2016 American College of Physicians The information contained
2016 American College of Physicians The information contained herein should never be used as a substitute for clinical judgment. BEYOND THE GUIDELINES: Would You Screen This Patient for Diabetes? Medicine Grand Rounds March 24, 2016 Discussants BIDMC Series Editor Moderator Martin J.
Abrahamson, MD FACP Gerald W. Smetana, MD Deborah Cotton, MD, MPH David M. Rind, MD The Series Editors have no conflicts of interest to disclose. Conflict of Interest Disclosure The speakers have no financial relationships with a commercial entity producing
healthcare-related products and/or services. Gerald W. Smetana, MD Deborah Cotton, MD, MPH Conflict of Interest Disclosure Dr. Martin Abrahamson discloses financial relationships with the following commercial entities producing healthcare-related products and/or services: Company Novo Nordisk Relationship Consultant
Content Area Diabetes WebMD Health Services Consultant Diabetes Health IQ Consultant
Diabetes Conflict of Interest Disclosure Dr. David Rind discloses financial relationships with the following commercial entities producing healthcare-related products and/or services: Company UpToDate Relationship Employee OUR PATIENT Medical History
Mr. P is a 69 year-old man with longstanding weight issues. He is 5 foot 10 inches tall Over the past 10 years, his weight has fluctuated between 216 and 244 pounds His corresponding body mass index (BMI) has ranged from 31.0 to 35.0 He has struggled with efforts to lose weight OUR PATIENT Medical History At present, he feels well. He tries to walk for exercise
This is often limited by knee pain due to osteoarthritis He has no polyuria, polydipsia, or fatigue He has no personal or family history of diabetes OUR PATIENT Past Medical and Surgical History Hypertension Colonic polyps Benign prostatic hypertrophy Elevated cholesterol
Gastritis Low back pain Cough variant asthma Knee osteoarthritis OUR PATIENT Social and Family History Worked in retail furniture business for 40 years Now retired Married with one adult child
No known family history of diabetes He and his primary care physician want to know if he should be screened for abnormal blood glucose OUR PATIENT Medications
Atorvastatin 40 mg qd Cyclobenzaprine 10 mg qhs prn Finasteride 5 mg qd Flovent 44 mcg 2 puffs bid Lisinopril 20 mg qd Tamsulosin 0.4 mg qhs Vitamin D OUR PATIENT Periodic Health Examination Well appearing Bp 116/70, height 70 inches, weight 225 pounds,
BMI 32.3 Chest - clear Cor Normal S1S2, no murmurs Abd soft, nontender, mildly obese Ext no edema Labs normal BUN, creatinine, electrolytes, CBC. Total cholesterol 185 mg/dl, LDL 94 mg/dl Would you recommend screening Mr. P for abnormal blood glucose? THE GUIDELINE Published Online October 27, 2015
The USPSTF concludes with moderate certainty that there is a moderate net benefit to measuring blood glucose to detect IFG, IGT, or diabetes and implementing intensive lifestyle interventions for persons found to have abnormal blood glucose. The USPSTF recommends screening for abnormal blood glucose as part of cardiovascular risk assessment in adults aged 40 to 70 years who are overweight or obese.(Grade B) *Siu AL, U.S. Preventive Services Task Force. Screening for Abnormal Blood Glucose and Type 2 Diabetes Mellitus: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2015;163:861-868. THE GUIDELINE Who to screen according to USPSTF?
