Dr. Robyn Houlden Professor, Division of Endocrinology Queen s University

Transcription

1 Diabetes in the elderly Dr. Robyn Houlden Professor, Division of Endocrinology Queen s University

2 Disclosures Grants/research support: AstraZeneca, Eli Lilly, Pfizer Speakers bureau/honoraria: NovoNordisk, Merck Frosst, AstraZeneca, Eli Lilly, Sanofi, Boehringer, Bristol Myers, Novartis

3 Learning Objectives Participants will be able to; identify the prevalence of diabetes in the elderly individualize glycemic targets select appropriate oral antihyperglycemic agents screen for diabetes recommend blood glucose monitoring frequency

4 Canadian Diabetes Association Definition of Elderly The definition of elderly varies, with some studies defining the elderly population as 60 years of age Administrative guidelines frequently classify people >65 years of age as elderly Although there is no uniformly agreed-upon definition of elderly, it is generally accepted that this is a concept that reflects an age continuum starting sometime after age 60 and is characterized by a slow, progressive frailty that continues until the end of life. Can J Diabetes 2008;32(suppl 1):S1-201.From Tessier D, Meneilly GS. Diabetes management in the elderly.in: Gerstein HC, Haynes RB, eds. Evidencebased Diabetes Care. Hamilton, ON: BC Decker Inc.; 2001:

5 Definition of aging At age 4 success is... not peeing in your pants At age 12 success is... having friends At age 16 success is... having a drivers license At age 20 success is... having sex At age 35 success is... having money At age 50 success is... having money At age 60 success is... having sex At age 70 success is... having a drivers license At age 75 success is....having friends At age 80 success is... not peeing in your pants

6 The Prevalence of Diabetes is Increasing prevalence expected to increase by ~6% per year 3 million Canadians currently have diagnosed diabetes 25% increase in prevalence from 2007

7 By 2030, the Number of Individuals 65 Years of Age With Diabetes Is Expected to Increase 2.3-Fold, Reaching 130 Million Worldwide Adults With Diabetes Worldwide People With Diabetes, millions Fold Increase Age Group, y Mackay J et al. The Atlas of Heart Disease and Stroke. Geneva, Switzerland. Wild S et al. Diabetes Care. 2004;27:

8 Diabetes prevalence in Ontario Prevalence increased 69% from 5.2% in 1995 to 8.8% in 2005 Rates increased to a greater extent in younger (94%) than older (63%) Mortality rate decreased by 25% from 1995 to 2005 Yearly diabetes prevalence rates, by sex and age-group, (fiscal years ). Overall prevalence rates are age-adjusted and sex-adjusted with 2001 census data. Lipscombe LL & Hux JE Lancet 2007; 369:

9 Diabetes incidence in Ontario 31% increase in annual incidence from 6.6/1000 persons in 1997 to 8.2/1000 in 2003 Yearly diabetes incidence rates per 1000 by sex and age-group, (fiscal years ). Overall incidence rates are age-adjusted and sex-adjusted with census data. Yearly rates are based on incident cases by March 31 of each year. Lipscombe LL & Hux JE Lancet 2007; 369:

10 Glucose Tolerance Is Decreased in the Elderly, Compared With the Young 10.0 Glucose mmol/l Old (N=18) Young (N=18) Plasma Glucose levels during a 100g OGTT after an ad lib diet OGTT = oral glucose tolerance test. Young = years old; Old = years old. Chen M et al. J Am Geriatr Soc. 1987;35:

11 Glucose Tolerance Declines With Age: The Increase in Postprandial Glucose Level Is Greater than the Increase in Fasting Plasma Glucose Level Postprandial Glucose and Fasting Plasma Glucose Levels for Individuals 20 to 74 Years of Age in the US Population With No Medical History of Diabetes (NHANES II; ) Plasma Glucose Concentration, mg/dl Age Group, y FPG 1-hour PPG 2-hour PPG FPG=fasting plasma glucose; PPG=postprandial glucose. Harris MI et al. Diabetes. 1987;36:

