Download Does identifying pre-diabetes

© 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
WebMD Health
Services
Health IQ
Relationship
Consultant
Content Area
Diabetes
Consultant
Diabetes
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
Normal
IFG or IGT
Type 2
Diabetes
Hemoglobin A1c (%)
Fasting plasma glucose
Mg/dl
Mmol/L
< 5.7
5.7-6.4
≥ 6.5
<100
< 5.6
100-125
5.6-6.9
≥ 126
≥ 7.0
Oral glucose tolerance
test
• Mg/dl
< 140
140-199
≥ 200
• Mmol/L
< 7.8
7.8-11.0
≥ 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 Rx’s
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!
Retinopathy
Abnormal ECG
Myocardial infarct
Angina Pectoris
Intermittent claudication
Stroke/TIA
Absent foot pulses and/or ischemic foot
Impaired reflexes and/or decreased vibration sense
Prevalence (%)
21
18
2
3
3
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
Diabetes Care
1997
NEJM
2001
Diet and/or
exercise
Intensive lifestyle
31%–46% risk reduction
NEJM
2002
Metformin
or lifestyle
Metformin: 31% risk
reduction
Lifestyle: 58% risk
reduction
58% risk reduction
*Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al.
*Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, et al. Effects of diet and exercise in
Reduction in the incidence of type 2 diabetes with lifestyle intervention or
preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and
metformin. N Engl J Med. 2002;346:393-403.
Diabetes Study. Diabetes Care. 1997;20:537-544.
*Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, et al. *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.
Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with
2002;359:2072-2077.
impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350.
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
1UK
Prospective Diabetes Study Group. UK Prospective Diabetes Study (UKPDS). VIII. Study design,
progress and performance. Diabetologia. 1991;34:877-890.
2Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendíc S, Rydén 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.
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
1Salas-Salvadó
J, Bulló 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.
2Karamanos 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.
3Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, et al. Primary prevention of cardiovascular disease
with a Mediterranean diet. N Engl J Med. 2013;368:1279-1290.
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
In which patient populations does
screening for diabetes improve
outcomes?
What does it mean to screen for
diabetes?
• 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 wouldn’t 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.
Does identifying pre -diabetes in
asymptomatic overweight or obese
adults lead to better outcomes than
delaying the diagnosis until the
onset of symptoms?
Apart from better managing CV risk,
what will we do differently?
• 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
What treatment strategies improve
outcomes in asymptomatic adults
with pre-diabetes?
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, Rydén 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-Salvadó J, Covas MI, Corella D, Arós 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.