Adults aged 40 to 70 years Seen in primary care setting Overweight or obese (BMI > 25) No symptoms of diabetes Consider screening earlier if Family h/o diabetes, h/o gestational diabetes, polycystic ovarian syndrome, or high prevalence racial or ethnic group Screen every 3 years THE GUIDELINE - Background
Cardiovascular disease is the leading cause of death in the U.S. One quarter of these deaths preventable Modifiable risk factors include hypertension, obesity, cigarette use, inactivity, elevated cholesterol, and abnormal blood glucose Type 2 diabetes develops slowly Up to one decade between onset of glucose intolerance and overt diabetes IFG = Impaired Fasting Glucose IGT = Impaired Glucose Tolerance THE GUIDELINE
Classification of Glucose Metabolism Test Hemoglobin A1c (%) Fasting plasma glucose Mg/dl Mmol/L Oral glucose tolerance test Mg/dl Mmol/L Normal IFG or IGT
126 7.0 < 140 < 7.8 140-199 7.8-11.0 200 11.1 *Siu AL, U.S. Preventive Services Task Force. Screening for Abnormal Blood Glucose and Type 2 Diabetes Mellitus: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2015;163:861-868.
THE GUIDELINE Prognosis for Impaired Fasting Glucose and Diabetes 12% of U.S. adults have diabetes; 27% prevalence among those aged 65 years 1.5 fold increase risk for mortality if diabetes Diabetes is the leading cause of end stage renal disease ESRD, blindness, and limb amputations in the U.S. 37% U.S. adults with IFG or IGT 15-30% of IFG progress to type 2 diabetes within 5 years if no therapeutic lifestyle changes *Selph S, Dana T, Bougatsos C, Blazina I, Patel H, Chou R. Screening for Abnormal Glucose and Type 2 Diabetes Mellitus: A Systematic Review to Update the 2008 U.S. Preventive Services Task Force Recommendation Evidence Synthesis No. 117. AHRQ Publication No. 13-05190-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
THE GUIDELINE Benefits of Early Detection Behavioral counseling and Rx of modifiable risk factors reduces progression to type 2 Diabetes No data show reduction in cardiovascular (CV) events or mortality with screening Harms of Early Detection Anxiety awaiting test results
Labelling effect Adverse events due to drug therapies Cost of increased medical visits and Rxs THE GUIDELINE Which Interventions Reduce Risk for Diabetes? Counseling on healthy diet Physical activity counseling
Intensive, multiple contacts over time Evidence for pharmacologic interventions to prevent diabetes is insufficient to recommend Screening and interventions for high blood pressure, smoking, and high cholesterol per existing USPSTF guidelines Recommendations of Others American Diabetes Association: Screen all adults over aged 40 and younger adults with risk factors 1. American Society of Clinical
Endocrinologists 2. American Academy of Family Physicians 3. Canadian Task Force on Preventive Health Care: Screen only if risk factors QUESTIONS TO DISCUSSANTS To structure a debate between our two discussants, we mutually agreed on the following key questions to consider when applying the guidelines to clinical practice, in general, and Mr. P in particular: 1. In which patient populations does screening for diabetes improve outcomes? 2. Does identifying pre-diabetes (impaired fasting glucose or impaired glucose tolerance) in asymptomatic overweight or
obese adults lead to better outcomes than delaying the diagnosis until the onset of symptoms? 3. What treatment strategies improve outcomes in asymptomatic adults with pre-diabetes? OUR MODERATOR & DISCUSSANTS Deborah Cotton, MD, MPH (Moderator) Deputy Editor, Annals of Internal Medicine Professor of Medicine, Boston University Martin J. Abrahamson, MD FACP Division of Endocrinology, BIDMC Associate Professor of Medicine, HMS David M. Rind, MD
Division of General Medicine, BIDMC Assistant Professor of Medicine, HMS Diabetes Mellitus in the USA A major public health problem 29 million (> 90% Type 2 diabetes) 25% undiagnosed 86 million pre-diabetes (only 11% know they are at risk) A costly disease $ 245 billion in 2012 7th leading cause of death *Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and
Its Burden in the United States, 2014. Atlanta, GA: US Department of Health and Human Services; 2014. *http://http://professional.diabetes.org/content/fast-facts-data-and-statistics-about-diabetes Risk of Serious Complications Is Increased Dramatically in People With Diabetes Mellitus Complication Relative Risk End-stage Renal Disease 6.1x Lower Extremity Amputation
10.5x Myocardial Infarction 1.8x Stroke 1.5x In 2010 there were 655,000 people with advanced retinopathy putting them at increased risk for blindness *Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014;370:1514-1523. *http://diabetes.niddk.nih.gov/dm/pubs/statistics
The Progression from Normal To Impaired Glucose Tolerance to Diabetes Follows a Continuum Diabetes is defined by the glucose levels at which there is an exponential increase in the risk for microvascular complications These complications CAN and DO affect people with pre diabetes The risk for macrovascular disease is increased in people with pre diabetes and diabetes Diabetes is associated with other morbidities Depression Increased absenteeism Decreased productivity
United Kingdom Prospective Diabetes Study (UKPDS) Median age at diagnosis 53 years Median fasting glucose at diagnosis 203 mg/dL (11.3 mmol/l) 55% presented with classic symptoms 30% were diagnosed on biochemistry alone 15% presented with an infection or complications of an infection *UK Prospective Diabetes Study Group. UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia. 1991;34:877-890. 50% of People With Newly Diagnosed Type 2 DM have Evidence of Diabetes-related Tissue Damage!
