Diabtes Update by Physician's Weekly

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Table of Contents 15

Exercise Advice to Reduce Risks in Patients With Diabetes —Todd D. Miller,MD, FACC, FAHA

The 2009 ADA Scientific Sessions

New Use for Diabetes Monitoring Test —Christopher D. Saudek, MD

Screening for Diabetes–Specific Distress —Lawrence Fisher, PhD

Screening & Treating Diabetic Nephropathy —George L. Bakris, MD

A message from the editor We at Physician’s Weekly are excited to present you with an eBook dedicated to diabetes. In recent months, our publication has featured a variety of news items in this field, focusing on clinical and evidence-based research and guidelines. The content in these articles relies on the expertise of our contributing physician authors. We anticipate that Physician’s Weekly will continue to feature news in this field of medicine in the coming months, and subsequent eBooks will emerge in the future. We hope that you find this information useful in your practice. Please let us know your thoughts by contacting us at editor@physweekly.com. Sincerely,

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Todd D. Miller, MD, FACC, FAHA Professor of Medicine Mayo Clinic College of Medicine Co-Director, Nuclear Cardiology Laboratory Mayo Clinic

October 19, 2009 • Issue No. 39 Click here to view this article online.

Exercise Advice to Reduce Risks in Patients With Diabetes An American Heart Association scientific statement emphasizes the importance of exercise in patients with type 2 diabetes to reduce their cardiovascular risk.

onsidering the increasing epidemic of type 2 diabetes in adults and the increasing numbers of overweight and obese individuals, it is important for clinicians to find ways to reduce the cardiovascular complications of diabetes. “Exercise has been established as an important way to reduce the impact of diabetes-related problems,” says Todd D. Miller, MD, FACC, FAHA. “When combined with a healthy diet, exercise can prevent or slow the development of type 2 diabetes and produce clinically significant improvements in glucose control and cardiovascular risk factors.”

New Recommendations Released In the June 30, 2009 issue of Circulation, the American Heart Association released a scientific statement on exercise training for type 2 diabetes, with a concentration on reducing cardiovascular risk. Dr. Miller, who co-authored the statement, says the document emphasizes the importance of exercise advice from primary care physicians (PCPs) and other providers.

“Patients should work with their providers to establish effective exercise regimens,” he says. “PCPs and other caregivers need to prescribe specific exercise routines in order to improve cardiovascular health and metabolic control.” According to the statement, patients with diabetes are recommended to get at least 150 min/week of moderate-intensity exercise, 90 min/week of vigorousintensity exercise, or some combination of the two to improve cardiovascular risk (Table 1). Patients should exercise on at least 3 non-consecutive days each week to maximize benefits, and individual sessions should be at least 10 minutes each or longer. The statement also encourages that patients undertake moderate- to high-intensity resistance training. “These guidelines can be achieved with varying contributions of moderate-to-vigorous cardiorespiratory exercise,” Dr. Miller notes. “Physicians should recognize that their focus should primarily be to improve conditioning rather than to lose weight, and this message should be conveyed to patients. Weight loss is desirable, but using visit www.physweekly.com

exercise alone as a means to weight loss would require substantially more exercise than what this statement recommends. Even if patients can’t achieve the recommended levels of exercise, some benefits with regard to diabetes and cardiovascular risk are still likely to occur. Reductions in risk associated with limited exercise are likely to be better for patients than remaining completely sedentary.”

erations when prescribing exercise programs [Table 2]. Ongoing, individual counseling should be used in conjunction with exercise consultations, group support, and other strategies that have been shown to be effective for adhering to exercise regimens.” The use of internet-based programs and telephone exercise counseling has also been shown in the literature to be of benefit for sustaining adherence to training regimens. “These strategies appear to be reasonably effective in maintaining exercise compliance, improving glycemic control, and enhancing functional capacity in patients with diabetes,” Dr. Miller adds. “Home-based exercise training with counseling is another strategy that offers convenience, flexibility, cost-effectiveness, and greater general appeal, but patients will still require ongoing counseling, supervision, support, and motivation.”

