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Back to Basics: Endocrinology Diabetes, Obesity, Metabolic Syndrome Dr. Amel Arnaout

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1 Back to Basics: Endocrinology Diabetes, Obesity, Metabolic Syndrome Dr. Amel Arnaout

2 Which of the following statements is true? A. Type 1 diabetes is not diagnosed after age 50 B. Type 2 diabetes is more strongly inherited than type 1 diabetes. C. The incidence and prevalence of DM-1 is on the rise D. Gestational diabetes does not increase the risk of developing diabetes in the future. E. People with type 2 diabetes never get DKA

3 Answer B and C B and C

4 Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa, Prevalence of diagnosed diabetes among individuals aged ≥ 1 year, by age group and sex, 2008/09 Diabetes in Canada: Prevalence of Diagnosed Diabetes by age and sex Prevalence increased with age. The sharpest increase occurred after age 40 years. The highest prevalence was in the year age group. Prevalence (%) ≥85Canada Age group (years) Females Males Total Overall Prevalence 6.4% 7.2% 6.8%

5 Classification of Diabetes TypeDefinition Type 1 DiabetesDiabetes due to pancreatic beta destruction and prone to ketosis Type 2 diabetesDiabetes that ranges from insulin resistance with relative insulin deficiency to a predominant secretory defect with insulin resistance Gestational Diabetes Mellitus Glucose intolerance with onset or first recognition in pregnancy Other typesVariety of uncommon diseases, genetic forms, or diabetes associated with drug use.

6 TYPE 1 Diabetes 10% Beta cell destruction (usually autoimmune) Low or absent Required for survival Often <30 (but can occur at any age) Usually lean Smaller Acute, severe Yes No Proportion of diabetes cases Pathogenesis Endogenous insulin secretion Need for insulin therapy Age of onset Body habitus Genetic component Symptoms at onset Ketoacidosis Long-term complications present at dx? TYPE 2 Diabetes 90% Insulin resistance, relative insulin deficiency Variable Required in <50%, to improve control rather than for survival Often >40 but even in kids Often obese Very large Often mild, slow onset Rare Retinopathy ~20%, CVD relatively common

7 Diminished insulin Hyperglycemia Liver 1. Insulin deficiency 2. Excess glucose output 3. Insulin resistance Pancreas Muscle and fat Excess glucagon Islet Diminished insulin α-cell produces excess glucagon β-cell produces less insulin The pathophysiology of T2DM includes three main defects

8 Diabetes mellitus - complications Stroke Cardiovascular Disease Diabetic Neuropathy Leading cause of non- traumatic lower extremity amputations 5 Diabetic Retinopathy Leading cause of blindness in working-age adults 1 Diabetic Nephropathy Leading cause of end-stage renal disease 2 1. Fong DS et al. Diabetes Care 2003; 26(Suppl 1):S99-S Molitch ME et al. Diabetes Care 2003; 26 (Suppl 1):S94-S Kannel WB et al. Am J Heart 1990; 120: Gray RP and Yudkin JS. In: Textbook of Diabetes Mayfield JA, et al. Diabetes Care 2003; 26(Suppl 1):S78-S79.

9 Diabetes Complications: Macrovascular DM is a major risk factor for cardiac disease DM is a major risk factor for cardiac disease Acute MI occurs years earlier in those with DM Acute MI occurs years earlier in those with DM Heart disease accounts for approximately 50% of all deaths among people with diabetes in industrialized countries Heart disease accounts for approximately 50% of all deaths among people with diabetes in industrialized countries REF: Diabetes in Ontario, An ICES Practice Atlas, 2002

10 Several large epidemiological studies have found a strong relationship between Several large epidemiological studies have found a strong relationship between glucose level and subsequent coronary events, even at ‘pre-diabetes’ levels (IGT and IFG) glucose level and subsequent coronary events, even at ‘pre-diabetes’ levels (IGT and IFG) glucose levels that are only modestly elevated place patients at risk. glucose levels that are only modestly elevated place patients at risk. REF: Coutiho M. et al Diabetes Care 1999;22: & DECODE Study Group. Arch Intern Med 2001;161: Diabetes Complications: Cardiovascula disease