1 14 7 *UK Prospective Diabetes Study Group. UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia. 1991;34:877-890. The high prevalence of complications at presentation of Type 2 diabetes in middle age suggests that the current organization of health care is sub-optimal, since diabetes is often diagnosed only when it becomes symptomatic and tissue damage has often already occurred. If the study shows that improved glycemic control will prevent complications, there will be a strong case for introducing regular screening of the population in middle age to detect diabetes before its
complications ensue. *UK Prospective Diabetes Study Group. UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia. 1991;34:877-890. Type 2 Diabetes Can Be Prevented 58% decreased risk with lifestyle modification 31% decreased risk with metformin *From New England Journal of Medicine, Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, Vol. 346, pp. 393-403, Copyright 2002, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Prevention of Type 2 Diabetes Completed Trials in Impaired Glucose Tolerance Trial Da Qing Finnish Prevention Study (FPS) Diabetes Prevention Program (DPP) Journal/Year Description Results
or lifestyle Metformin: 31% risk reduction Lifestyle: 58% risk reduction *Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20:537-544. *Tuomilehto J, Lindstrm J, Eriksson JG, Valle TT, Hmlinen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350. 58% risk reduction
*Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. *Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072-2077. Da Qing Diabetes Prevention Study: 23 Year Follow Up Patients enrolled in 1986 577 adults with prediabetes diet or exercise or both vs control group 6 year intervention study Follow up in 2009 all-cause mortality, cardiovascular mortality and incidence of diabetes Data available for more than 90% of participants
*Li G, Zhang P, Wang J, An Y, Gong Q, Gregg EW, et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol. 2014;2:474480. Da Qing 23 Year Outcome Decrease In Cardiovascular, All Cause Mortality and Incidence of Diabetes Cardiovascular mortality (%) All cause mortality (%) Diabetes (%)
Intervention group 11.9 28.1 72.6 Control group 19.6 38.4
89.9 Hazard ratio 0.59 0.71 0.55 P value 0.033
0.049 0.001 *Li G, Zhang P, Wang J, An Y, Gong Q, Gregg EW, et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol. 2014;2:474480. In which patient populations does screening for diabetes improve outcomes? Anyone at increased risk for the development of diabetes Overweight/obese History of gestational diabetes or large (> 9lb) babies Polycystic ovarian syndrome Hypertension
Dyslipidemia Family history of type 2 DM Certain ethnic minority groups History of vascular disease Age > 45 years Does identifying pre-diabetes (impaired fasting glucose or impaired glucose tolerance) in asymptomatic overweight or obese adults lead to better outcomes than delaying the diagnosis until the onset of symptoms? YES! Opportunity to Intervene and Prevent Diabetes and its Complications
Remember At time of diagnosis 50% of people with type 2 DM have evidence of end organ tissue damage1 Identifying people with pre-diabetes provides the opportunity to intervene to prevent diabetes 2/3 of people admitted with an acute MI have either IGT or diabetes and were not aware of the diagnosis prior to the event2 Opportunity for treating CV risk factors aggressively prior to CV events UK Prospective Diabetes Study Group. UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia. 1991;34:877-890. 2
Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendc S, Rydn L, et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet. 2002;359:2140-2144. 1 What treatment strategies improve outcomes in asymptomatic adults with pre-diabetes? Lifestyle modification Diet and exercise delay the progression to overt diabetes Other than Da Qing no long term impact on mortality - yet Mediterranean diet Reduces progression to diabetes1 Decreases risk for development of gestational diabetes2 May reduce cv mortality3
Metformin prevents diabetes no known impact on mortality Salas-Salvad J, Bull M, Estruch R, Ros E, Covas MI, Ibarrola-Jurado N, et al. Prevention of diabetes with Mediterranean diets: a subgroup analysis of a randomized trial. Ann Intern Med. 2014;160:1-10. 2 Karamanos B, Thanopoulou A, Anastasiou E, Assaad-Khalil S, Albache N, Bachaoui M, et al. Relation of the Mediterranean diet with the incidence of gestational diabetes. Eur J Clin Nutr. 2014;68:8-13. 3 Estruch R, Ros E, Salas-Salvad J, Covas MI, Corella D, Ars F, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279-1290. 1 Suggestions for Mr. P Intensive lifestyle modification
Lose 5 to 10% body weight Mediterranean diet More intense exercise both strength training and aerobic, taking physical limitations in to account I would not start metformin, unless the HbA1c is above 7% but low threshold to start metformin if no response to lifestyle modification I n w h i c h p a ti e n t p o p u l a ti o n s d o e s s c r e e n i n g fo r diabetes improve outcomes? W h at d o e s i t m e a n to s c re e n fo r d i a b ete s ? Diabetes, historically, is a disease of excess sweet urine We are not screening for diabetes
We are screening for diabetes Diabetes is characterized by a lab value (whether A1c, fasting glucose or OGTT result) above some cutpoint Diabetes is a surrogate outcome Surrogate Outcomes A surrogate outcome is an outcome that is not important to patients in and of itself, but is believed to be a surrogate for a patient-important outcome, such as reduction in HIV viral load or reduction in LDL-cholesterol Ask yourself: If treating to change this outcome has some degree of cost or burden, and were the only thing to change for the patient (that is, they wouldnt feel better, live longer, have fewer events), would patients accept treatment?
If the answer is no, you are dealing with a surrogate outcome. Why might we screen for diabetes? The USPSTF recommends screening for abnormal blood glucose as part of cardiovascular risk assessment While diabetes is not really a cardiac risk equivalent, A1c clearly affects CV risk As such, it is reasonable to measure A1c in patients at risk for abnormal glucose metabolism who are on the borderline of requiring treatment for increased CV risk We might incidentally find patients with diabetes or even diabetes, but this is not the goal of the screening
Screening for diabetes does not improve outcomes *Reprinted from The Lancet, Vol. 380, Simmons RK, Echouffo-Tcheugui JB, Sharp SJ, et al, Screening for type 2 diabetes and population mortality over 10 years (ADDITION-Cambridge): A cluster-randomised controlled trial, pp. 1741-1748, 2012, with permission from Elsevier. D o e s i d e n ti f y i n g p r e - d i a b e t e s i n a s y m p t o m a ti c o v e r w e i g h t o r o b e s e a d u l t s l e a d t o b e tt e r o u t c o m e s t h a n d e l a y i n g t h e d i a g n o s i s u n ti l t h e o n s e t o f s y m p t o m s ? A p a r t f r o m b e tt e r m a n a g i n g C V r i s k , w h a t w i l l w e d o d i ffe r e n t l y ?