Approaches to Adherence Exercise counseling is recommended so that physicians can assess and adjust levels of physical activity and provide motivation and support. “Research shows that advice received from PCPs is likely to be followed,” Dr. Miller says. “PCPs, physician assistants, nurses, diabetes counselors, and other healthcare providers should collaborate to play a role by giving advice about physical activity during every encounter with patients who have diabetes. Unfortunately, many providers lack specific guidance on how to prescribe exercise training programs. If providers are unsure, they should refer patients to clinical exercise physiologists who have the specific skills and knowledge to apply exercise training principles to patients with diabetes.”

Educate Patients Many individuals, particularly older adults with diabetes, are deconditioned and have limited strength and flexibility. Their engagement in physical activity may be more challenging because of comorbidities. As such, Dr. Miller says all patients with diabetes should be educated on how to prepare for exercise; the frequency, intensity, and duration at which it should be performed; the types of exercise to be performed; and typical and atypical symptoms of problems that may arise. “Exercise training in patients with diabetes is feasible, well tolerated, and beneficial,” he says, “but it’s important to remember that individualized exercise prescriptions are needed. This

In addition to counseling, patient commitment to exercise training is paramount to adherence. “Patients need to exhibit a willingness to change their ways by preparing for exercise and then complete and maintain their training programs,” says Dr. Miller. “Physicians need to pay attention to their competence, motivation, past experiences, and many other consid-

Table 1

Summarizing Exercise Prescriptions for Patients With Diabetes

Mode of Exercise Cardiorespiratory (large-muscle activities)

Frequency

Intensity

Duration

3-7 days/week

Moderate

150 minutes/week

Vigorous intensity

90 minutes/week

Moderate to high intensity: 2-4 sets of 9-10 repetitions at a weight that cannot be lifted >8-10 times, with 1-2 minute rest periods between sets

OR Cardiorespiratory (large-muscle activities)

3 days/week AND ENCOURAGE

Resistance (large-muscle group, multijoint exercises)

3 days/week

Source: Adapted from: Marwick TH, et al. Circulation. 2009;119:3244-3262.

Table 2

Approaches to Adherence

Health Behaviors & Counseling The following factors contribute to adoption of healthy exercise patterns:

Other effective strategies for the adoption of healthy exercise patterns include:

Perceived barriers and benefits

Ongoing, individual counseling

Self-efficacy or competence

Exercise consultation

Motivation

Group support

Past experiences

Stress management

Social support

Coping skills training

Access

Motivational interviewing techniques

Provider support

Community-based interventions

Presence of anxiety and depression

Web-based programs Using patients as coaches Telephone exercise counseling

Source: Adapted from: Marwick TH, et al. Circulation. 2009;119:3244-3262.

strategy can help account for cardiac and non-cardiac considerations. We need to implement exercise training regimens that will last for the long term in order to truly reduce cardiovascular risks in patients with diabetes.”

Supervised exercise training

Todd D. Miller, MD, FACC, FAHA, has indicated to Physician’s Weekly that he has received research grants from Boehringer Ingel heim, Boston Scientific, Bristol Myers Squibb, KAI Pharmaceuticals, Lantheus Medical Imaging, Molecular Insight Pharmaceuticals, Radiant Medicals, Spectranetics, and TargeGen. He has also been a consultant or worked on the advisory board for TherOx, Inc. and The Medicines Company.