11 Diabetes…. Diabetes…. Is the leading cause of non traumatic amputation Is the leading cause of non traumatic amputation Increases the risk of amputation by 20 fold Increases the risk of amputation by 20 fold those living in the north or in low income neighborhoods and those with poor access to physician services are at particular risk for amputation. those living in the north or in low income neighborhoods and those with poor access to physician services are at particular risk for amputation. REF: Diabetes in Ontario, An ICES Practice Atlas, 2002 Diabetes Complications: Peripheral vascular disease (Macro and microvascular disease)

12 Diabetes Is a leading cause of adult-onset blindness Is a leading cause of adult-onset blindness Prevalence of diabetic retinopathy is ~ 70% in persons with type 1 and 40% with person with type 2 diabetes. Prevalence of diabetic retinopathy is ~ 70% in persons with type 1 and 40% with person with type 2 diabetes. REF: Diabetes in Ontario, An ICES Practice Atlas, 2002 Diabetes Complications: Microvascular – Retinopathy

13 Diabetes Diabetes Is the leading cause of ESRD Is the leading cause of ESRD Increases the risk of developing ESRD by up to 13- fold Increases the risk of developing ESRD by up to 13- fold Refs: Meltzer S, et al CMAJ 1998; 159 (8 suppl):S1-S29, & Parchman ML, et al Medical Care 2002; 40(2): Diabetes Complications: Microvascular - Nephropathy

14 DM-2 Risk Factors Modifiable Risk Factors Physical Activity Physical Activity Obesity Obesity Diet Diet& Non-Modifiable Risk Factors Ethnicity Ethnicity Family History Family History Age Age

15

16 Source: Choi B, Shi F. Diabetologia 2001, 44: Diabetes Risk Factors: Modifiable

17 The Epidemic: Ethnic Groups at High Risk for DM AboriginalLatino South Asian Asian African Descent

18 Prevention strategies Primary Prevention Primary Prevention Prevent diabetes through reduction of modifiable risk factors in general population Prevent diabetes through reduction of modifiable risk factors in general population Secondary Prevention Secondary Prevention Screening those at high-risk for diabetes Screening those at high-risk for diabetes Tertiary Prevention Tertiary Prevention Upon diagnosis of diabetes, prevention of complications morbidity, and mortality Upon diagnosis of diabetes, prevention of complications morbidity, and mortality REF: Diabetes Blueprint

19 Primary Prevention Model Goal Goal Reducing modifiable risk factors for diabetes Reducing modifiable risk factors for diabetes Target Target General population & high-risk groups General population & high-risk groups Messages Messages Healthy lifestyle choices Healthy lifestyle choices Current Delivery Models of Primary Prevention Current Delivery Models of Primary Prevention Population Health Population Health Primary Care Primary Care

20 REF: Health Canada Primary Prevention Model: Population Health – National CDS Health Canada NADA

21 Goal Goal Early identification of those with dysglycemia Early identification of those with dysglycemia Target Target High-risk individuals and groups High-risk individuals and groups Messages Messages Diabetes awareness Diabetes awareness Current delivery model of secondary prevention relies on primary care Current delivery model of secondary prevention relies on primary care Secondary Prevention

22 Secondary Prevention: Is It Effective? Yes…. Yes…. Patients diagnosed with IGT can be prevented from progressing to type 2 diabetes Patients diagnosed with IGT can be prevented from progressing to type 2 diabetes 58% reduction with lifestyle changes (DPP, DPS) 58% reduction with lifestyle changes (DPP, DPS) 30% reduction with medication (DPP, Stop NIDDM) 30% reduction with medication (DPP, Stop NIDDM)

23 Tertiary Prevention: Is it Effective? Yes… Yes… Strong evidence for tertiary prevention particularly for microvascular disease Strong evidence for tertiary prevention particularly for microvascular disease DCCT, UKPDS DCCT, UKPDS And for macrovascular as legacy effect (UKPDS and EDIC follow up studies) And for macrovascular as legacy effect (UKPDS and EDIC follow up studies) How to translate this evidence into practice? How to translate this evidence into practice?

