Download Dr. Eric Johnson – Updates in diabetes testing - ascls-nd

Diabetes and the Lab
Eric L. Johnson, M.D.
Assistant Medical Director
Altru Diabetes Center
Altru Health System
Associate Professor
Department of Family and Community Medicine
University of North Dakota
School of Medicine and Health Sciences
Grand Forks, ND
Objectives
• Review common evidence based
laboratory measures in the screening,
diagnosis and management of diabetes
and related conditions
• Discuss future directions and practice of
laboratory measures in the screening,
diagnosis and management of diabetes
and related conditions
Disclosures
• Speaker’s Bureau- Novo Nordisk,
Medtronic
• Advisory Panel- Novo Nordisk, Sanofi
• PI or Sub PI on numerous multicenter
medication trials at Altru Health System
Research Site
What We Will Do
• Diabetes overview and definitions
• Discuss screening for diabetes with common
laboratory methods
• Discuss relationship of blood glucose to
complications of diabetes
• Short review of other relevant diabetes labs
• Discuss future and novel directions in lab testing
in diabetes
• Case studies
U.S. Prevalence of Diabetes
• Diagnosed: 29 million people—
9.3% of population
• 90%+ have Type 2
• Undiagnosed: 8 million people
• 83 million people have pre-diabetes
CDC
Diabetes In The U.S.
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9.3% of all Americans
12.3% of adults age 20 and older
26% of adults age 65 and older
About 2 million diagnoses yearly
Could be 33% by 2050
Prediabetes
37% of adults age 20 and older
51% of Americans 65 and older
CDC
Diabetes Complications
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Eye disease/blindness ~28.5% of adults over 40 with
diabetes have some form of retinopathy (on the rise in
U.S. with more cases of type 2 diabetes)
Heart Disease (common)
Stroke (common)
Kidney disease
Nerve damage
Liver disease
Amputation
Infection
Dementia
Estimated Prevalence and Cost
of Diabetes in North Dakota
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~6.7% of adults (~40,000 people)
Medical cost of diabetes: $209,700,000
Indirect Cost: $99,140,000
Total Cost: $308,800,000
Estimated Prevalence and Cost
of Diabetes in Minnesota
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~6% (~300,000 people)
Medical cost of diabetes: $1,750,000,000
Indirect Cost: $929,000,000
Total Cost: $2,679,000,000
Diabetes and All-Cause Mortality
• Diabetes deaths annually in the U.S.
~233,000
• Meta-analysis 97 studies 820,900 people
• HR 1.8 death from any cause
• HR 1.25 death from cancer
• HR 2.32 death from vascular disease
• HR 1.73 death from any other cause
HR=hazard ratio Emerging Risk Factors Collaboration. N Engl J Med 2011, 364(9): 829-
Risks for Complications in Diabetes
• Abnormal blood sugar
• Abnormal cholesterol
• Abnormal blood pressure
• Sedentary lifestyle
• Smoking
Diabetes Mellitus
• Type 1: Usually younger, insulin at
diagnosis
• Type 2: Usually older, often oral agents at
diagnosis
• Type “1.5” (Latent Autoimmune)
mixed features ~10% of type 2
• Gestational: Diabetes of Pregnancy
Type 1 Diabetes Mellitus
• Autoimmune Disease- destruction of
betacells (insulin producers) in pancreas
• Lab work up can include antibody testing
(GAD 65, IAA, IA2, sometimes HLA)
• Lab work can include C-peptide (part of
insulin precursor)- low or zero in T1DM
• Insulin can also be measured directly
Model of the pathogenesis and natural history of
type 1 diabetes.