References Marwick TH, Hordern MD, Miller T, et al. Exercise training for type 2 diabetes mellitus. Impact on cardiovascular risk. A scientific statement from the American Heart Association. Circulation. 2009;119:3244-3262. To download the complete study, go to http://circ.ahajournals.org/cgi/ content/full/119/25/3244. Fox CS, Pencina MJ, Meigs JB, et al. Trends in the incidence of type 2 diabetes mellitus from the 1970s to the 1990s: the Framingham Heart Study. Circulation. 2006;113:2914-2918. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: General Information and National Estimates of Diabetes in the United States, 2007. Atlanta, Ga: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2008. Kadoglou NP, Iliadis F, Angelopoulou N, et al. The anti-inflammatory effects of exercise training in patients with type 2 diabetes mellitus. Eur J Cardiovasc Prev Rehabil. 2007;14:837-843. Pi-Sunyer X, Blackburn G, Brancati FL, et al; Look AHEAD Research Group. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the Look AHEAD trial. Diabetes Care. 2007;30:1374-1383. Eden KB, Orleans CT, Mulrow CD, Pender NJ, Teutsch SM. Does counseling by clinicians improve physical activity? A summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;137:208-215. Marcus BH, Williams DM, Dubbert PM, et al. Physical activity intervention studies: what we know and what we need to know: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity); Council on Cardiovascular Disease in the Young; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research. Circulation. 2006;114:2739-2752. Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C, White RD. Physical activity/exercise and type 2 diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2006;29:1433-1438.

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August 17, 2009 â&#x20AC;˘ Issue No. 31 Click here to view this article online.

The 2009 ADA Scientific Sessions The American Diabetes Association held its 2009 annual meeting from June 5 to 9 in New Orleans. The features below highlight some of the news emerging from the meeting.

Combo Therapy Effective Against Diabetes, Hypertension

The Particulars: A double-blind study of 1,423 patients with hypertension was conducted in which patients were randomized to treatment with telmisartan and amlodipine combination therapy or with telmisartan and amlodipine as monotherapy. Of the study population, 16.2% had diabetes.

tensive patients with diabetes achieved recommended BP targets. Telmisartan 80 mg plus amlodipine 10 mg produced the largest BP decreases and highest BP control rates. The telmisartan/amlodipine combinations were more effective than telmisartan and amlodipine as monotherapies.

Data Breakdown: The combination of telmisartan and amlodipine produced clinically relevant blood pressure (BP) reductions and was equally effective in hypertensive patients with and without diabetes. With telmisartan plus amlodipine, up to 30.4% of hyper-

Take Home Pearl: Combining telmisartan and amlodipine appears to be effective in reducing BP and achieving clinically relevant BP control within recommended targets in patients with type 2 diabetes.

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Extended-Release Drug Promising for DPN The Particulars: Pure mu-opioids have been used for the management of pain in patients with diabetic neuropathic pain (DPN) but have been associated with gastrointestinal and central nervous system adverse effects. Researchers assessed the investigational extended-release (ER) formulation of tapentadol in patients with moderate to severe pain due to chronic DPN. Data Breakdown: Tapentadol ER 100 mg to 250 mg twice daily was safe and effective for the management of chronic neuropathic pain in patients with

DPN. Patients receiving tapentadol ER maintained improvements observed in the open-label phase. Placebo-treated patients significantly worsened from the start of the double-blind phase. Tapentadol ER was associated with a relatively low rate of study discontinuations due to treatment-emergent adverse events. Take Home Pearl: Patients who respond initially to the ER formulation of tapentadol for the treatment of DPN appear to experience ongoing benefits throughout 12 additional weeks of treatment.

Evaluating Treatment Approaches & Mortality The Particulars: The BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) study compared intensive medical treatment with prompt coronary revascularization by either bypass surgery or angioplasty to intensive medical treatment alone. The study also assessed whether controlling diabetes with drugs to improve insulin sensitization had an advantage for heart health or survival. Data Breakdown: After an average follow up of 5 years, no differences in mortality rates or in cardiovascular events were observed between types of early coro-

nary revascularization when compared with medical therapy alone. However, among the subgroup of participants who were pre-identified as candidates for coronary bypass surgery, the group receiving prompt surgery had significantly fewer heart attacks or strokes when compared with those who initially received intensive medical therapy alone. Take Home Pearl: Prompt revascularization does not appear to hold any advantage over intensive medical therapy alone with regard to total mortality.