24 Tertiary Prevention Goals Goals Glucose, blood pressure, and lipid control to reduce the development of complications Glucose, blood pressure, and lipid control to reduce the development of complications Complication screening for early identification and management Complication screening for early identification and management

25 OBESITY

26 Why are Obesity and Type 2 DM Increasing in Frequency? More sedentary lifestyles More sedentary lifestyles Worldwide changes in urbanization and nutrition Worldwide changes in urbanization and nutrition Aging population due to demographic growth rates (baby boomers) and increased life expectancy Aging population due to demographic growth rates (baby boomers) and increased life expectancy and accessed March 16, 2006

27 Obesity The most common metabolic condition in industrialized nations The most common metabolic condition in industrialized nations Statistics Canada: 48% of Canadians between ages yr are overweight (BMI>25), about 25% are obese Statistics Canada: 48% of Canadians between ages yr are overweight (BMI>25), about 25% are obese Associated with dyslipidemia, impaired glucose tolerance and insulin resistance Associated with dyslipidemia, impaired glucose tolerance and insulin resistance Risk factor for developing metabolic syndrome, type 2 Dm, cardiovascular disease Risk factor for developing metabolic syndrome, type 2 Dm, cardiovascular disease Huge economic costs Huge economic costs

28

29

30 METABOLIC SYNDROME

31 Metabolic Syndrome A constellation of risk factors Significantly increased CVD risks Significantly increased CVD risks Significantly increased risks for type 2 diabetes Significantly increased risks for type 2 diabetes

32 Definition of Metabolic Syndrome – need central obesity plus 2 others for diagnosis

33 Clinical Features of the Metabolic Syndrome Abdominal obesity Abdominal obesity Hyperglycemia Hyperglycemia Atherogenic dyslipidemia Atherogenic dyslipidemia Hypertension Hypertension Proinflammatory state Proinflammatory state Prothrombotic state Prothrombotic state

34 Metabolic Syndrome A common condition associated with increased cardiovascular disease risks A common condition associated with increased cardiovascular disease risks Treatment is aimed at lifestyle modification to achieve desirable body weight and reduce abdominal obesity Treatment is aimed at lifestyle modification to achieve desirable body weight and reduce abdominal obesity Multiple medical therapy may be required to achieve metabolic targets (lipids, glucose and BP) Multiple medical therapy may be required to achieve metabolic targets (lipids, glucose and BP) Lifestyle modification benefits everyone! Lifestyle modification benefits everyone!

35 DIABETES

36 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 Diagnosis of Diabetes 2013

37 Diagnosis of Prediabetes* TestResultPrediabetes Category Fasting Plasma Glucose (mmol/L) Impaired fasting glucose (IFG) 2-hr Plasma Glucose in a 75-g Oral Glucose Tolerance Test (mmol/L) 7.8 – 11.0Impaired glucose tolerance (IGT) Glycated Hemoglobin (A1C) (%) Prediabetes * Prediabetes = IFG, IGT or A1C %  high risk of developing T2DM 2013

38 Definitions of Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT) and Diabetes Fasting Glucose (mmol/L) h Post-load Glucose (mmol/L) Diabetes IFG + IGT Normal Glucose IGT IFG * 1. ADA Diabetes Care 2006;29(Suppl 1):S47,2. CDA Can J Diabetes 2003;27(Suppl 2):S7, 3.WHO 1999 NDC/NCS.99.2 accessed Mar from 5.6*