12 Age Is Associated With a Decline in β-cell Function Disposition index, a measure of β-cell function, was significantly lower in older individuals (60 75 years) vs younger individuals (26 44 years; P<0.01) Disposition index is calculated by multiplying insulin sensitivity by the acute insulin response to IV glucose (AIRglucose) Mean Disposition Index, 10 2 minute Disposition Index by Age Group 2.13 Young, Healthy Individuals (26 44 years) P< Older, Healthy Individuals (60 75 years) AIR=acute insulin response; IV=intravenous. Utzschneider KM et al. Diabetes. 2004;53:

13 The Elderly Are More Insulin Resistant Than Younger Individuals Insulin sensitivity index was diminished by 63% in older individuals, compared with younger individuals Insulin Sensitivity Index Insulin Sensitivity Index 6.5 P< Younger (mean age 27 years) Older (mean age 69 years) Chen M et al. J Clin Endocrinol Metab. 1985;60:13 20.

14 In a Hypoglycemic Clamp Study of Healthy Men, Symptom Recognition of Hypoglycemia Was Lower Among Older Men Change in Plasma Glucose Plasma glucose (mmol/l) Young Men Without Diabetes Elderly Men Without Diabetes Change in Total Symptom Score Time (min) Glucose Glucose infusion Glucose infusion maintained reduced stepwise from infusion restored at 5 mmol/l 5.0 to 2.4 mmol/l to 5 mmol/l Matyka K et al. Diabetes Care 1997; 20(2):135-41

15 Older Diabetic Patients Fail to Perceive Hypoglycemic Symptoms Means ± SE scores of self-rated autonomic (A) and neuroglycopenic (B) symptoms during the baseline period, at the beginning and end of the 30-min hypoglycemic plateau (indicated by gray shade), and 30 min after restoration of euglycemia in 13 middle-aged (39-64 years) ( ) and 13 older ( 65 years) ( ) type 2 diabetic patients. *P < 0.05; **P<0.01. Bremer et al. Diabetes Care. 2009; 32 (8):

16 Elderly People Without Diabetes, Compared With Young People Without Diabetes, Have Impaired Release of Epinephrine in Response to Hypoglycemia Glucose threshold for epinephrine release was higher in younger individuals (~3.2 mmol/l) than in older individuals (~2.9 mmol/l; P<0.01) Glucose Threshold, mmol/l Glucose Threshold for Epinephrine Release Young (25 30 years; n=10) P< Old (67 84 years; n=9) Meneilly GS et al. J Clin Endocrinol Metab. 1994;78:

17 Predictors of Severe Hypoglycemic Events Those who experienced severe hypoglycemia requiring treatment by an emergency facilities were older, had a longer duration of diabetes and a higher HbA1c. Hypoglycemia was associated with a age and duration of diabetes for insulin treated type 1 diabetes and with age for type 2 diabetes. Adapted from Leese GP et al. Diabetes Care 26: , 2003

18 Baseline Characteristics of those with Subsequent Severe Hypoglycemia in Older Patients with Diabetes Characteristics No Severe hypo (n=275) Severe hypo (n=27) p value Age (years) 75.9 ± ± Sex (% male) Duration of diabetes (years) 10.9 ( ) 15.9 ( ) Uses walking aid (%) Independent with finances (%) Independent with medications (%) Dementia (%) <0.001 Insulin ± oral agents HbA1c (%) 7.1 ( ) 7.7 ( ) 0.07 *N=302 elderly diabetic patients were followed for subsequent hypoglycemia requiring ambulance, emergency department or hospital service Adapted from Bruce et al. Diabetologia. 2009; 52:

19 Prevalence of Common Chronic Conditions Increases With Age in Men and Women Distribution of Individuals With 2 or More Chronic Conditions Across Age Groups Distribution of Population, % Men Women Age, y Prevalence was based on 9 common chronic conditions determined in individuals 60 years of age Arthritis Hypertension Cataracts Heart disease Varicose veins Diabetes Cancer (except nonmelanoma skin cancer) Osteoporosis or hip fracture Stroke Guralnick JM et al. Advance data from vital and health statistics; no National Center for Health Statistics