Long-Term Data on Rosiglitazone & CV Outcomes The Particulars: Rosiglitazone is an insulin sensitizer used for glucose-lowering alone or in combination with metformin and/or a sulfonylurea. The RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) study was designed to evaluate the long-term impact of rosiglitazone on cardiovascular (CV) outcomes and blood glucose control as compared with metformin and sulfonylureas. Data Breakdown: On the composite outcomes of cardiovascular death, stroke, and heart attack, results

slightly favored rosiglitazone over metformin and sulfonylureas. At the end of the study, rosiglitazone was shown to be superior in controlling blood glucose levels when compared with metformin and sulfonylureas. After 5 years, patients in the rosiglitazone group had A1C levels 0.29% lower than people on sulfonylureas and 0.26% lower than those on metformin. Take Home Pearl: When used in appropriately selected patients, rosiglitazone appears to carry no overall increase in CV risk with regard to major morbidity or mortality.

A New Way to Diagnose Diabetes? The Particulars: Currently, the fasting plasma glucose and the oral glucose tolerance tests are used to diagnose diabetes. An international expert committee assembled by the American Diabetes Association, International Diabetes Federation, and European Association for the Study of DiaÂbetes assessed the potential for using the A1C assay to diagnose diabetes. Data Breakdown: In reviewing data examining A1C levels and long-term complications, an A1C value of

6.5% or greater is recommended for use in the diagnosis of diabetes.Â Investigators reported that this cutpoint should not be construed as an absolute dividing line between normal glycemia and diabetes.Â However, an A1C level of 6.5% is sufficiently sensitive and specific to identify people with diabetes. Take Home Pearl: The A1C assay is recommended for use when diagnosing diabetes because values vary less than in other tests.

Improving BP in Diabetes The Particulars: Exenatide is a glucagon-like peptide-1 receptor agonist intended to improve glucose control in adults with type 2 diabetes. Investigators examined 6-month blood pressure (BP) outcomes with exenatide using 7-year data from a national EMR database. All patients in the study started exenatide during or after 2005 and had one or more additional exenatide orders after their index date. They also had prior orders for metformin, a sulphonylurea, and/or a thiazolidinedione. Data Breakdown: About 44% and 43% of patients receiving exenatide achieved systolic and diastolic BP targets, respectively, at 6 months. Among patients

who were not at systolic and diastolic BP targets at baseline and received exenatide, 22% achieved BP goals. BP outcomes did not differ between patients treated with antihypertensive agents and those who were not treated. Take Home Pearl: Exenatide appears to lead to clinically meaningful BP improvements in patients with type 2 diabetes irrespective of background antihypertensive medications. For more information on the annual meeting news from the American Diabetes Association 2009 Scientific Sessions, as well as further data on the studies presented in this feature story, go to http://professional.diabetes.org.

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April 27, 2009 • Issue No. 16 Click here to view this article online.

New Use for Diabetes Monitoring Test Christopher D. Saudek, MD Director Johns Hopkins Diabetes Center Hugh P. McCormick Professor of Endocrinology and Metabolism Division of Endocrinology Johns Hopkins University School of Medicine

iabetes is largely under-diagnosed, and its prevalence continues to increase by leaps and bounds throughout the United States. Further, about 25% of newly diagnosed patients already have established diabetic retinopathy and/or microalbuminuria. Several challenges can hinder a timely diagnosis of diabetes. First, the diagnosis is usually based on fasting-plasma glucose (FPG) or an oral glucose tolerance test (OGTT), both of which require patients to fast for 8 to 10 hours before testing is performed. Second, population screening for diabetes in asymptomatic patients is ordinarily recommended by doing questionnaires that evaluate risk without making a definitive diagnosis. The upshot is that current screening methods for diabetes may fail to identify a significant portion of the population with diabetes. These strategies can also miss patients at high risk for developing the dis-

ease. In the July 2008 Journal of Clinical Endocrinol ogy and Metabolism, my colleagues and I published a consensus recommendation suggesting that hemoglobin A1C tests be used as an accepted method for identifying patients with diabetes. The A1C test has long been used as the gold-standard for monitoring established diabetes, and could be an effective means for diagnosing diabetes.

