The Diabetes Epidemic: Global Projections,

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Harvey Watkins
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1 Diabetes mellitus

2 The Diabetes Epidemic: Global Projections, IDF. Diabetes Atlas. 2014

3 The Diabetes Epidemic: Global Projections,

4 3 多 1 少

5 Plasma insulin (pmol/l) 正常胰島素生理分泌 Nmal free insulin levels (Mean) Meals Time of day

6 糖尿病的分類

9 Type 1 diabetes

10 有關的功能 (%) 血糖 (mg/dl) 第 2 型糖尿病之自然發展史肥胖空腹血糖障礙糖尿病控制不良高血糖餐後血糖空腹血糖胰島素 ß- 細胞衰退胰島素抗性罹患糖尿病的年限胰島素分泌 Adapted from International Diabetes Center (Minneapolis, Minn)

11 Case 1 陳太太來到你的門診, 主訴健康檢查時的空腹血糖值為 140mg/dL, 否認有多吃多喝多尿, 詢問是否有糖尿病嗎? 1. 可診斷糖尿病, 因血糖值大於 126mg/dL 2. 可診斷糖尿病, 因血糖值大於 100mg/dL 3. 不可診斷糖尿病, 因不符合診斷標準 4. 不可診斷糖尿病, 因沒有相關症狀

12 Criteria f the Diagnosis of DM 1. Symptoms of diabetes plus random blood glucose concentration 200 mg/dl 2. Fasting plasma glucose 126 mg /dl 3. 2-hour plasma glucose 200 mg/dl during 75-g al glucose tolerance test 4. HbA1c > 6.5% X 2

14 Management of prediabetes Targeting weight loss of 7% of body weight Increasing physical activity to at least 150 min/week of moderate activity (50~70% maximal heart beat) therapy f prevention of type 2 diabetes 1. BMI >35 kg/m2 2. Aged <60 years 3. Women with pri GDM

15 Diabetes Guideline Management AACE (AACE Endocr Pract. 2013): HbA1c< 6.5 ADA (Diabetes Care. 2013) : HbA1c< 7.0 Preprandial capillary plasma glucose: 80~130mg/dL Peak postprandial capillary plasma glucose: <180mg/dL IDF (global guideline f type 2 diabetes. 2012): HbA1c< 7.0 Preprandial capillary plasma glucose: 115mg/dL Peak postprandial capillary plasma glucose: <160mg/dL Guidelines sets recommend comprehensive approach f risk facts

17 Glycemic Control in Inpatient Critically ill patients Blood glucose levels should be kept 140~180 mg/dl. These patients will usually require intravenous insulin. Non critically ill patients NICE-SUGAR trial (2009) Premeal blood glucose targets : mg/dl Random blood glucose < 180 mg/dl ADA guildline

- Healthy diet - Increased activity level

18 ADA-EASD Position Statement: Management of Hyperglycemia in T2DM ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Lifestyle - Weight optimization - Healthy diet - Increased activity level Diabetes Care 2012;35: Diabetologia 2012;55:

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 3.

injectables - - Sulfonylureas - Thiazolidinediones - DPP-4 inhibits - SGLT-2

agonists - Amylin mimetics - GLP-1 recept agonists Diabetes Care 2012;35:1364

20 ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Oral agents & non-insulin injectables - - Sulfonylureas - Thiazolidinediones - DPP-4 inhibits - SGLT-2 inhibits - Meglitinides - a-glucosidase inhibits - Colesevelam - Dopamine-2 agonists - Amylin mimetics - GLP-1 recept agonists Diabetes Care 2012;35: ; Diabetologia 2012;55: Diabetes Care 2015;38: ; Diabetologia 2015; /s

21 Multiple, Complex Pathophysiological Abnmalities in T2DM GLP-1R agonists incretin effect DPP-4 inhibits A G I s gut carbohydrate delivery & absption hepatic glucose production _ pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA Bile acid sequestrants Insulin Glinides S U s Amylin mimetics SGLT2 inhibits renal glucose excretion _ DA agonists T Z D s? peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

23 Oral Class Mechanism Advantages Disadvantages Cost Biguanides Sulfonylureas Meglitinides Activates AMPkinase (?other) Hepatic glucose production Closes K ATP channels Insulin secretion Closes K ATP channels Insulin secretion Extensive experience No hypoglycemia Weight neutral? CVD Extensive experience Microvascular risk Postprandial glucose Dosing flexibility Gastrointestinal Lactic acidosis (rare) B-12 deficiency Contraindications Hypoglycemia Weight Low durability? Blunts ischemic preconditioning Hypoglycemia Weight? Blunts ischemic preconditioning Dosing frequency Low Low Mod. TZDs PPAR-g activat Insulin sensitivity No hypoglycemia Durability TGs (pio) HDL-C? CVD events (pio) Weight Edema/heart failure Bone fractures LDL-C (rosi)? MI (rosi) Low Table 1. Properties of anti-hyperglycemic agents Diabetes Care 2015;38: ; Diabetologia 2015; /s