20 Prevalence of Macrovascular Complications Is Higher Among the Elderly With Diabetes Macrovascular Complications Stroke Coronary heart disease Heart attack Chest pain Congestive heart failure years years Prevalence, % American Association of Clinical Endocrinologists

21 What are appropriate glycemic targets in the elderly with diabetes?

22 Microvascular Events and Glucose Control UKPDS 1 (n = 3,867) ADVANCE 2 (n = 11,140) VADT 3 (n = 1,791) ACCORD 4 (n = 10,251) A1c achieved (%)* 7.0 vs vs vs vs. 7.5 All microvascular 25% (p = ) 14% (p = 0.01) N/A NS Nephropathy NS 21% of nephropathy progression (p = 0.006) and appearance of microalbuminuria (p = 0.02) in progression of microalbuminuria (p = 0.01) and progression to macroalbuminuria (p = 0.04) 21% in appearance of microalbuminuria 32% in appearance of macroalbuminuria Retinopathy in need for retinal photocoagulation (p = ) and cataract extraction (p = 0.046) NS NS 33% in progression of retinopathy Neuropathy NS NS NS 12% in loss of sensation to the 10g monofilament * Avarage A1c achieved, intensive vs. standard NS = non significant 1. UKPDS Group. Lancet 1998;352: ADVANCE Collaborative Group. N Engl J Med 2008;358: Duckworth W, et al. N Engl J Med 2009;360: Ismail Beigi F, et al. Lancet 2010; 376:

23 Macrovascular Events and Glucose Control UKPDS 1 (n = 3,867) ADVANCE 2 (n = 11,140) ACCORD 3 (n = 10,251) VADT 4 (n = 1,791) A1c achieved (%) 7.0 vs vs vs vs. 8.4 Follow Up (years) 10* 5* 3,5** 5,6* All macrovascular MI CV deaths, CVA, MI CV deaths, MI, CVA Any major CV event Relative Risk Reduction (%) 16% p = % p = % p = % p = 0.14 Myocardial Infarct See above 2% NS (Non fatal MI) 24% p = (Non fatal MI) 18% NS Total Mortality 6% NS 7% NS +35% p = 0.02 (CV deaths) +7% NS NS = non significant 1. UKPDS Group. Lancet 1998;352: ADVANCE Collaborative Group. N Engl J Med 2008;358: ACCORD Study Group. N Engl J Med 2008;358: Duckworth W, et al. N Engl J Med 2009;360:

24 UKPDS: Legacy Effect of Earlier Glucose Control Aggregate Endpoint Any diabetes related endpoint RRR: 12% 9% P: Microvascular disease RRR: 25% 24% P: Myocardial infarction RRR: 16% 15% P: All-cause mortality RRR: 6% 13% P: RRR = Relative Risk Reduction, P = Log Rank Holman et al N Eng J Med 2008; of 50

25 Effect of Age on Risk of Severe Hypoglycemia. A Post Hoc Analysis from ACCORD (A1c 7 vs 7.9%) Adapted from Miller et al. BMJ. 2009; 339:1-12

26 2013 Canadian Diabetes Association Guidelines - Individualizing A1C Targets Extensive coronary artery disease at high risk of ischemic events which must be balanced against the risk of hypoglycemia

27 Rockwood et al. CMAJ 2005;173:489

28 Glycemic Targets Normal Values Recommended Targets for Glycemic Control A1C 6.0 % 7.0 % Preprandial 4.0 to 6.0 mmol/l 4.0 to 7.0 mmol/l 2h postprandial 5.0 to 8.0 mmol/l 5.0 to 10.0 mmol/l (5.0 to 8.0 mmol/l if A1c targets not being met)

29 L I F E S T Y L E Perform clinical assessment Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin A1C < 8.5% If not at target (2-3 mos) Start metformin A1C 8.5% Start metformin immediately Consider initial combination with another antihyperglycemic agent If not at target (3-6 mos) Add an agent best suited to the individual: Patient Characteristics Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Comorbidities (renal, cardiac, hepatic) Preferences & access to treatment Other Symptomatic hyperglycemia with metabolic decompensation Agent Characteristics BG lowering efficacy and durability Risk of inducing hypoglycemia Effect on weight Contraindications & side-effects Cost and coverage Other Initiate insulin +/- metformin See next page