39 Recognize pitfalls of A1C: conditions that can affect value Factors affecting A1C Increased A1CDecreased A1CVariable Change in A1C ErythropoiesisB12/Fe deficiency Decreased erythropoiesis Use of EPO, Fe, or B12 Reticulocytosis Chronic liver Dx Altered hemoglobin Fetal hemoglobin Hemoglobinopathies Methemoglobin Altered glycationChronic renal failure (use of EPO decreases A1C) ASA, vitamin C/E Hemoglobinopathies ↑ erythrocyte pH Erythrocyte destruction SplenectomyHemoglobinopathies Chronic renal failure Splenomegaly Rheumatoid arthritis HAART meds, Ribavirin Dapsone AssaysHyperbilirubinemia Carbamylated Hb ETOH Chronic opiates Hypertriglyceridemia

40 Pros and Cons of Diagnostic Tests TestAdvantagesDisadvantages FPGEstablished standard Fast and easy Single Sample Sample not stable Day-to-day variability Inconvenient to fast Glucose homeostasis in single time point 2hPG in 75 g OGTT Established standardSample not stable Day-to-day variability Inconvenient, Unpalatable Cost A1CConvenient Single sample Low day-to-day variability Reflects long term [glucose] $$$ Affected by medical conditions, aging, ethnicity Standardized, validated assay required Not used for age <18, pregnant women or suspected T1DM

41 Treatment of Diabetes – Target A1C

42 Individualizing A1C Targets which must be balanced against the risk of hypoglycemia Consider % if: 2013

43 DCCT n=1441 T1DM Intensive (≥ 3 injections/day or CSII) vs Conventional (1-2 injections per day)

44 Reduction in Retinopathy The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329: Primary PreventionSecondary Intervention 76% RRR (95% CI 62-85%) 54% RRR (95% CI 39-66%) RRR = relative risk reduction CI = confidence interval

45 DCCT/EDIC Study Research Group. N Engl J Med 2005;353:2643–2653. DCCT/EDIC: Early intensive therapy reduced the risk of nonfatal MI, stroke or death from CVD 57% risk reduction (P=0.02; 95% CI: 12–79%) MI, stroke or CV death Conventional treatment Intensive treatment Years since entry

46 UKPDS: N = 3867 T2DM A1C (%) Conventional 7.9% Intensive 7.0% 7 UKPDS Study Group. Lancet 1998:352:

47 Adapted from Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412. UKPDS: decreased risk of diabetes-related complications associated with a 1% decrease in A1C Percentage decrease in relative risk corresponding to a 1% decrease in HbA1C ** Any diabetes- related endpoint 21% ** Diabetes- related death 21%** All cause mortality 14% * Stroke 12% ** Peripheral vascular disease † 43% ** Myocardial infarction 14% ** Micro- vascular disease 37% ** Cataract extraction 19% Observational analysis from UKPDS study data † Lower extremity amputation or fatal peripheral vascular disease *P = 0.035; **P <

48 After median 8.5 years post-trial follow-up 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: Legacy Effect of Earlier Glucose Control Holman R, et al. N Engl J Med 2008;359.

49 Therapeutic strategies for the management of type 2 diabetes.

50 Start metformin immediately Consider initial combination with another antihyperglycemic agent Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin A1C <8.5% Symptomatic hyperglycemia with metabolic decompensation A1C  8.5% Initiate insulin +/- metformin If not at glycemic target (2-3 mos) Start / Increase metformin If not at glycemic targets LIFESTYLELIFESTYLE 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 See next page… AT DIAGNOSIS OF TYPE 2 DIABETES Agent Characteristics BG lowering efficacy and durability Risk of inducing hypoglycemia Effect on weight Contraindications & side-effects Cost and coverage Other 2013

51 Oral Medications to Treat Type 2 Diabetes

52 Major Classes of Medications 1. Drugs that sensitize the body to insulin and/or control hepatic glucose production 2. Drugs that stimulate the pancreas to make more insulin 3. Drugs that slow the absorption of starches absorption of starches Thiazolidinediones Biguanides Sulfonylureas Meglitinides Alpha-glucosidase inhibitors

53 New Class of Medications Incretins Derived from gut hormone GLP-1 Derived from gut hormone GLP-1 Glucagon like peptide 1 Glucagon like peptide 1