Oral Class Mechanism Advantages Disadvantages Cost a-glucosidase inhibits DPP-4 inhibits Bile acid sequestrants Dopamine-2 agonists SGLT2 inhibits Inhibits a-glucosidase Slows carbohydrate digestion

24 Oral Class Mechanism Advantages Disadvantages Cost a-glucosidase inhibits DPP-4 inhibits Bile acid sequestrants Dopamine-2 agonists SGLT2 inhibits Inhibits a-glucosidase Slows carbohydrate digestion / absption Inhibits DPP-4 Increases incretin (GLP-1, GIP) levels Bind bile acids? Hepatic glucose production Activates DA recept Alters hypothalamic control of metabolism insulin sensitivity Inhibits SGLT2 in proximal nephron Increases glucosuria No hypoglycemia Nonsystemic Postprandial glucose? CVD events No hypoglycemia Well tolerated No hypoglycemia LDL-C No hypoglyemia? CVD events Weight No hypoglycemia BP Effective at all stages Gastrointestinal Dosing frequency Modest A1c Angioedema / urticaria? Pancreatitis? Heart failure Gastrointestinal Modest A1c Dosing frequency Modest A1c Dizziness, fatigue Nausea Rhinitis GU infections Polyuria Volume depletion LDL-C Cr (transient) Mod. High High High High Table 1. Properties of anti-hyperglycemic agents Diabetes Care 2015;38: ; Diabetologia 2015; /s

25 Injectabl e Class Amylin mimetics GLP-1 recept agonists Insulin Mechanism Advantages Disadvantages Cost Activates amylin recept glucagon gastric emptying satiety Activates GLP-1 R Insulin, glucagon gastric emptying satiety Activates insulin recept Myriad Weight Postprandial glucose Weight No hypoglycemia Postprandial glucose Some CV risk facts Universally effective Unlimited efficacy Microvascular risk Table 1. Properties of anti-hyperglycemic agents Gastrointestinal Modest A1c Injectable Hypo if insulin dose not reduced Dosing frequency Training requirements Gastrointestinal? Pancreatitis Heart rate Medullary ca (rodents) Injectable Training requirements Hypoglycemia Weight gain? Mitogenicity Injectable Patient reluctance Training requirements High High Variabl e Diabetes Care 2015;38: ; Diabetologia 2015; /s

Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education

26 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Sulfonylurea moderate risk gain hypoglycemia low Thiazolidinedione low risk gain edema, HF, fxs low DPP-4 inhibit intermediate low risk neutral rare SGLT2 inhibit intermediate low risk loss GU, dehydration GLP-1 recept agonist low risk loss GI Insulin (basal) est risk gain hypoglycemia variable Triple therapy Sulfonylurea If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): TZD Thiazolidinedione SU DPP-4 Inhibit SU SGLT-2 Inhibit SU GLP-1 recept agonist SU Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i Insulin SGLT2-i GLP-1-RA GLP-1-RA Insulin Insulin GLP-1-RA Insulin Insulin Combination injectable therapy Figure 2. An -hyperglycemic therapy in T2DM: General recommenda ons If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGL T2-i: Basal Insulin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38: ; Diabetologia 2015; /s

27 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Sulfonylurea moderate risk gain hypoglycemia low Thiazolidinedione low risk gain edema, HF, fxs low DPP-4 inhibit intermediate low risk neutral rare SGLT2 inhibit intermediate low risk loss GU, dehydration GLP-1 recept agonist low risk loss GI Insulin (basal) est risk gain hypoglycemia variable Triple therapy Sulfonylurea If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): TZD Thiazolidinedione SU DPP-4 Inhibit SU SGLT-2 Inhibit SU GLP-1 recept agonist SU Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i Insulin SGLT2-i GLP-1-RA GLP-1-RA Insulin Insulin GLP-1-RA Insulin Insulin Combination injectable therapy Figure 2. An -hyperglycemic therapy in T2DM: General recommenda ons If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGL T2-i: Basal Insulin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38: ; Diabetologia 2015; /s

