibitors Plus ARBs May Not Be Optimal Hypertension Treatment
Jeffrey L. Probstfield, MD, of the University of Washington, Seattle, discussed optimal guidelines for primary care physicians regarding the combination of ARBs with angiotensin-converting enzyme (ACE) inhibitors in high-risk patients. According to a report online at Doctor's Guide, until the ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial) results, the dosage and type of ARBs to be combined with ACE inhibitors for high-risk patients was often ambiguous.
Patients in ONTARGET were randomized in a double-blind fashion to receive one of three treatment regimens. A group of 8,576 patients received ramipril 10 mg/day, a second group of 8,542 patients received telmisartan (Micardis, Boehringer-Ingelheim) 80 mg/day, and a third group of 8,502 patients received both drugs (combination therapy). Investigators considered the primary endpoint of the trial death as a result of cardiovascular events, MI, stroke, or heart failure, the report said.
At a mean follow-up of 56 months, patients who received telmisartan and combination therapy had a lower mean BP versus the ramipril-assigned patients. The primary outcome occurred in 16.5% of patients assigned to the ramipril group, compared with 16.7% of patients in the telmisartan group, and 16.3% of the combination therapy group.
The researchers concluded that administering both telmisartan and ramipril resulted in similar outcomes for patients with either vascular disease or high-risk diabetes. The researchers, however, found that the combination therapy did not necessarily result in a therapeutic benefit, and as a result, there remain some questions about the optimal use of these therapies in the primary care setting.
Dr. Probstfield noted that ONTARGET and the similarly designed TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease) study, which compared telmisartan with placebo, both demonstrated that telmisartan was safe and well tolerated among the patient cohorts. He also stated that as a result of these findings, the combination therapy of the ARBs and the ACE inhibitors may not be indicated for all high-risk patient groups
NEWS FROM THE AMERICAN COLLEGE OF PHYSICIANS INTERNAL MEDICINE 2009
Philadelphia
April 23 to 25, 2009
Type 2 Diabetes Patients With Microalbuminuria: ACE Inhibitor or ARB as First Line?
In a nephrology discussion group, Jeffrey S. Berns, MD, Professor of Medicine and Pediatrics, University of Pennsylvania School of Medicine, discussed the question, "In type 2 diabetics with microalbuminuria, should and ACE inhibitor or an ARB be first line? When should both be used? When should a renin inhibitor be used?"
The natural history of diabetic nephropathy, best characterized in inidividuals with type 1 diabetes but assumed to be similar in those with type 2 diabetes, is for an initial period of supranormal glomerular filtration rate (GFR) with little or no albuminuria, or only intermittent albuminuria, to be followed by a phase in which GFR falls to normal levels with development of persistent and eventually increasing microalbuminuria. According to Dr. Berns' discussion, over the ensuing decade or more, proteinuria worsens in the 40% or so of individuals destined to get diabetic nephropathy, eventually to the nephrotic range, and GFR begins a "more-or-less inexorable decline."
An extensive literature supports the use of inhibition of the renal-angiotensin-aldosterone system (RAAS) with ACE inhibitors and ARBs in reducing microalbuminuria and proteinuria in people with type 2 diabetes,1,2 but, he said it is in fact only very recently that a strong relationship between microalbuminuria and progression of chronic kidney disease (CKD) has been established in this patient population.3 Although the literature supporting the use of RAAS blockade to prevent progression of microalbuminuria to established diabetic nephropathy (ie, fixed proteinuria above the microalbuminuric range) is not all that robust, some studies do support this concept,4 Dr. Berns wrote in the course handouts he supplied.