54 GLP-1 Effects in Humans: Understanding Glucoregulatory Role of Incretins Adapted from Flint A, et al. J Chin Invest. 1998;101: ; Larsson H, et al. Acta Physiol Scand. 1997;160: ; Nauck MA, et al. Diabetologia. 1996;39: ; Drucker DJ. Diabetes. 1998;47:

55 Thiazolidinediones Thiazolidinediones decrease insulin resistance by making muscle and adipose cells more sensitive to insulin. They also suppress hepatic glucose production. Thiazolidinediones decrease insulin resistance by making muscle and adipose cells more sensitive to insulin. They also suppress hepatic glucose production. Efficacy Efficacy Decrease fasting plasma glucose ~ mmol/L Decrease fasting plasma glucose ~ mmol/L Reduce A1C ~ % Reduce A1C ~ % 6 weeks for maximum effect 6 weeks for maximum effect Other Effects Other Effects Weight gain, edema Weight gain, edema Hypoglycemia (if taken with insulin or agents that stimulate insulin release) Hypoglycemia (if taken with insulin or agents that stimulate insulin release) Contraindicated in patients with abnormal liver function or CHF Contraindicated in patients with abnormal liver function or CHF Improves HDL cholesterol and plasma triglycerides; usually LDL neutral Improves HDL cholesterol and plasma triglycerides; usually LDL neutral Medications in this Class: pioglitazone (Actos), rosiglitazone (Avandia), Medications in this Class: pioglitazone (Actos), rosiglitazone (Avandia),

56 Biguanides Biguanides decrease hepatic glucose production and increase insulin-mediated peripheral glucose uptake. Biguanides decrease hepatic glucose production and increase insulin-mediated peripheral glucose uptake. Efficacy Efficacy Decrease fasting plasma glucose mmol/L Decrease fasting plasma glucose mmol/L Reduce A1C % Reduce A1C % Other Effects Other Effects Diarrhea and abdominal discomfort Diarrhea and abdominal discomfort Risk of Lactic acidosis in those at risk (renal failure, CHF) Risk of Lactic acidosis in those at risk (renal failure, CHF) Cause small decrease in LDL cholesterol level and triglycerides Cause small decrease in LDL cholesterol level and triglycerides No specific effect on blood pressure No specific effect on blood pressure No weight gain, with possible modest weight loss No weight gain, with possible modest weight loss Contraindicated in patients with impaired renal function (eGFR<33 ml/min) Contraindicated in patients with impaired renal function (eGFR<33 ml/min) Medications in this Class: metformin (Glucophage), metformin hydrochloride extended release (Glumetza) Medications in this Class: metformin (Glucophage), metformin hydrochloride extended release (Glumetza)

57 Sulfonylureas Sulfonylureas increase endogenous insulin secretion Sulfonylureas increase endogenous insulin secretion Efficacy Efficacy Decrease fasting plasma glucose mmol/L Decrease fasting plasma glucose mmol/L Reduce A1C by % Reduce A1C by % Other Effects Other Effects Hypoglycemia Hypoglycemia Weight gain Weight gain No specific effect on plasma lipids or blood pressure No specific effect on plasma lipids or blood pressure Generally the least expensive class of medication Generally the least expensive class of medication Medications in this Class: Medications in this Class: glyburide (DiaBeta), glimepiride (Amaryl), gliclizide (Diamicron) glyburide (DiaBeta), glimepiride (Amaryl), gliclizide (Diamicron)

58 Meglitinides Meglitinides stimulate insulin secretion (rapidly and for a short duration) in the presence of glucose. Meglitinides stimulate insulin secretion (rapidly and for a short duration) in the presence of glucose. Efficacy Efficacy Decreases peak postprandial glucose Decreases peak postprandial glucose Decreases plasma glucose mmol/L Decreases plasma glucose mmol/L Reduce A1C % Reduce A1C % Other Effects Other Effects Hypoglycemia (although may be less than with sulfonylureas if patient has a variable eating schedule) Hypoglycemia (although may be less than with sulfonylureas if patient has a variable eating schedule) Weight gain Weight gain No significant effect on plasma lipid levels No significant effect on plasma lipid levels Safe at higher levels of serum Cr than sulfonylureas Safe at higher levels of serum Cr than sulfonylureas Medications in this Class: repaglinide (Gluconorm), nateglinide (Starlix) Medications in this Class: repaglinide (Gluconorm), nateglinide (Starlix)