30 From prior page L I F E S T Y L E Class α glucosidase inhibitor (acarbose) (delay digestion and absorption of dietary carbohydrate) Incretin agents: DPP 4 Inhibitors GLP 1 receptor agonists Add an agent best suited to the individual (agents listed in alphabetical order): Relative A1C Lowering Hypoglycemia Rare neutral to to Rare Rare Weight Other therapeutic considerations Cost neutral Improved postprandial control, GI side effects $$ GI side effects Insulin Yes No dose ceiling, flexible regimens $ $$$$ Insulin secretagogue: Meglitinide Sulfonylurea (stimulate insulin secretion) Thiazolidinediones (reduce insulin resistance in muscle and adipose tissue) Yes* Yes *Less hypoglycemia in context of missed meals but usually requires TID to QID dosing Gliclazide and glimepiride associated with less hypoglycemia than glyburide Rare CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6 12 weeks required for maximal effect If not at target (3-6 mos) $$$ $$$$ $$ $ $$ Add another agent from a different class Add/Intensify insulin regimen Make timely adjustments to attain target A1C within 3 to 6 months

31 CDA Guidelines: Diabetes in the Elderly In elderly people with type 2 diabetes, sulfonylureas should be used with caution because the risk of hypoglycemia increases exponentially with age In general, initial doses of sulfonylureas in the elderly should be half those used for younger people, and doses should be increased more slowly Gliclazide and gliclazide MR and glimepiride are the preferred sulfonlyureas Meglintinides should be considered in patients with irregular eating habits Can J Diabetes 2008;32(suppl 1):S1-201

32 Repaglinide Exceptional Access Program Inadequate A1C (> 7%) using maximal doses of a sulfonylurea and metformin, or on maximal of one and demonstrated contraindication, or intolerance to the other, or Demonstrated intolerance or contraindication to both a sulfonlyurea and metformin, or Adequate glycemic control (A1C < 7%) who develop intolerance or a contraindication to sulfonlyurea or metformin, or A1C < 7% with greater than 50% of fasting blood glucose or postprandial glucose levels not at target and using maximally tolerated doses of a sulfonlyurea and metformin

33

34

35 GLP-1 actions are glucose-dependent in patients with T2DM mmol/l Fasting glucose pmol/l Insulin pmol/l * Infusion * * * * * * * * * * * * * mg/dl mul/l Placebo GLP-1 Glucagon * * * * *p<0.05 n= Minutes Nauck MA, et al. Diabetologia. 1993;36:741 4.

36 Natural GLP-1 has multiple actions in the body insulin secretion (glucose dependent) MEAL but natural GLP- 1 is broken down rapidly DPP-4 glucagon secretion (glucose dependent) glucose production gastric emptying GLP-1 Drucker DJ. Enhancing Incretin Action for the Treatment of Type 2 Diabetes. Diabetes Care 2003;26: ; Girard J. The incretins: from the concept to their use in the treatment of type 2 diabetes. Part A: incretins: concept and physiological functions. Diabetes and Metabolism 2008; 34:550-59; Elbrond B et al. Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of a Single-Dose of NN2211, a Long-Acting Glucagon-Like Peptide 1 Derivative, in Healthy Male Subjects Diabetes Care 2002;25(8): food intake satiety

37 insulin secretion (glucose dependent) DPP-4 INHIBITOR DPP-4 GLP-1 receptor agonist GLP-1 glucagon secretion (glucose dependent) glucose production gastric emptying DPP-4 inhibitors prevent GLP-1 receptor agonists breakdown of natural increase GLP-1 GLP-1 levels provide PHYSIOLOGICAL provide PHARMACOLOGIC levels of GLP-1 action levels of GLP-1 action food intake satiety Combettes MM et al. Curr Opin Pharmacol 2006;6: ; Mari et al. J Clin Endocrinol Metab 2005;90: ; Drucker DJ et al. Lancet 2006;368: ; Elbrond B et al. Diabetes Care 2002;25(8): ; Degn KB et al. Diabetes 2004;53:

38 Effects of GLP-1: Dose-response relationship Diarrhea Nausea Abdominal pain Vomiting Increasing plasma GLP-1 concentrations Gastric emptying Appetite Food intake = Weight loss Pharmacological effects GLP-1 levels achieved with GLP-1-receptor agonists Insulin secretion Glucagon secretion = improved glycemic control Holst JJ, et al. Trends Mol Med 2008; 14: GLP-1 effects Physiological effects GLP-1 levels achieved with DPP-4 inhibitors

39 Incretin therapies: Administration DPP-4 INHIBITORS GLP-1 RECEPTOR AGONISTS Linagliptin Saxagliptin Sitagliptin Exenatide Liraglutide 5 mg oncedaily 2.5, 5 mg once daily 25, 50, 100 mg once daily Twice-daily Once-daily Anytime Anytime Anytime Up to 60 minutes before AM and PM meal Anytime Oral Oral Oral Injectable (subcutaneous) Injectable (subcutaneous)

40 Comparable A1C Reduction with Sitagliptin or Glipizide Added to Metformin 8.2 Per protocol Population LSM change from baseline at 52 weeks (for both groups): 0.7% A1C (%) ± SE Sulfonylurea a + metformin (n = 411) Sitagliptin b + metformin (n = 382) Achieved primary hypothesis of noninferiority to sulfonylurea Weeks a Specifically glipizide 20 mg/day; b sitagliptin 100 mg/day with metformin ( 1500 mg/day); LSM = least squares mean. Adapted from: Nauck MA, et al. Diabetes Obes Metab 2007; 9:

41 Sitagliptin + Metformin vs. Sulfonylurea + Metformin: Relative Effects on Body Weight and Hypoglycemia All patients as treated Population Least squares mean change from baseline Hypoglycemia 3 Sulfonylurea a + metformin (n = 416) Sitagliptin b + metformin (n = 389) 50 Sulfonylurea a + metformin (n = 584) Sitagliptin b + metformin (n = 588) 2 Body weight (kg ± SE) between groups at Week 52 = 2.5 kg p < Patients with 1 episode over 52 weeks (%) % p < Week 52 5% Weeks a Specifically glipizide 20 mg/day. b Sitagliptin (100 mg/day) with metformin ( 1500 mg/day). Adapted from: Nauck MA, et al. Diabetes Obes Metab 2007; 9:

42 Effects of the addition of sitaglitpin or sulfonlyurea A1C and body weight in subgroup analysis of pts 65 yrs from 2 randomized, double-blind studies in pts with inadequate glycemic control on MF ( 1500 mg/d) Study 1-52 week (N=243) Study 2-30 week (N=217) SITA GLIP SITA GLIM ΔA1C, % -0.7 (-0.9, -0.5) -0.7 (-0.8, -0.5) -0.4 (-0.6, -0.3) -0.5 (-0.7, -0.4) ΔBW, kg -1.4 (-2.6, -0.3) 1.1* (0.0, 2.1) -0.9 (-1.5, -0.2) 1.1* (0.5, 1.8) HYPO, % of pts * ** ΔA1C and ΔBW are least squares mean change from BL (95% CI) *p<0.001 or **p<0.05 for difference between groups within study Adapted from Seck et al. Abstract 2332-PO. ADA 2011

43 Incretin therapies comparison: A1C reductions Mean change in A1C from baseline at 52 weeks 0.00% Baseline A1C: 8.5% Baseline A1C: 8.4% Baseline A1C: 8.4% Sitagliptin 100 mg QD (n=219) Liraglutide 1.2 mg QD (n=225) Liraglutide 1.8 mg QD (n=221) -0.20% Mean change in A1C (%) -0.40% -0.60% -0.80% -1.00% -1.20% -0.88% -1.40% -1.29% -1.60% p< p< % Pratley R et al. Int J Clin Pract 2011;published online ahead of print.