Atkinson M A Cold Spring Harb Perspect Med
2012;2:a007641
©2012 by Cold Spring Harbor Laboratory Press
Type 2 Diabetes
• Not autoimmune
• No antibodies
• Insulin resistance causes eventual betacell
“burnout”
• Insulin resistance may be secondary to
obesity, family history, smoking, sedentary
lifestyle, some medications
• Eventually will be insulin deficient to the
point that they will need insulin
Natural History of Type 2 Diabetes
Obesity
IFG*
Uncontrolled
Hyperglycemia
Diabetes
Glucose (mg/dL)
350 –
Postmeal Glucose
300 –
250 –
Fasting Glucose
200 –
150 –
100 –
Relative Function (%)
50 –
250 –
Insulin Resistance
200 –
150 –
100 –
-cell Function
-Cell Failure
50 –
0–
-10
-5
0
5
10
Years of Diabetes
15
20
25
*IFG=impaired fasting glucose.
Copyright® 2000 International Diabetes Center, Minneapolis, USA. All rights reserved. Adapted with permission.
30
The Ominous Octet
Islet -cell
Decreased
Incretin Effect
Impaired
Insulin Secretion
Increased
Lipolysis
Islet a-cell
Increased Glucose
Reabsorption
Increased
Glucagon Secretion
Increased
HGP
DeFronzo Diabetes 2008
Neurotransmitter
Dysfunction
Decreased Glucose
Uptake
Type 1.5
Latent Autoimmune Diabetes
• Usually look like Type 2 at onset
• Rapidly progress to a Type 1 presentation
after a few weeks or months
• A “slow smoldering” autoimmune response
• Usually end up treating like a type 1
Type 1 Diabetes Diagnosis
• Usually symptomatic, weight loss,
polyuria, polydipsia, polyphagia, fatigue,
ill-appearning
• Usually very hyperglycemic (>250)
• Always positive for urine ketones (and
serum ketones)
Type 2 Diagnosis
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Usually more subtle
Fatigue is often presenting complaint
Many discovered incidentally
Ketosis present in about 20%, usually with
another associated problem
(illness, infection, heart attack, stroke)
Diabetes Risk and Prevention
Risk:
• Type 1- mostly unknown, some familial
• Type 2- obesity, smoking, sedentary
lifestyle, familial
Prevention:
• Type 1- none known
• Type 2- lifestyle management
(likely applies to GDM as well)
Diabetes Guideline
Management
• 2 main sets of guidelines utilized in U.S.
• American Diabetes Association (ADA)
• American Association of Clinical
Endocrinology (AACE)
• Lots of overlap, AACE considered
“more intense”
Diabetes Guideline
Management
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Evidence based
Well accepted
Clinically relevant
Can be incorporated into clinical practice
Emphasize comprehensive risk
management
• Ties together “numbers” with risk
Key Laboratory Testing in
Diabetes Diagnosis
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Fasting plasma glucose
2 hour post-prandial glucose
Casual (random) glucose
A1C
Oral glucose tolerance test (OGTT)usually 2 hours
• Insulin antibody and/or GAD antibody and
sometimes HLA typing
• Sometimes C-peptide
Other Lab Testing in Diabetes
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Serum creatinine
Creatinine Clearance (GFR)
Electrolytes
Liver function tests (fatty liver disease-common in Type 2)
Urine for microalbumin or gross protein (dipstick)
24 hour urine collection-protein
Lipid profiles (usually done fasting)
Thyroid (often TSH, can be antibodies, T4, T3)
Tissue Transglutamase IgA and IgG
Vitamin D
Vitamin B12
Diabetes Complications and
Lab Testing
• Lab testing is useful for screening,
prevention, prediction, and management
of many diabetes complications
Screening and Diagnosis of
Diabetes
Diabetes Diagnosis
Category
FPG (mg/dL)
2h 75gOGTT
A1C
Normal
<100
<140
<5.7
140-199
5.7-6.4
>200
>6.5
Prediabetes 100-125
Diabetes
>126**
Or patients with classic hyperglycemic symptoms with plasma glucose >200
** On 2 separate occasions
Diabetes Care 36:Supplement 1, 2013
https://www.aace.com/publications/guidelines 2011
Why Is >100 Abnormal?
