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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. • • • • • • 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 • • • • • • • • • 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 • • • • ~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 • • • • ~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 • • • • 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 • • • • • 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 • • • • • 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 • • • • • • • • • • • 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 • • • • 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 • • • • • • • 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 • • • • • 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: • • • • • • 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 • • • • • • 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 • • • • • 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