Assessing Advantages & Specific Criteria Unlike the FPG or OGTT, the A1C test does not require patients to fast overnight because it reflects long-term glycemia. Also, FPG and OGTT are affected by relatively short-term changes in diet and exercise, whereas A1C is not. Patients often come to routine doctor visits without fasting, or they may make temporary improvements in diet and exercise in anticipation of their visit, “hiding” what is diabetic-level glycemia in their normal life. The A1C test is a familiar test to clinicians; it’s available, and in fact already used by many clinicians to diagnose diabetes, although not officially accepted as a diagnostic criterion. In our consensus recommendation, we suggested that A1C measurements of 6.5% or greater should be accepted as a valid criterion for diagnosing dia-

betes (Table). Levels that are suspicious but less than the diagnostic threshold (a positive screening test) could require further investigation by physicians. In addition to the A1C values, we suggest that random plasma glucose values in the range of 130 mg/dL to 199 mg/dL be regarded as a positive screen, requiring further evaluation. The use of A1C is not without limitations and potential drawbacks. For example, there’s some evidence that there are racial disparities in A1C that are independent of glycemic levels. Hemoglobinopathies can obscure results, depending on the type of assay used. These obstacles, however, are avoidable and our recommendations suggest methods to circumvent or minimize their impact.

Continue Screening Efforts With A1C The need for patients to fast before testing and the lack of agreed-upon screening criteria for diabetes are serious deficiencies that may contribute to avoidable morbidity and mortality. Screening with A1C testing could help identify some of the millions of Americans who have undiagnosed diabetes. In order to better address the escalating numbers of people with undiagnosed diabetes, efforts are now being made to collect more evidence that could be beneficial for the clinical community.

Proposed Criteria for Diagnosing Diabetes* Table

FPG ≥126 mg/dL A1C ≥6.5% RPG ≥200 mg/dL Diagnosis requires confirmation unless unequivocal symptoms of hyperglycemia are present. Diagnosis based on A1C requires confirmation using a glucose-dependent test (FPG or OGTT) or, if first A1C is ≥7.0%, by a second A1C ≥6.5%.* In asymptomatic persons with A1C ≥6.5%, if FPG ≥126 mg/dL or RPG ≥200 mg/dL, diagnosis is confirmed.* If screening is positive but less than the diagnostic threshold, two tests are required to reach the diagnostic threshold. Abbreviations: FPG, fasting plasma glucose; RPG, random plasma glucose; OGTT, oral glucose tolerance test. * Criteria that are proposed additions to currently accepted criteria Source: Adapted from: Saudek, et al. J Clin Endocrinol Metab. 2008;93:2447-2453.

Christopher Saudek, MD, has indicated to Physician’s Weekly that a conference he spoke at was sponsored by Metrika, Inc.

References Saudek CD, Herman WH, Sacks DB, et al. A new look at screening and diagnosing diabetes mellitus. J Clin Endocrinol Metab. 2008;93:2447-2453. Saudel CD, Derr RL, Kalyani RR. Assessing glycemia in diabetes using self-monitoring blood glucose and hemoglobin A1c. JAMA. 2006;295:16881697. Nathan DM, Kuenen J, Borg R, et al. Translating the A1C assay into estimated average glucose values. Diabetes Care. 2008;31:1473-1478. Edelman D, Olsen MK, DudLey TK, et al. Utility of hemoglobin A1c in predicting diabetes risk. J Gen Intern Med. 2004;19:1175-1180. Ko GT, Chan JC, Tsang LW, Cockram CS. Combined use of fasting plasma glucose and HbA1c predicts the progression to diabetes in Chinese subjects. Diabetes Care. 2000;23:1770-1773. Geberhiwot T, Haddon A, Labib M. HbA1c predicts the likelihood of having impaired glucose tolerance in high-risk patients with normal fasting plasma glucose. Ann Clin Biochem. 2005;42:193-195. Knowler WC. Screening for NIDDM. Opportunities for detection, treatment, and prevention. Diabetes Care. 1994;17:445-450.