• Evidence that more diabetes related eye
disease begins at this number
• Evidence that other diabetes related
complications may begin at this number,
including cardiovascular disease
A1C Definition
• Glucose is bound non-enzymatically to the
hemoglobin molecule
• Directly proportional to the time-integrated
mean BG concentration during the
preceding 2 to 3 months
• An ‘average’ of Glucose values over 2-3
months
• Usually done every 3-6 months clinically
Henry: Clinical Diagnosis by Laboratory Methods, 2005
Rakel: Conn's Current Therapy 2006, 58th ed., 2006
A1C ~ “Average Glucose”
A1C
%
6
6.5
7
7.5
8
8.5
9
9.5
10
eAG
mg/dL
126
140
154
169
183
197
212
226
240
mmol/L
7.0
7.8
8.6
9.4
10.1
10.9
11.8
12.6
13.4
Formula: 28.7 x A1C - 46.7 - eAG
calculator at professional.diabetes.org/eAG
American Diabetes Association
A1C Technical Issues
• “Mismatch” with Fingerstick
• Genetic variants that alter value (i.e., HbS,
HbE, HbC, and HbD)
• Acquired conditions that alter value (i.e.,
kidney disease, anemias, conditions
affecting erthrocyte turnover, pregnancy)
A1C Lab Measurement
• Over 100 ways to measure A1C
• Most common methods are antibodies
(immunoassays) or cation-exchange
chromatography
• National Glycohemoglobin Standardization
Program (NGSP) has been instrumental in
standardizing A1C testing among
laboratories
A1C Advantages For
Diagnosing Diabetes
• Convenience- doesn’t require fasting or a 2 hour
test
• May capture those who don’t yet have abnormal
fasting plasma glucose
• Reflects chronicity and duration of abnormal
glucose values
• Short-term Factors that affect fasting glucose
don’t affect A1C
Fasting Glucose for Diabetes
Diagnosis: Advantages
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Glucose assay easily automated
Widely available
Inexpensive
Single sample
Fasting Glucose for Diabetes
Diagnosis: Disadvantages
• Patient must fast ≥8 h
• Large biological variability
• Diurnal variation
• Sample not stable
• Numerous factors alter glucose concentrations,
e.g., stress, acute illness
• No harmonization of glucose testing
• Need 2 values for diagnosis
Fasting Glucose for Diabetes
Diagnosis: Disadvantages
• Concentration varies with source of the sample (venous,
capillary, or arterial blood)
• Concentration in whole blood is different from that in
plasma
• Guidelines recommend plasma, but many laboratories
measure serum glucose
• FPG less tightly linked to diabetes complications (than
A1C)
• Reflects glucose homeostasis at a single point in time
2 hour Glucose Testing
Advantages
• 2 hour post challenge or post prandial may
be the most sensitive marker of glucose
intolerance
• 2 hour is most predictive of cardiovascular
disease and mortality
• ADA and WHO actually prefer 2 hour
2 Hour Glucose Testing
Disadvantages
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Lacks reproducibility
Extensive patient preparation
Time-consuming and inconvenient
Unpalatable
Expensive
Influenced by numerous medications
Subject to the same limitations as FPG
Type 2 Diabetes Screening in
Children/Adolescents
• Overweight
-BMI >85th percentile
-weight for height >85th percentile
-weight >120% of ideal for height
Plus risk factors similar to adults
Gestational Diabetes
• Occurs in 2-9% of pregnancies
• ~135,000 cases in U.S. annually
• Increasing numbers- obesity, but
many probably have prexisting
diabetes or prediabetes
• Lifestyle management
• Insulin
(usually preferred, better efficacy)
or sulfonylureas (in very select cases)
Am J Obstet Gynecol 192:1768–1776, 2005
Diabetes Care 31(S1) 2008
Diabetes Care 25:1862-1868, 2002
Gestational Diabetes and
Type 2 Diabetes Risk
• Gestational Diabetes should be
considered a pre-diabetes condition
• Women with gestational diabetes have a