59 Alpha-glucosidase Inhibitors Alpha-glucosidase inhibitors block the enzymes that digest starches in the small intestine Alpha-glucosidase inhibitors block the enzymes that digest starches in the small intestine Efficacy Efficacy Decrease peak postprandial glucose mmol/L Decrease peak postprandial glucose mmol/L Decrease fasting plasma glucose mmol/L Decrease fasting plasma glucose mmol/L Decrease A1C % Decrease A1C % Other Effects Other Effects Flatulence or abdominal discomfort Flatulence or abdominal discomfort No specific effect on lipids or blood pressure No specific effect on lipids or blood pressure No weight gain No weight gain Contraindicated in patients with inflammatory bowel disease or cirrhosis Contraindicated in patients with inflammatory bowel disease or cirrhosis Medications in this Class: acarbose (Glucobay) Medications in this Class: acarbose (Glucobay)

60 2013 guidelines.diabetes.ca | BANTING ( ) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

61 Insulin Therapy

62 Types of Insulin

63 Types of Insulin (continued)

64

65 Normal Pancreatic Function Meal Bolus: At mealtime, insulin is rapidly released in response to food. Basal: Beta cells secrete small amounts of insulin throughout the day. Basal Insulin Bolus Insulin Expected insulin changes during the day for individuals with a healthy pancreas. Expected insulin changes during the day for individuals with a healthy pancreas. *Insulin effect images are theoretical representations and are not derived from clinical trial data.

66 Action Profiles of Bolus & Basal Insulins Plasma Insulin levels Hours Note: action curves are approximations for illustrative purposes. Actual patient response will vary. regular 6-10 hours NPH 12–20 hours lispro/aspart 4–6 hours  BASAL INSULINS detemir ~ 6-23 hours (dose dependant) glargine ~ hours Mayfield, JA.. et al, Amer. Fam. Phys.; Aug. 2004, 70(3): 491 Plank, J. et.al. Diabetes Care, May 2005; 28(5):  BOLUS INSULINS

67 Expected insulin changes during the day Expected insulin changes during the day for individuals with a healthy pancreas. for individuals with a healthy pancreas. *Insulin effect images are theoretical representations and are not derived from clinical trial data Mayfield, JA. et al., Amer. Fam. Phys.; Aug. 2004, 70(3): BID NPH and Regular Insulin Therapy - Compared to Normal Physiology Bolus needs: Regular Basal needs: NPH Meal

68 Expected insulin changes during the day Expected insulin changes during the day for individuals with a healthy pancreas. for individuals with a healthy pancreas. *Insulin effect images are theoretical representations and are not derived from clinical trial data. Multiple Daily Injections (MDI) – Strive to Mimic Normal Physiology MDI insulin therapy addresses: Bolus needs: Lispro, Aspart Basal needs: Glargine, Detemir Meal

69 Insulin Regimens Type 2 Usually – a single bedtime injection of basal insulin added to OAD. Usually – a single bedtime injection of basal insulin added to OAD. Occasionally - twice daily injections of basal insulin with OAD. Occasionally - twice daily injections of basal insulin with OAD. Twice daily injection of “pre-mixed” insulin Twice daily injection of “pre-mixed” insulin Intensive insulin – basal/bolus (THE ONLY RECOMMENDED OPTION FOR DM TYPE 1) Intensive insulin – basal/bolus (THE ONLY RECOMMENDED OPTION FOR DM TYPE 1) 40% basal/20% mealtime with each meal 40% basal/20% mealtime with each meal

70 Case 1 Breakfast Lunch Dinner Bedtime  Is this patient well controlled?  Does this patient require insulin? 55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5% 55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5% On metformin, glyburide, On metformin, glyburide,