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March 23, 2009 • Issue No. 12 Click here to view this article online.

Screening for Diabetes-Specific Distress Lawrence Fisher, PhD, ABPP Professor Department of Family & Community Medicine University of California, San Francisco

iabetes-specific distress is defined as the emotional burden experienced by patients that is caused by concerns of disease management, support, and access to care. Distinct from depression, it’s a common condition often mistaken for major depressive disorder (MDD), which is typically treated with medications or a referral for behavioral, psychological, or psychosocial interventions. Unfortunately, many patients who experience diabetes-specific distress without clinical depression don’t benefit from MDD treatments because depression and this type of distress appear to be independent conditions.

Currently, screening for diabetes-specific distress occurs infrequently in clinical practice. In order to evaluate the linkage between this distress and diabetes management, my colleagues and I developed a brief diabetes-specific distress screening instrument for use in clinical settings. In the May/June 2008 Annals of Family Medicine, we published a study that reanalyzed the 17-item Diabetes Distress Scale (DDS17), a previously validated questionnaire that identifies patients with high levels of diabetes-specific distress. Our reanalysis of previous data was performed to extract fewer items that we can use for a screening tool that would be both valid and reliable.

A Shorter Screening Tool A 2-item Diabetes Distress Screening Scale (DDS2) met stringent criteria for sensitivity and specificity in our investigation. It can effectively screen patients for distress, using the full 17-item scale as a criterion. The DDS2 asks respondents to rate on a 6-point scale

the degree to which they feel overwhelmed by their diabetes and the degree to which they feel they’re failing with their diabetes regimens. If patients rate their distress as a 5 or 6 on the DDS2 screener, they should be administered the full-scale DDS17 in order to assure that the condition truly exists. Using the full DDS17 after a positive DDS2 screen is recommended so that clinicians can determine what kinds of specific distress patients are experiencing. In turn, this can direct subsequent interventions. Diabetes-specific distress occurs in close to 20% of patients with diabetes, compared with MDD, which has been estimated to occur in 10% to 12% of patients with the disease. In light of the high prevalence of each condition, physicians should continue to screen for MDD and pay attention to diabetesspecific distress. It’s likely that distress can impact quality of life and adherence to treatments. Based on our findings, patients with diabetes should be given the DDS2 and should also receive the 2-item screener for clinical depression developed from the Patient Health Questionnaire 9.

Consider the Benefits Questionnaires do not have to be administered by physicians only; nurses and other providers can help in these efforts. Furthermore, they can be administered in waiting or examination rooms so as not to interfere with busy clinician visits. Patient responses can be reviewed by physicians during visits and a dialogue can be initiated with patients if MDD or diabetes-specific distress is suspected. This conversa tion should further examine the specific sources of distress or depression in order to potentially improve outcomes. Utilizing helpful questionnaires like the DDS2 can aid clinicians in treating the whole patient by identifying sources of distress and tailoring interventions to address them.

Lawrence Fisher, PhD, ABPP, has indicated to Physician’s Weekly that he has or has had no financial interests to report.

References Fisher L, Glasgow RE, Mullan JT, et al. Development of a brief diabetes distress screening instrument. Ann Fam Med. 2008;6:246-252. Fisher L, Skaff MM, Mullan JT, et al. Clinical depression versus distress among patients with type 2 diabetes: not just a question of semantics. Diabetes Care. 2007;30:542-548. Ciechanowski PS, Russo JE, Katon WJ, et al. The association of patient relationship style and outcomes in collaborative care treatment for depression in patients with diabetes. Med Care. 2006;44:283-291. Hermanns N, Kulzer B, Krichbaum M, et al. How to screen for depression and emotional problems in patients with diabetes: comparison of screening characteristics of depression questionnaires, measurement of diabetes-specific emotional problems and standard clinical assessment. Diabetologia. 2006;49:469-477. Polonsky WH, Anderson BJ, Lohrer PA, et al. Assessment of diabetes-related distress. Diabetes Care. 1995;18:754-760. Polonsky WH, Fisher L, Earles J, et al. Assessing psychosocial distress in diabetes: development of the diabetes distress scale. Diabetes Care. 2005;28:626-631. Ciechanowski PS, Katon WJ, Russo JE. Depression and diabetes: impact of depressive symptoms on adherence, function, and costs. Arch Intern Med. 2000;160:3278-3285. Delahanty LM, Grant RW, Wittenberg E, et al. Association of diabetes-related emotional distress with diabetes treatment in primary care patients with Type 2 diabetes. Diabet Med. 2007;24:48-54.