7-fold future risk of type 2 diabetes
vs.women with normoglycemic pregnancy
• 35-60% go on to have DM
Lancet, 2009, 373(9677): 1773-9
Gestational Diabetes (GDM)
Screening
• Screen for type 2 diabetes first prenatal
visit if risk factors
• Not known to have diabetes, screen for
GDM at 24 –28 weeks of gestation
• Controversy exists: ACOG (supported by
NIH), ADA
Diabetes Care 34:Supplement 1, 2011
Lancet, 2009, 373(9677): 1773-9
Gestational Diabetes (GDM)
ADA
• Overnight fast, 75g OGTT
• Fasting >92 mg/dl
• 1h
>180 mg/dl
• 2h
>153 mg/dl
Thought to identify more patients with
glucose intolerance
Diabetes Care 35:Supplement 1, 2012
Diabetes Care 2010; 33: 676–682
Gestational Diabetes (GDM)
ACOG
• 2 Step approach
• 1 hour 50gm OGT (screening) >130
Then proceed to 3 hour OGTT
Thought to identify those who actually need
to be treated
ACOG 3 hour OGTT
• Fasting
>95
• 1 hour
>180
• 2 hours
>155
• 3 hours
>140
• 2 or more of the above values
Can follow 1 hour screen, or as initial
diagnostic test
GDM Screening
• A1C not ideal for GDM screening, but may
be good for type 2 screening
• Fructosamine not good for screening
• Occasionally, it’s not GDM or pre-existing
type 2- may be a new type 1
• Most clinics use ACOG
Gynecol Obstet Invest 2011;71:207-212
Diabetes Care 34:Supplement 1, 2011
Lancet, 2009, 373(9677): 1773-9
GDM Complications
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Macrosomia
Fractures
Shoulder dystocia
Nerve palsies (Erb’s C5-6)
Pregnancy outcomes can be very
poor with HTN/nephropathy
• Neonatal hypoglycemia
Gabbe, Obstetrics: Normal and Problem Pregnancies 2002
Gestational Diabetes:Outcomes
• Hyperglycemia and Adverse Pregnancy
Outcomes (HAPO) Study 28,000 women
• Good GDM management improves
outcomes
NEJM (358) 2008
Diabetes Care 2012
Blood Glucose/A1C
and Relationship to Complications
A1C
• Many questions about A1C in recent years
with relationship to complications
• Let’s try to sort it out…..
Diabetes Complications
Macrovascular Complications (Large Vessel)
• Cardiovascular disease
– Coronary Heart disease (CHD)
– Stroke
– Peripheral arterial disease
(PAD)/amputation
– Primarily related to Blood Pressure,
Lipids, and post-prandial blood sugar
Diabetes Complications
Microvascular Complications (Small Vessel)
• Eye disease (retinopathy)
• Kidney disease (nephropathy)
• Nerve disease (neuropathy)
• Primarily related to A1C and fasting blood
sugar
Diabetes Complications
Other complications
• Liver disease (NAFLD, NASH)
• All cause mortality risk
Diabetes and All-Cause Mortality
Diabetes also associated with death from:
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Pneumonia and other infectious diseases
Mental disorders
Nonhepatic digestive diseases
External causes and intentional self-harm
Nervous-system disorders
COPD
Emerging Risk Factors Collaboration. N Engl J Med 2011, 364(9): 829-4
Avoiding Diabetes Complications
• Blood glucose control A1C <7%
• Treat lipid profiles with appropriate statin
doses vs risk factors/age
• Treat blood pressure to target <140/<90
For most non-pregnant adults
Anti-Lipid Therapy
Age
<40 years
40–75 years
>75 years
Risk factors
None
ASCVD risk factor(s)†
ASCVD
None
ASCVD risk factors
ASCVD
ACS and LDL >50 mg/dL
who cannot tolerate highdose statin
None
ASCVD risk factors
ASCVD
ACS and LDL >50 mg/dL
who cannot tolerate high
dose statin
Recommended statin
intensity*
None
Moderate or high
High
Moderate
High
High
Moderate plus ezetimibe
Moderate
Moderate or high
High
Moderate plus ezetimibe
*In addition to lifestyle therapy.
†ASCVD risk factors include LDL cholesterol ≥ 100 mg/dL (2.6 mmol/L), high blood pressure, smoking, overweight or obesity,
and family history of premature ASCVD.