44 Incretin therapies comparison: Body weight Mean change in body weight from baseline at 52 weeks Baseline body weight: 93.1 kg Baseline body weight: 93.7 kg Baseline body weight: 94.6 kg 0 Sitagliptin 100 mg QD (n=219) Liraglutide 1.2 mg QD (n=225) Liraglutide 1.8 mg QD (n=221) -0.5 Change in body weight (kg) kg kg kg p< p< Pratley R et al. Int J Clin Pract 2011;published online ahead of print.

45 Effect of liraglutide on body weight over 52 weeks ***p< for change from baseline Garber et al. Lancet 2009;373: (LEAD 3)

46 Liraglutide reduces visceral body fat Change in body fat, kg (%) Change in body fat DEXA scan -1.6* (-1.1%*) -2.4* (-1.2%*) +1.1 kg (+0.4%) Change in percentage fat (%) Visceral vs. subcutaneous fat CT scan Visceral Subcutaneous -7.8* -8.5* +3.4 Liraglutide 1.2 mg + met Liraglutide 1.8 mg + met Glimepiride + met 86% of weight loss was fat tissue (liraglutide 1.8 mg) Data are mean±sem; *p<0.05 vs. glim+met; n=160. LEAD 2 substudy, originally presented as Jendle et al. Diabetes 2008;57(Suppl. 1):A32.

47 Weight loss with GLP1s is variable 0 Q1: mean weight change for the 25% of subjects who had the largest weight loss Q1 Q2: mean weight change for the 25 50% weight loss quartile Q2 Q3: mean weight change for the 50 75% weight loss quartile Q3 Q4: mean weight change for the % weight loss quartile, that is, the 25% who had the smallest weight loss Nauck et al. Diabetes Care 2009;32;84 90 (LEAD-2)

48 Most commonly reported adverse events: GLP-1 Receptor Agonists Proportion of patients (%) Exenatide 10 μg BID Liraglutide 1.8 mg QD p< Weeks Nausea with GLP-1 receptor agonists was mild to moderate and transient in nature Nausea with liraglutide settles within 8-10 weeks, whereas this does not happen with exenatide Buse JB, et al. Lancet. 2009;374:39-47.

49 Starting once-daily Victoza *Based on clinical response and after at least one week on 1.2 mg dose, the dose can be increased from 1.2 mg to 1.8 mg once daily to achieve maximum efficacy for glycemic control.

50

51 Age-Related Decline in Kidney Function in Patients With Type 2 diabetes GFR, ml min m 2 Age-Stratified Distribution of GFR in 662 Patients With Type 2 Diabetes Age Group, y Moderate renal impairment Mild renal impairment Severe renal impairment 90th percentile 75th percentile Median 25th percentile 10th percentile In patients with type 2 diabetes, the median GFR was lower for patients 70 to 80 years of age than for those <40 years (median GFR 65 min m 2 vs 127 min m 2, respectively) After 40 years of age, a decline in GFR of 1.8 ml min 1 year 1 was observed in this population CKD=chronic kidney disease; GFR=glomerular filtration rate. Shaded area: National Kidney Foundation definition of mild renal impairment. Premaratne E et al. Diabetologia. 2005;48:

52 Antihyperglycemic Agents in Kidney Disease CKD Stages (GFR) 5 ESKD* (<15) 4 Severe (15-29) 3 Moderate (30-59) 2 Mild (60-89) 1 (> 90) 25 DPP-4 Inhibitors GLP-1R Agonists 5 mg OD mg OD 5 mg OD 25 mg OD 50 mg OD 100 mg OD Sulfonylurea GFR (ml/min) CKD = Chronic Kidney Disease GFR = Glomerular Filtration Rate * ESKD End Stage Kidney Disease

53 Screening for diabetes

54 Diagnostic Criteria for Diabetes FPG 7.0 mmol/l Fasting = no caloric intake for at least 8 hours or A1C 6.5% (in adults) Using a standardized, validated assay, in the absence of factors that affect the accuracy of the A1C and not for suspected type 1 diabetes or 2hPG in a 75 g OGTT 11.1 mmol/l or Random PG 11.1 mmol/l Random= any time of the day, without regard to the interval since the last meal 2hPG = 2 hour plasma glucose; FPG = fasting plasma glucose; OGTT = oral glucose tolerance test; PG = plasma glucose