28 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Sulfonylurea moderate risk gain hypoglycemia low Thiazolidinedione low risk gain edema, HF, fxs low DPP-4 inhibit intermediate low risk neutral rare SGLT2 inhibit intermediate low risk loss GU, dehydration GLP-1 recept agonist low risk loss GI Insulin (basal) est risk gain hypoglycemia variable Triple therapy Sulfonylurea If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): TZD Thiazolidinedione SU DPP-4 Inhibit SU SGLT-2 Inhibit SU GLP-1 recept agonist SU Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i Insulin SGLT2-i GLP-1-RA GLP-1-RA Insulin Insulin GLP-1-RA Insulin Insulin Combination injectable therapy Figure 2. An -hyperglycemic therapy in T2DM: General recommenda ons If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGL T2-i: Basal Insulin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38: ; Diabetologia 2015; /s

29 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Sulfonylurea moderate risk gain hypoglycemia low Thiazolidinedione low risk gain edema, HF, fxs low DPP-4 inhibit intermediate low risk neutral rare SGLT2 inhibit intermediate low risk loss GU, dehydration GLP-1 recept agonist low risk loss GI Insulin (basal) est risk gain hypoglycemia variable Triple therapy Sulfonylurea If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): TZD Thiazolidinedione SU DPP-4 Inhibit SU SGLT-2 Inhibit SU GLP-1 recept agonist SU Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i Insulin SGLT2-i GLP-1-RA GLP-1-RA Insulin Insulin GLP-1-RA Insulin Insulin Combination injectable therapy If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGL T2-i: Basal Insulin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38: ; Diabetologia 2015; /s

Monotherapy Efficacy * Hypo risk Weight Side effects Me min Costs intolerance

Healthy eating, weight control, increased physical activity & diabetes education low risk

monotherapy, proceed to 2-drug combination (der not meant to denote any specific

Sulfonylurea moderate risk gain hypoglycemia low Thiazolidinedione low risk gain edema,

low risk loss GU, dehydration GLP-1 recept agonist low risk loss GI Insulin (basal) est

after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote

agonist SU Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i Uncontrolled

therapy SGLT2-i GLP-1-RA Insulin SGLT2-i GLP-1-RA Insulin Basal Insulin SGLT2-i Insulin

triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA,

$In refracty patients consider adding TZD SGL T2-i: Mealtime Insulin GLP-1-RA Diabetes$

30 Monotherapy Efficacy * Hypo risk Weight Side effects Me min Costs intolerance contraindica on HbA1c 9% Dual therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Sulfonylurea moderate risk gain hypoglycemia low Thiazolidinedione low risk gain edema, HF, fxs low DPP-4 inhibit intermediate low risk neutral rare SGLT2 inhibit intermediate low risk loss GU, dehydration GLP-1 recept agonist low risk loss GI Insulin (basal) est risk gain hypoglycemia variable Triple therapy Sulfonylurea If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): TZD Thiazolidinedione SU DPP-4 Inhibit SU SGLT-2 Inhibit SU GLP-1 recept agonist SU Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i Uncontrolled hyperglycemia (catabolic features, BG mg/dl, HbA1c 10-12%) Combination injectable therapy SGLT2-i GLP-1-RA Insulin SGLT2-i GLP-1-RA Insulin Basal Insulin SGLT2-i Insulin DPP-4-i Insulin Insulin SGLT2-i GLP-1-RA If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGL T2-i: Mealtime Insulin GLP-1-RA Diabetes Care 2015;38: ; Diabetologia 2015; /s

32 ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulins Human Insulins - Neutral protamine Hagedn (NPH) - Regular human insulin - Pre-mixed fmulations Insulin Analogues - Basal analogues (glargine, detemir, degludec) - Rapid analogues (lispro, aspart, glulisine) - Pre-mixed fmulations Diabetes Care 2012;35: ; Diabetologia 2012;55: Diabetes Care 2015;38: ; Diabetologia 2015; /s

33 Insulin level ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulins Rapid (Lispro, Aspart, Glulisine) Sht (Regular) Hours Long (Detemir) (Degludec) Long (Glargine) Hours after injection

34 Time of Action Preparation Onset Peak Effective Maximum Duration Duration Aspart Actrapid Insulatard Glargine 1.1 nil Novomix dual (h)

35 Insulin Mixtures: Mixtard (70% NPH / 30% RI) NovoMix 30 (70% protamine aspart / 30% aspart) NovoMix 50 (50% protamine aspart / 50% aspart) Humalog Mix 50 (50% lispro protamine / 50% lispro) Humalog Mix 25 (75% lispro protamine / 25% lispro)

36 Case 2 值班時, 一位新住院的肺炎病人自述其有糖尿病, 但沒帶平時服用的降血糖藥物來醫院, 當時測 stat 的 F/S 為 390mg/dL, 此時對病人的血糖控制最佳的治療方式為? 1. 請病人回家拿原本口服藥續服 2. 開立 1# BID PO 3. Insulin therapy: insulin aspart 6u TID and insulin glargine 12u HS SC 4. RI 8u STAT SC