The Diabetes Prevention Program (DPP) trial found that the incidence of progression to diabetes per 100 person-years was: Placebo 11.0 cases Metformin 7.8 cases Lifestyle changes 4.8 cases So, what will we recommend? For obese patients with pre-diabetes?: Lifestyle changes For obese patients without pre-diabetes?: Lifestyle changes
What about giving metformin? In DPP, metformin treatment resulted in weight loss, though not as much as with lifestyle changes We have more effective weight loss drugs than metformin, such as topiramate/phentermine Development of diabetes is not a patientimportant outcome, it is a surrogate Metformin has not been shown to reduce the risk that patients with pre-diabetes will develop micro- or macro-vascular complications W h a t t r e a t m e n t s t ra t e g i e s i m p ro v e o u t c o m e s i n a sy m p t o m a ti c a d u l t s w i t h p r e - d i a b e t e s ? Treatment in pre-diabetes Many patients with pre-diabetes will be at high CV risk,
and statins produce similar reductions in relative risk across nearly every patient subgroup that has been studied Note that administering statin therapy will increase the risk of developing diabetes while decreasing CV risk, showing again that diabetes is a surrogate outcome Lifestyle changes are likely the most effective strategy for preventing progression to diabetes, with the probable exception of bariatric surgery Lifestyle changes Dietary changes should be aimed at weight loss Perhaps some added benefit with a Mediterranean-style diet
Exercise should be combined with dietary changes Combination of aerobic exercise and weight training is the preferred strategy Do lifestyle changes improve outcomes? Lifestyle changes reduce progression to diabetes (as we saw in the DPP) But diabetes remains a surrogate Meta-analysis of 10 RCTs (n = 23,152) using pharmacologic and non-pharmacologic therapy found: Mortality RR 0.96, 95% CI 0.84-1.10) CV mortality RR 1.04, 95% CI 0.61-1.78 Mortality effects of lifestyle and drug
interventions in patients with prediabetes *Gyberg V, Rydn L, European Journal of Cardiovascular Prevention & Rehabilitation, 18(5): 745-753, Copyright 2011, Reprinted by Permission of SAGE Publications, Ltd. Conclusions Measure A1c? Yes, if it will help decide on need for aspirin and statin therapy No, if that decision is already clear Screen for diabetes? No evidence of any benefit Intervention other than statins? Diet and exercise reduces risk of diabetes
whether patient is found to have pre-diabetes or not How does this apply to Mr. P? BMI 31.8 On intensive statin therapy (atorvastatin 40 mg daily) If we find he has pre-diabetes or diabetes: Exercise, diet, aspirin If we find he has normal glucose metabolism: Exercise, diet, aspirin Measuring an A1c will not change his management Will screening affect motivation? There is conflicting evidence about whether knowing a test result like an A1c will affect patient behavior
Mr. P. feels he would be more motivated to lose weight if he knew he had diabetes We can certainly make tailored decisions for individual patients about performing a blood test to affect their behavior It is not clear though, why that blood test should be an A1c rather than, for instance, transaminases to screen for NASH. (Also a disorder that will be treated identically with diet and exercise should we find it) I would not deny screening to Mr. P. if he wants it, but see no medical indication for such screening Would you recommend screening Mr. P for abnormal blood glucose? We would like to thank
Our Patient, Mr. P Martin Abrahamson, MD & David Rind, MD Risa Burns, MD, MPH Deborah Cotton, MD, MPH Howard Libman, MD Eileen Reynolds, MD Gerald Smetana, MD Last Minute Productions BIDMC Media Services Lizzie Williamson
Appendix A: Diabetes Prevention Program Outcome Study 15 year Follow Up: Lifestyle and Metformin Continue to Show Benefit *Reprinted from The Lancet Diabetes & Endocrinology, Vol. 3, Group DPPR, Long-term effects of l lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol, pp. 866-875, Copyright 2015, with permission from Elsevier. Appendix B: Mediterranean Diet and CV Outcomes *From New England Journal of Medicine, Estruch R, Ros E, Salas-Salvad J, Covas MI, Corella D, Ars F, et al. Primary prevention of cardiovascular disease with a Mediterranean diet, Vol. 368, pp. 1279-1290, Copyright 2013, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
2016 American College of Physicians The information contained herein should never be used as a substitute for clinical judgment.
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