71 Case 1 - Bedtime Insulin Breakfast Lunch Dinner Bedtime  Start with 10 units 1, or use units/kg and titrate 2  Ex. 84 kg X 0.1 = 8 units OR 84 kg X 0.2 = 17 units  Continue metformin, glyburide. Continuing TZD would be off-label in Canada NPH, Glargine or Detemir - 10 units 55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5% 55 year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5% On metformin, glyburide, On metformin, glyburide, Riddle et.al., Diabetes Care, 2003, 26(11): CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S135

72 Hypoglycemia – Recognition Hypoglycemia = development of symptoms or a plasma glucose <4.0 mmol/L. Hypoglycemia = development of symptoms or a plasma glucose <4.0 mmol/L. Symptoms of hypoglycemia AutonomicNeuroglycopenic TremblingPalpitationsSweatingAnxietyHungerNauseaTingling Difficulty concentrating Vision changes Difficulty speaking HeadacheDizzinessConfusionWeaknessDrowsinessTiredness Severity of hypoglycemia Mild: Autonomic symptoms are present. The individual is able to self-treat. Moderate: Autonomic and neuroglycopenic symptoms are present. The individual is able to self-treat. Severe: Individual requires assistance of another person. Unconsciousness may occur. Plasma glucose is typically <2.8 mmol/L. CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S43

73 Diabetic ketoacidosis

74 Diagnostic criteria Diagnostic criteria Hyperglycemia Hyperglycemia Glucose >11.1 mmol/l; usually > 15 mmol/l Glucose >11.1 mmol/l; usually > 15 mmol/l Metabolic acidosis (increased anion gap) Metabolic acidosis (increased anion gap) pH < 7.35 pH < 7.35 decreased bicarbonate <15 (best estimation with venous) decreased bicarbonate <15 (best estimation with venous) Positive serum ketones Positive serum ketones Urine ketones: may be absent in early stages Urine ketones: may be absent in early stages

75 Insulin deficiency Decreased peripheral glucose utilization Decreased peripheral glucose utilization increased glucose production increased glucose production liver - gluconeogenesis (from aminoacids, glycerol), glycogenolysis liver - gluconeogenesis (from aminoacids, glycerol), glycogenolysis increased ketogenesis increased ketogenesis increased lipolysis in adipocytes - provides free fatty acids for ketones and glycerol for gluconeogenesis increased lipolysis in adipocytes - provides free fatty acids for ketones and glycerol for gluconeogenesis

76

77 1

78 Clinical features Hyperglycemia: thirst, polyuria, circulatory collapse Hyperglycemia: thirst, polyuria, circulatory collapse Ketosis: “acetone breath’ Ketosis: “acetone breath’ Acidosis/ compensatory respiratory alkalosis: tachypnea Acidosis/ compensatory respiratory alkalosis: tachypnea

79

80 Consequences of DKA Hyperglycemia Hyperglycemia osmotic diuresis osmotic diuresis dehydration dehydration loss of K, Na, HCO3 in urine loss of K, Na, HCO3 in urine hyperosmolar state hyperosmolar state increase free water into blood  hyponatremia, cerebral dehydration  decreased level of consciousness increase free water into blood  hyponatremia, cerebral dehydration  decreased level of consciousness acidosis acidosis compensatory respiratory alkalosis compensatory respiratory alkalosis K shifts (hyperkalemia) K shifts (hyperkalemia)

81 Laboratory Calculations for diagnosis and treatment Serum osmolality Serum osmolality 2(Na + K) + glucose +BUN 2(Na + K) + glucose +BUN serum Na serum Na for each 3-4 mmol/l increase in glucose, Na should decrease by 1 for each 3-4 mmol/l increase in glucose, Na should decrease by 1 anion gap anion gap Na -(Cl+HCO3) Na -(Cl+HCO3) compensation for metabolic acidosis compensation for metabolic acidosis If suspect other causes for acidosis; meausre serum lactate and salicylate If suspect other causes for acidosis; meausre serum lactate and salicylate