37 How to Adjust The Dosage of Insulin Insulin regimen QID finger sugar AC, PC, 3PM, 9PM Total daily dosage: 0.5~1u/body weight(kg) Divided into 40%:60%: 40% dose in the daytime(sht active); 60% dose at night(long active) Sht-acting insulin: 1/5 total daily dosage, TID Long-acting insulin: 2/5 total daily dosage, HS QD

38 Case 3 Primary care 的病人其血糖使用 insulin(insulin aspart 6u TID and Insulin glargine 8u HS) 治療後, 其血糖為 : 5/1 5/2 5/3 AC PC PM PM 要如何調整 insulin 劑量?

39 F/S AC PC 3PM 9PM

40 Case 4 Primary care 的病人其血糖使用 insulin(insulin aspart 6u TID and Insulin glargine 8u HS) 治療後, 其血糖為 : 5/1 5/2 5/3 AC PC PM PM 要如何調整 insulin 劑量?

41 Case 3 Primary care 的病人其血糖使用 insulin(insulin aspart 6u TID and Insulin glargine 8u HS) 治療後, 其血糖為 : 5/1 5/2 5/3 AC PC PM PM 要如何調整 insulin 劑量?

42 值班時 X 醫師, 1305B 九點血糖為 340mg/dL, 請問要怎麼處理?

43 值班時 X 醫師, 1305B 九點血糖為 340mg/dL, 請問要怎麼處理? 1.Symptom/signs N/V, abdominal pain, consciousness change Check serum sugar, ketone body, ABG, osmolarity 2.Insulin 1u RI F/S 15-25mg/dL(20mg/dL)????? Glucotoxicity: hyperglycemia insulin resistance insulin effect

44 值班時 X 醫師, 1227B 九點血糖為 91mg/dL, 請問要不要 Hold 晚上的 Insulin glargine 14U? 病人說睡不著, 想找醫師!

45 值班時 X 醫師, 1227B 九點血糖為 91mg/dL, 請問要不要 Hold 晚上的 NPH? 1. 睡前進食 2. 減少 dose of NPH

46 Acute Complications of DM Diabetic ketoacidosis (DKA) Hyperglycemic hyperosmolar state (HHS) Hypoglycemia

48 ADA Diagnostic Criteria of DKA & HHS DKA: blood glucose >250 mg/dl, arterial ph <7.3, bicarbonate <15 meq/l, and moderate ketonuria ketonemia. HHS: blood glucose >600 mg/dl, arterial ph >7.3, bicarbonate >15 meq/l, mild ketonuria ketonemia, and effective serum osmolality >320 mosm/kg H 2 O.

49 Manifestations of DKA Symptoms Nausea/Vomiting Thirst/Polyuria Shtness of breath Abdominal pain Altered mental status Physical Findings Tachycardia Dehydration/Hypotension Tachypnea/Kissmaul respirations/respiration distress Abdominal tenderness Lethargy/Obtundation/Cerebral edema/coma

50 Manifestations of HHS Symptoms LESS Nausea/Vomiting Thirst/Polyuria Shtness of breath LESS Abdominal pain Altered mental status Physical Findings Tachycardia Dehydration/Hypotension Tachypnea/Kissmaul respirations/respiration distress LESS Abdominal tenderness Lethargy/Obtundation/Cerebral edema/coma

52 值班時 X 醫師, 1122B 九點血糖為 40mg/dL, 請問要怎麼處理?

53 Hypoglycemia Clinical hypoglycemia A plasma ( serum) glucose concentration low enough to cause symptoms and/ signs, including impairment of brain function Whipple s triad Symptoms, signs, both consistent with hypoglycemia A low plasma glucose concentration Resolution of those symptoms signs after the plasma glucose concentration is raised

54 Hypoglycemia Neurogenic autonomic symptoms Hypoglycemia insulin glucagon epinephrine Palpitations, trem, arousal/anxiety Sweating, hunger, paresthesias Neuroglycopenic symptoms Behavial changes, fatigue, confusion to seizure, loss of consciousness

55 Hypoglycemia Rule of 15 f treating low blood glucose Treat with 15 grams of carbohydrate Glucose tablets (3 five-gram tablets 4 gram tablets) Intravenous glucose (20g) followed by a constant infusion of 5 10% dextrose if indicated Check blood glucose in 15 minutes(15-30mins) Ingestion of a me substantial snack a meal Glycemic response to al glucose is often transient

56 Thanks f your attention

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach Update to a Position Statement of the American Diabetes Association (ADA) and the European Association f the Study of Diabetes