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George L. Bakris, MD Professor of Medicine Director, Hypertensive Diseases Unit University of Chicago Medical Center

January 12, 2009 • Issue No. 2 Click here to view this article online.

Screening & Treating Diabetic Nephropathy Improving glycemic control, aggressive antihypertensive treatment, and the use of ACE inhibitors, or ARBs, can slow rates of progression of diabetic nephropathy.

This Physician’s Weekly feature covering screening and treatment for diabetic nephropathy was completed in cooperation with experts at the American Diabetes Association.

iabetic nephropathy occurs in an estimated 20% to 40% of patients with diabetes. “Nephropathy is a major cause of sickness and death in people with diabetes,” says George L. Bakris, MD. “The condition often leads to the need for dialysis or kidney transplantation in patients with diabetes.” Although there are no early symptoms in the initial stages of diabetic nephropathy, several nonspecific signs and symptoms manifest later in the disease, including fatigue, a foamy appearance of the urine, headache, nausea, and edema.

The Importance of Regular Screenings Diabetic nephropathy is commonly accompanied by other complications, especially hypertension, retinopathy, and cardiovascular disease. According to recommendations from the American Diabetes Association (ADA), vigilant screening is paramount (Table 1). Patients with type 1 diabetes who have had the disease for 5 years or more are recommended to undergo annual testing to assess urine albumin excretion and kidney function. For those with type 2 diabetes, this testing should be done annually once patients are diagnosed. “Patients with microalbuminuria who progress to macroalbuminuria are most likely to develop end-stage renal disease [ESRD], so regular screenings are important,” says Dr. Bakris. “The presence of microalbuminuria alone doesn’t visit www.physweekly.com

Defining Abnormalities & Staging CKD

Table 1

Category

Spot collection

Normal

<30 µg/mg creatinine

Microalbuminuria Macro (clinical)-albuminuria

30-299 µg/mg creatinine 300 µg/mg creatinine

Stages of CKD GFR (mL/min per 1.73 m2

Stage

Description

Kidney damage*with normal or increased GFR

Kidney damage* with mildly decreased GFR

60-89

Moderately decreased GFR

30-59

Severely decreased GFR

15-29

Kidney failure

<15 or dialysis

body surface area)

* Kidney damage defined as abnormalities on pathologic, urine, blood, or imaging tests. Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate. Source: Adapted from: American Diabetes Association. Diabetes Care. 2008;31:S12-S54.

mean nephropathy is present, especially in the absence of hypertension. Conversely, increasing levels of microalbuminuria are a marker of diabetic nephropathy.” The ADA also recommends measuring serum creatinine levels at least once a year in all adults with diabetes to estimate the glomerular filtration rate (GFR), and stage level of chronic kidney disease (CKD), if present (Table 1). Efforts should also be made to optimally control glucose and blood pressure levels to reduce the risk or slow the progression of nephropathy, says Dr. Bakris. “Intensive diabetes management aimed at achieving A1C levels of less than 7% has been shown to delay the onset of microalbuminuria and the progression of micro- to macroalbuminuria in diabetes. Other investigations have provided strong evidence that lowering blood pressure to levels well below 140/90 mm Hg can also reduce nephropathy risks.”