55 In the absence of symptomatic hyperglycemia, if a single laboratory test is in the diabetes range, a repeat confirmatory laboratory test (FPG, A1C, 2hPG in a 75- g OGTT) must be done on another day. It is preferable that the same test be repeated (in a timely fashion) for confirmation, but a random PG in the diabetes range in an asymptomatic individual should be confirmed with an alternate test. In the case of symptomatic hyperglycemia, the diagnosis has been made and confirmatory test is not required before treatment is initiated.

56 In individuals in whom type 1 diabetes is likely (younger or lean or symptomatic hyperglycemia, especially with ketonuria or ketonemia), confirmatory testing should not delay initiation of treatment to avoid rapid deterioration. If results of two different tests are available and both are above the diagnostic cutpoints, the diagnosis of diabetes is confirmed. [Grade D, Consensus].

57 Diagnostic Testing With 3 Different Tests Discordance: many people identified as having diabetes using A1C will not be identified as having diabetes by traditional glucose criteria, and vice versa. FPG A1C 2hPG When results of more than one test are available (amongst FPG, A1C, 2hPG in a 75-g OGTT) and the results are discordant, the test whose result is above the diagnostic cut-point should be repeated, and the diagnosis is made on the basis of the repeat test.

58 A1C Level and Future Risk of Diabetes: Systematic Review A1C Category (%) 5-year incidence of diabetes <5 to 9% to 25% to 50% Zhang X et al. Diabetes Care. 2010;33:

59 Diagnosis of Prediabetes* Test Result Prediabetes Category Fasting Plasma Glucose (mmol/l)) Impaired fasting glucose (IFG) 2 hr Plasma Glucose in a 75 g Oral Glucose Tolerance Test (mmol/l) Impaired glucose tolerance (IGT) Glycated Hemoglobin (A1C) (%) Prediabetes * Prediabetes refers to impaired fasting glucose, impaired glucose tolerance, or an A1C between 6.0 to 6.4%, each of which places individuals at high risk of

60 Factors influencing A1C Reduced A1c Hemolytic anemia Acute blood loss Homozygotes for hemoglobin variants (HbS, HbE, HbC, and HbD) Falsely increased A1c (interferes with assay) hypertriglyceridemia, hyperbilirubinemia, uremia, chronic alcoholism, or chronic ingestion of salicylates Increased A1c iron deficiency anemia (malondialdehyde, which is increased in subjects with iron deficiency anemia, augments glycation of hemoglobin)

61 A1c rises up to 0.1% per decade? Need for age-adjusted A1c thresholds for the elderly

62

63 *If both FPG and A1C are available, but discordant, use the test that appears furthest to the right side of the algorithm.

64

65

66 In the absence of symptomatic hyperglycemia, if a single laboratory test is in the diabetes range, a repeat confirmatory laboratory test (FPG, A1C, 2hPG in a 75 g OGTT) must be done on another day. It is preferable that the same test be repeated (in a timely fashion) for confirmation. If results of two different tests are available and both are above the diagnostic cutpoints, the diagnosis of diabetes is confirmed.

67

68

69 **Prediabetes = IFG or IGT or A1C 6.0 to 6.4%

70 **Prediabetes = IFG or IGT or A1C 6.0 to 6.4%

71 Monitoring

72

73

74

75

76

77 Diabetes in the Elderly Otherwise healthy, elderly people with diabetes should be treated to achieve the same glycemic and targets as younger people with diabetes In people with multiple comorbidities, a high level of functional dependency and limited life expectancy, the goals should be less stringent, and the A1C target should be 7.5 to 8.5% In particular, aging and cognitive impairment are risk factors for severe hypoglycemia with intensification of therapy, and as such, more relaxed targets should be applied in these patients Certain oral antihyperglycemic agents (metformin, incretins) are associated with a lower risk of hypoglycemia