The risk of any one patient with type 2 diabetes and microalbuminuria progressing to advanced CKD or end-stage renal disease (ESRD) is small, even though the relative risk reduction with RAAS blockade may be substantial, many patients need to be treated to prevent one case of ESRD, he wrote.5
Early intervention with RAAS blockade does appear to be cost effective, however, particularly in patients aged <50 to 60 years. It has the potential to prevent many cases of ESRD.6 There has been increasing use of combination therapy for RAAS blockade over recent years, using both an ACE inhibitor and ARB, either of these with spironolactone, or both an ACE inhibitor and ARB with spironolactone.7-10 Dr. Berns said there are no studies documenting a clinical benefit other than proteinuria reduction with combination RAAS blockade, and some studies find that dual RAAS blockade is not superior to an ACE inhibitor alone.11 Individual studies and most meta-analyses support the antiproteinuric effect of combination ACE inhibitor plus ARB therapy, evidence that such an approach slows progression of CKD and prevents development of ESRD is lacking—even in higher risk proteinuric patients, let alone lower-risk patients with microalbuminuria.7,9,10,12,13
Recent information, primarily from ONTARGET,14,15 indicates that use of an ACE inhibitor with an ARB is not beneficial and may even be harmful in patients who are low risk of CKD and CKD progression despite the greater antiproteinuric effect. It is recommended that RAAS blockade be used in many patients with type 2 diabetes who have microalbuminuria, ACE inhibitor plus ARB dual therapy should generally be avoided in type 2 diabetes patients with only microalbuminuria, according to Dr. Berns' handout. The new class of renin inhibitors offer another means of interfering with the RAAS system, and have been shown in one study to reduce proteinuria when added to an ARB.16 Whether this will be associated with a beneficial effect on CKD progression and is safe in the long term remains to be determined. At this point, Dr. Berns said the use of aliskiren (Tekturna, Novartis) to reduce microalbuminuria can not be recommended.
Does Treatment of High Triglycerides, Low HDL Improve Cardiovascular Outcomes?
In a lipid discussion group, Matthew J. Sorrentino, MD, FACC, Associate Professor of Medicine, Section of Cardiology, University of Chicago Pritzker School of Medicine, discussed the above question.
Elevated triglyceride levels are commonly seen in patients with the metabolic syndrome and diabetes, two groups known to have an increased cardiovascular risk, Dr. Sorrentino said. Increased triglycerides are associated with more highly atherogenic lipoproteins (small dense LDL-C) and insulin resistance.
Prospective epidemiologic studies have shown an association between triglyceride levels and coronary artery disease (CAD) with relative risk between 1.2 and 1.6.1 The risk for CAD risk appears to be significantly increased in individuals that have low high-density lipoprotein (HDL-C) and elevated triglycerides even in the absence of elevated total cholesterol.2 The Prospective Cardiovascular Munster Study, investigating the incidence of CAD in >4,500 men, identified a very high-risk group that had an LDL/HDL ratio of >5.3
Individuals with triglyceride levels >200 mg/dL had twice the number of CAD events versus those with triglycerides <200 mg/dL. The Helsinki Heart Study found a similar threefold increased risk of cardiac events in subjects with a high LDL/HDL ratio and triglyceride levels >200 mg/dL,4 according to Dr. Sorretino's discussion guide. The Framingham Heart Study showed that women with high triglycerides and low HDL-C had a significant increased risk of CAD and that this lipid pattern was an independent risk factor for cardiac events.5
Secondary prevention studies, such as the 4S (Scandinavian Simvastatin Survival Study), have also shown an increase in major coronary events as triglyceride levels increase.6
The NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) recommends LDL-C as the primary target of therapy in individuals at increased CVD risk.7 Non–HDL-C, which incorporates HDL-C and triglyceride values, is a secondary therapeutic target after goal LDL-C is attained. Non–HDL-C is targeted at 30 mg/dL above the LDL-C goal.