ACS, acute coronary syndrome.
Targets for Glycemic (blood sugar) Control
In Most Non-Pregnant Adults
A1c (%)
Fasting (preprandial) plasma
glucose
Postprandial (after meal)
plasma glucose
ADA
AACE
<7*
≤6.5
80-130 mg/dL <110 mg/dL
<180 mg/dL
<140 mg/dL
*<6 for certain individuals
• American Diabetes Association. Diabetes Care. 2012;35(suppl 1)
• Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement
at http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf. Accessed January 6, 2006.
• AACE Diabetes Guidelines – 2002 Update. Endocr Pract. 2002;8(suppl 1):40-82.
Target A1C and Complications
• Guidelines primarily based on DCCT
(Type 1) and UKPDS (Type 2) and
subsequent studies
• Questions regarding A1C and
cardiovascular disease in more recent
ACCORD, ADVANCE, and VADT studies
Type 1 Diabetes: DCCT
Microvascular Complications
Retinopathy
Nephropathy
Neuropathy
Microalbuminuria
15
Relative Risk
13
11
9
7
5
3
1
6
7
8
9
10
11
12
A1C (%)
Adapted with permission from Skyler J. Endocrinol Metab Clin North Am. 1996;25:243
DCCT Research Group. N Engl J Med. 1993;329:977
Type 2 Diabetes: UKPDS
Blood Glucose, A1C, and CVD
• ACCORD, ADVANCE,VADT did not show
improved CVD outcomes with A1C less than
~6.0%-6.5%
• ADVANCE confirmed less microvascular
disease (nephropathy) in tightly controlled
• Other data suggest post-prandial, variable
glucose, difficult to target may contribute to CVD
• Lower A1C associated with less microvascular
disease (nephropathy, neuropathy, retinopathy)
N Engl J Med 2008; 358:2545-2559
N Engl J Med 2008; 358:2560-2572
(UKPDS, DCCT)
N Engl J Med 2009; 360:129-139
Diabetes Care October 2011 34 (10) 22372243
Blood Glucose, A1C, and CVD
• Recent study showed A1C=6 or >8,
higher CVD risk
• Meta-analysis of Five Trials
UKPDS2, PROactive3, ADVANCE4, ACCORD5, VADT6
Intensive therapy reduced cardiovascular
death, but not all cause mortality
Colayco DC et al Diabetes Care. 2011;34(1):77-83
Ray K et al The Lancet. 2009; 373:1765 - 1772
A1C and Complications
• So?
• What Now?.......
A1C and Complications
• Data suggests lower A1C’s earlier in
course of diabetes beneficial
• Long term poor control may not benefit
from more stringent control now,
particularly with reference to CVD- Blood
Pressure and Lipid Management need to
be targeted
Diabetes Care January 2009;32 (1) 187-192
Ann Intern Med. 2011 Apr 19;154(8):554-9.