82 Treatment GOAL: GOAL: replace volume loss (with normal saline) replace volume loss (with normal saline) stop ketone production (with insulin) stop ketone production (with insulin) replace K loss (K initially high but falls rapidly with treatment) replace K loss (K initially high but falls rapidly with treatment) lower serum glucose lower serum glucose *Need to correct INSULIN DEFICIENCY *Look for precipitating cause and treat

83 Fluid Fluid NS 1L per hour first 2 hours, then 1L over 4 hrs NS 1L per hour first 2 hours, then 1L over 4 hrs NS until glucose < 15 NS until glucose < 15 then D5/NS or D5 depending if still replacing volume then D5/NS or D5 depending if still replacing volume insulin insulin intravenous intravenous 50 units regular in 500 normal saline (0.1U/ml) 50 units regular in 500 normal saline (0.1U/ml) Bolus 0.1 unit per kg body weight (IM/IV) Bolus 0.1 unit per kg body weight (IM/IV) Infusion 0.1 unit/kg/hour Infusion 0.1 unit/kg/hour Glucoscans q1h, adjust IV rate and IV D5 Glucoscans q1h, adjust IV rate and IV D5 * Do not stop insulin infusion until acidosis/ AG corrected bicarbonate generally avoided bicarbonate generally avoided potassium potassium start when K , 20 mmol/L (hold insulin if K is <3.3 and give 40 meq/h start when K , 20 mmol/L (hold insulin if K is <3.3 and give 40 meq/h

84 Hyperosmolar non-ketotic state Severe hyperglycemia generally in DM type 2 Severe hyperglycemia generally in DM type 2 dehydration dehydration serum hyperosmolality serum hyperosmolality lack of significant ketosis (still some circulating insulin) lack of significant ketosis (still some circulating insulin) * takes less insulin to prevent ketosis than to stop hyperglycemia * takes less insulin to prevent ketosis than to stop hyperglycemia

85 Stressor - increased insulin resistance Stressor - increased insulin resistance relative insulin deficiency relative insulin deficiency increased glucose production, decreased utilization increased glucose production, decreased utilization reduced renal excretion of glucose reduced renal excretion of glucose secondary to renal disease, aging kidneys secondary to renal disease, aging kidneys

86

87 Treatment of HONK Correct increased serum osmolality Correct increased serum osmolality Blood glucose will fall in response to fluid repletion Blood glucose will fall in response to fluid repletion If Na>155 mmol/L, start 0.45% NS as initial fluid If Na>155 mmol/L, start 0.45% NS as initial fluid Insulin infusion only if persistent hyperglycemia after fluid replete Insulin infusion only if persistent hyperglycemia after fluid replete

88 SCREENING AND PREVENTION OF COMPLICATIONS

89 ≥40 yrs old or ≥40 yrs old or Macrovascular disease or Macrovascular disease or Microvascular disease or Microvascular disease or DM >15 yrs duration and age >30 years or DM >15 yrs duration and age >30 years or Warrants therapy based on the 2012 Canadian Cardiovascular Society lipid Warrants therapy based on the 2012 Canadian Cardiovascular Society lipid Among women with childbearing potential, statins should only be used in the presence of proper preconception counseling & reliable contraception. Stop statins prior to conception Who Should Receive Statins?

90 Who Should Receive ACEi or ARB Therapy? ≥55 years of age or ≥55 years of age or Macrovascular disease or Macrovascular disease or Microvascular disease Microvascular disease At doses that have shown vascular protection [p erindopril 8 mg daily (EUROPA), ramipril 10 mg daily (HOPE), telmisartan 80 mg daily (ONTARGET)] Among women with childbearing potential, ACEi or ARB should only be used in the presence of proper preconception counseling & reliable contraception. Stop ACEi or ARB either prior to conception or immediately upon detection of pregnancy 2013 EUROPA Investigators, Lancet 2003;362(9386): HOPE study investigators. Lancet. 2000;355: ONTARGET study investigators. NEJM. 2008:358:

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