Statins are considered first-line pharmacological therapy because of their ability to lower LDL-C and their effectiveness in improving outcomes across the risk spectrum. Statins appear to give the greatest risk reduction among patients with the lowest HDL-C both from primary prevention studies such as the AFCAPS/TexCAPS (Air Force/Texas Coronary Atherosclerosis Study)8 and in patients with known CVD such as evaluated in the HPS (Heart Protection Study).9
Other pharmacological agents may have benefit especially in patients with a low-HDL/high-triglyceride pattern, he wrote in the discussion guide. Niacin has been shown to increase HDL-C by 20% to 30% as well as reduce triglycerides by 40% to 50% and LDL by 20% at doses of 1.5 to 3.0 grams per day. Niacin may be the most effective agent currently available to raise HDL-C, Dr. Sorrentino said. The Coronary Drug Project, using 3.0 grams of short-acting niacin per day, achieved a 27% decrease in nonfatal MI in the treatment group after 6 years.10 The addition of niacin to a statin can bring about a further reduction in LDL-C and a significant increase in HDL-C. In HATS (HDL-Atherosclerosis Treatment Study), a small group of patients with CAD low baseline HDL-C, achieved significant clinical and angiographic benefit from the combination of simvastatin and 2 to 4 grams of niacin daily.11
Fibrates, due in part to their triglyceride-lowering effects, have also been studied in both primary and secondary prevention studies, Dr. Sorrentino wrote. The HHS (Helsinki Heart Study) was a primary prevention trial that studied 1,200 mg of gemfibrozil in more than 4,000 asymptomatic men and showed a 34% reduction in the incidence of CHD compared with placebo. The subgroup that achieved the greatest benefit, with a 71% lower incidence of CHD events, had an LDL/HDL ratio >5 and a triglyceride level > 203 mg/dL.4 The secondary prevention VA-HIT (Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial) treated more than 2,500 men with CAD and lower-than-average HDL-C with either 1,200 mg of gemfibrozil or placebo.12 The mean HDL-C increased 6%, and the mean triglyceride level decreased 31% with no significant change in LDL-C. The gemfibrozil-treated group achieved a 24% reduction in the combined outcome of death, nonfatal MI, and stroke.
Dr. Sorretino said general recommendations on the treatment of dyslipidemia in the metabolic syndrome and diabetes can be made based on these outcome studies. LDL-C should be the primary target of therapy and the percentage reduction and treatment goal should be determined based on the patients's risk level. Non–HDL-C is a secondary target of therapy for individuals with triglyceride levels >200 mg/dL.
Statin medications are the first line of therapy. If a statin drug is contraindicated, then niacin or fibrates can be considered depending on which lipid factor is most outside of the normal range. Combination therapy with a statin and niacin or a statin plus a fibrate is an appealing treatment option, but there is little outcome data to support a strong recommendation. Combination therapy, he said, has the greatest appeal for the highest-risk individuals. Further research is needed to better elucidate the risk reduction that can be achieved with combination therapy.
Should Patients With a BMI ≥30 kg/m2 Be Agressively Treated for Borderline BP, Glucose, Lipid Elevations?
In a lipid discussion group, Louis J. Aronne MD, FACP, Clinical Professor of Medicine, Weill Cornell New York Presbyterian Hospital, discussed the above question.
Clinical studies have shown that general obesity is known to be a significant risk factor for CVD, and it is estimated that 20% to 30% of CVD mortality may be attributable to excess body weight. However, obesity is rarely the only risk factor present contributing to CVD risk, according to Dr. Arrone. In the Framingham cohort and their offspring the extent of CHD risk factor clustering in >2,000 overweight/obese individuals found that obesity as a single risk factor for CHD occurred in only 13% of men and 9% of women. Clusters of ≥2 risk factors occurred in 56% of obese men and 62% of obese women, he wrote in the discussion guide for the session. Compared with obese individuals without other risk factors, men and women with ≥3 risk factors had a relative CVD risk that was 2.07-fold and 10.9-fold greater, respectively.1
Obesity is also a strong risk factor for type 2 diabetes. It has been estimated that the odds of developing type 2 diabetes are close to sixfold higher in obese compared with normal-weight individuals.2 A prospective cohort study of >27,000 men from the Health Professionals Follow-Up assessed the utility of overall obesity versus abdominal obesity in predicting type 2 diabetes and found that both were independent and strong predictors,3 Dr. Aronne said. In fact, the usefulness of monitoring abdominal obesity, easily measured as waist circumference (WC) lies in its ability to predict declining insulinsensitivity in normal weight and overweight normoglycemic individuals.4 A comparison of abdominal and overall obesity in the San Antonio Heart Study found that WC was more predictive of the metabolic syndrome than BMI during an 8-year follow-up in 1968 adults.5 In a follow-up to the Olivetti Heart study, increases in abdominal obesity were associated with increases in fastingglucose levels, fasting and postload insulin levels, as well as increased serum triglyceride levels,6 his handout stated.
In a CVD risk factor screening of >6,000 women in 12 cities across the United States, a WC ≥35 inches was highly associated with elevated BP, total cholesterol, and fasting glucose; a Framingham global risk score ≥10; CVD; and type 2 diabetes.7 Thus, patients with an elevated BMI have multiple cardiovascular risk factors which interact to markedly increase the risk of CVD, and more aggressive management is warranted," Dr. Aronne concluded.
|