Summarizing
Blood Glucose, A1C, and Diabetes
Complications
• A1C
Probably more associated with microvascular
complications
• Glucose variability, post-prandial glucose
Probably more associated with macrovascular
complications
• Optimal A1C may be unclear for all patients with
CVD risk
Optimal A1C
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Age
Co-Morbid Conditions/Complications
Length of Diabetes
Resources
Ability to manage complex regimens
Hypoglycemia
Goals of Glucose Management
• More stringent (<6.5) may be reasonable:
-No significant CVD
-Short duration
-Long life expectancy
Diabetes Care 36:Supplement 1, 2013
Goals of Glucose Management
Less stringent (<7.5-8+) may be reasonable:
• History of severe hypoglycemia
• Limited life expectancy
• Advanced complications or comorbid
conditions
• Longstanding difficult to control diabetes
Diabetes Care 36:Supplement 1, 2013
Other Important Labs In
Diabetes
Lipids and Cardiovascular
Complications:
– Total cholesterol <200
– Triglycerides
<150
– HDL (“good”)
>40 men, >50 women
– LDL (“bad”)
<100, <70 high risk
These are no longer “targets”, but abnormals
represent “at risk”
Cardiovascular Complications in
Diabetes
• Affects about 65% of adults with diabetes
• Targeting blood pressure and lipids can
reduce risk by about 25-40%
• LDL cholesterol is thought to be most
tightly associated with CVD risk
• This is usually done annually at minimum
Kidney Disease Screening
• Serum Creatinine - may have age, disease, or
muscle mass differences
• Creatinine Clearance (or Glomerular Filtration
Rate-GFR)- a better measure
• CrCl- measure of creatinine filtered in kidneys
• GFR- measure of blood filtered in kidneys
• http://www.nkdep.nih.gov/lab-evaluation.shtml
National Kidney Foundation Technical
Discussion
Kidney Disease Screening
• Urine for albumin- very predictive of future
kidney disease (<30mg is normal on
dipstick testing)
• Gross proteinuria “trumps” microalbumin
(Proteinuria >300mg)
• These tests are usually done annually
Chronic Kidney Disease (CKD)
• Stage 1: GFR >90 with other evidence of
kidney damage (microalbumin- or protein-uria,
or abnnormal serum creatinine)
• Stage 2: GFR 60-90 with same qualifiers as Stage 1
• Stage 3: GFR 30-59
• Stage 4: GFR 15-29
• Stage 5: GFR <15
Chronic Kidney Disease
• Usually a direct result of diabetes and/or
concominannt hypertension
• May have secondary hyperparathyroidism
• Elevated serum Parathyroid hormone
(PTH) from hypocalcemia
• Abnormalities with phosphorus, Vitamin D
Other Tests in Diabetes
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Thyroid (TSH) (Type 1)
Celiac (TTG IgA and IgG) (Type 1)
Serum B12 (Type 2)
Vitamin D (25-OH) (Type 2)
LFT’s (often minimal chronic changes with
fatty liver disease)
Future Directions And Other
Lab Testing In Diabetes
Continuous Glucose Monitoring Logbook Data
Home A1C Testing
• Limited use
• Recall that A1C “turns over” slowly 8-12
weeks
• Expensive
Other Novel Cardiovascular
Inflammatory Markers
Mayo Panel:
• High Sensitivity C-reactive Protein
(hsCRP)
• Homocysteine
• Lipoprotein a
• Fibrinogen
• LDL subfraction/particle size
Novel Cardiovascular Risk
Assessment
• Heart attack and/or stroke and/or peripheral arterial
disease at a relatively young age (under age 55 in men,
under age 65 in women)
• Asymptomatic patients who have a family history of early
atherosclerosis
• Patients with elevated levels of novel risk factors
including C-reactive protein (CRP), fibrinogen,
lipoprotein(a) and homocysteine
Cases
Case #1
• 12 year old female
• Thirst, unintentional weight loss of 15# in 3
weeks
• Fasting blood sugar 460
• “3+” Ketones in urine
• Diagnosis?
Case #1
• Diagnosis is type 1 diabetes
• Do we need antibody tests?
• Should be tested for thyroid disease (TSH)
and celiac disease (TTG IgA and IgG)
Case #2
• 42 y/o hispanic female with hx of GDM 6
years ago, term 10lb 5 oz male infant
• Has not been seen for follow-up in
3 years
• Obese, noting fatigue
• FBS done at annual pap/px is 149
Does this patient have diabetes?
What next?
Case #2
• Diagnosis of diabetes generally
requires 2 abnormal values
• Patient is at high risk for developing
type 2 diabetes
• GDM is a pre-diabetes condition
Repeat FBS 3 days later…….
Case #2
• Repeat FBS 135
• Dx: Type 2 diabetes
- FBS >126 on 2 separate occasions
- A1C 6.3
- Could have done an A1C as a
“stand alone” test (>6.5)
• Note that different tests don’t “cancel
each other out”
Summary
• Diabetes is common
• Laboratory markers and tests are very
useful for screening and diagnosis of
diabetes
• Laboratory markers and tests are very
useful for management of diabetes and
avoidance of complications