Medications Can Have a Strong Impact According to the ADA’s 2008 Standards of Medical Care, two classes of medications—ACE inhibitors and angiotensin receptor blockers (ARBs)—have been effective in treating patients with micro- and 18

Table 2

Treating Nephropathy

• When treating non-pregnant patients with microor macroalbuminuria, either ACE inhibitors or ARBs should be used as part of a blood pressure lowering regimen to achieve a goal around 130/80 mm Hg. • There are few adequate head-to-head comparisons of ACE inhibitors and ARBs, but there is clinical trial support for each of the following statements: - ACE inhibitors have been shown to delay the progression of nephropathy in patients with type 1 diabetes with hypertension and any degree of albuminuria. - Both ACE inhibitors and ARBs have been shown to delay the progression to macroalbuminuria in patients with type 2 diabetes, hypertension, and microalbuminuria. - ARBs have been shown to delay the progression of nephropathy in patients with type 2 diabetes, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine >1.5 mg/dL). - If one class is not tolerated, the other should be substituted. • Reduction of protein intake to 0.8–1.0 g · kg body wt-1 · day-1 in individuals with diabetes and the earlier stages of CKD and to 0.8 g · kg body wt-1 · day-1 in the later stages of CKD may improve measures of renal function (eg, urine albumin excretion rate and GFR) and is recommended. • Continued monitoring of urine albumin excretion to assess response to therapy and progression of disease is recommended. Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker. Source: Adapted from: George L. Bakris, MD, and American Diabetes Association. Diabetes Care. 2008;31:S12-S54.

macroalbuminuria. Data have demonstrated that lowering systolic blood pressure levels with ACE inhibitors appears to be more beneficial than other antihypertensive drug classes in delaying diabetic nephropathy progression in type 1 diabetes (Table 2). They can also slow the decline in GFR in patients with microalbuminuria if blood pressure is lowered to such levels. In patients with type 2 diabetes, hypertension, and normal albuminuria levels, ACE inhibitors help delay progression of microalbuminuria. ACE inhibitors have also been shown to reduce major cardiovascular disease outcomes in patients with diabetes, further supporting their use. In clinical studies, ARBs have been shown to reduce the rate of progression from micro- to macroalbu-

minuria and ESRD in type 2 diabetes. “It’s important for physicians to start ACE inhibitor or ARB regimens at doses that have been shown to be beneficial in clinical trials,” Dr. Bakris explains. “Unfortunately, some providers are starting these regimens at sub-therapeutic doses. Additionally, these drug therapies should not be stopped when creatinine levels increase. Data have demonstrated that these regimens should be continued if creatinine levels increase by 30% to 40% and hyperkalemia is well managed because these patients stand to benefit the most.” Other drugs (eg, diuretics, calcium channel blockers, and b-blockers) should be used as additional therapy to further lower blood pressure in patients already treated with ACE inhibitors or ARBs, or as alternate therapy in rare cases where patients cannot tolerate these drug classes, according to the ADA.

Considering a Referral Continued surveillance of diabetic nephropathy is important to help assess responses to therapy and

disease progression, but some cases may be more challenging than others. Dr. Bakris says that physicians should consider referring patients to experts whenever they are uncertain about the etiology of kidney disease, if they are having difficulty managing patients, or if patients have advanced kidney disease. “Physicians should refer patients to nephrologists when estimated GFRs are at or below 45 mL/min per 1.73 m2. This can help reduce costs, improve quality of care, and keep patients off dialysis longer. At the very least, doctors should still educate their patients about the progressive nature of nephropathy and inform them that preserving their renal function aggressively can significantly improve their outcomes.” George L. Bakris, MD, has indicated to Physician’s Weekly that he has served as a consultant, been on the speaker’s bureau or on an advisory board for Abbott, Boehringer-Ingelheim, BristolMyers Squibb/Sanofi-Aventis, Forest, GlaxoSmithKline, Merck, Novartis, Walgreens, Gilead, and Daiichi Sankyo. He has also received grants from the NIH, GlaxoSmithKline, and Forest. For more information on this article, including references, please visit: www.physweekly.com.

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