Obesity, Insulin Resistance, Metabolic Syndrome, and the Natural History of Type 2 Diabetes

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2 Obesity, Insulin Resistance, Metabolic Syndrome, and the Natural History of Type 2 Diabetes Genetics, environment, and lifestyle (obesity, inactivity, poor diet) Impaired fasting glucose Decreased β-cell function Insulin resistance Impaired glucose tolerance Ominous octet T2DM Ongoing hyperglycemia DEATH Ongoing, worsening macrovascular and microvascular complications Hypertension Endothelial dysfunction Hyperinsulinemia HDL-C, Triglycerides Eye, nerve, and kidney damage Atherosclerosis Myocardial infarction Cardiovascular event Blindness Chronic renal failure Amputation Disability HDL-C = high density lipoprotein-cholesterol; T2DM = type 2 diabetes mellitus.

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4 Relative Risk A1C and Microvascular Complications: DCCT Retinopathy Nephropathy Neuropathy Microalbuminuria DCCT Research Group. N Engl J Med. 1993;329:977. Skyler J. Endocrinol Metab Clin North Am. 1996;25:243. A1C (%) A1C = glycated hemoglobin; DCCT = Diabetes Control and Complications Trial.

5 UKPDS: Benefits of Glycemic Control Every 1% decrease in A1C led to significant reductions in diabetes-related complications 14% 21% 37% 43% Risk of myocardial infarction Risk of diabetesrelated death Risk of microvascular complications Risk of amputation or PVD Death Decrease was statistically significant for all comparisons shown UKPDS: United Kingdom Prospective Diabetes Study Stratton IM et al. BMJ. 2000;321:

6 UKPDS: Follow-up A1C Mean A1C levels for patients originally assigned to receive either sulfonylurea insulin or conventional therapy are shown Clinical data were not available in years 6 through 10 (when questionnaires were used) UKPDS: United Kingdom Prospective Diabetes Study Holman R et al NEJM, 2008;359:

7 UKPDS: Follow-up All-cause mortality A similar long-term benefit in terms of reduced mortality risk was observed for patients who received initial intensive treatment UKPDS: United Kingdom Prospective Diabetes Study Holman R et al NEJM, 2008;359:

8 Myocardial Infarction Hazard Ratio UKPDS 10-year follow-up (fatal or non-fatal myocardial infarction or sudden death) Intensive (metformin) vs. conventional glucose control Conventional Intensive Δ Holman R et al NEJM, 2008;359:

9 Glycemic Management of Type 2 Diabetes: Treatment Goals Lowering A1C Preventing Hypoglycemia Individualized Algorithm

10 Risk of Hypoglycemia Plays a significant role in choice of agents in AACE algorithm For patients at highest risk of hypoglycemia, may consider close evaluation of agents chosen as well as therapeutic goal Patients with type 2 diabetes at highest risk of low blood glucose include those with: Diabetes duration >15 years Advanced macrovascular disease Hypoglycemia unawareness Limited life expectancy Severe comorbidities Garvey et al. Endocr. Pract. 2016;22 (Suppl 3); AACE/ACE Diabetes Algorithm Endocr. Pract. 2015;21 (Suppl 1); AACE/ACE Obesity Algorithm Part 2

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12 Algorithm To Achieve Glycemic Goals Baseline A1C 6.5% - 7.5% Monotherapy may be effective in this range Metformin first choice for monotherapy if no contraindications Consider DPP-4 if PP and FPG, GLP-1 if PP, TZD if metabolic syndrome or NAFLD, AGI if PP Do not recommend secretagogue (SU or glinide) in this range due to risk of hypoglycemia; short-lived effect If monotherapy is unsuccessful, move on to dual oral rx; often need to augment reduction in PP BG to get to goal in this A1C range DPP-4=dipeptidyl peptidase-4; PP=post-prandial; FPG=fasting plasma glucose; GLP- 1 = glucagon-like peptide-1; TZD=thiazolidinedione; NAFLD=non-alcoholic fatty liver disease; AGI=alpha-glucosidase inhibitor; SU=sulfonylurea; A1C=glycated hemoglobin; SGLT-2=sodium glucose transport-2 AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm Endocr Pract.2017,doi: /EP CS. Inzucchi S et al. Diabetes Care 2015;38:

13 Algorithm To Achieve Glycemic Goals Baseline A1C 7.6% - 9.0% Dual therapy with metformin provides superior glycemic control over metformin alone. If dual oral rx is unsuccessful, consider triple therapy If triple oral rx fails to achieve A1C goal, initiate insulin GLP-1 RA = glucagon-like peptide-1 receptor agonist DPP4-i=dipeptidyl peptidase 4 inhibitor TZD=thiazolidinedione SGLT-2=sodium glucose cotransporter 2 inhibitor QR=quick-release AG-i=alpha-glucosidase inhibitor SU=sulfonylurea GLN=glinide AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm Endocr Pract.2017,doi: /EP CS. Inzucchi S et al. Diabetes Care 2015;38:

14 Algorithm to Achieve Glycemic Goals Baseline A1C > 9.0% If patient is asymptomatic with recent onset of disease and drug naïve, may consider starting with dual or triple oral regimens If symptomatic, start insulin Once A1C has improved to <7.5%, consider initiation of dual oral therapy with tapering and possible discontinuation of insulin rx AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm Endocr Pract.2017,doi: /EP CS.

15 Current Antihyperglycemic Medications Insulin Replacement Therapy Glinides Restore postprandial insulin patterns Sulfonylureas Generalized insulin secretagogue TZDs Reduce peripheral insulin resistance Biguanide Reduce hepatic insulin resistance GLP-1 Analogs Stimulate cells, suppress glucagon 12 Groups with Different Mechanisms of Action SGLT-2 Inhibitors Block renal glucose reabsorption DPP-4 Inhibitors Restore GLP-1 Level Amylin Analog Suppress glucagon -Glucosidase Inhibitors Delay CHO absorption Dr. Phil Levy Colesevelam Bile acid sequestrant Bromocriptine Hypothalamic pituitary reset

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17 Primary Risk Factors for CVD: Treatment Goals Hyperglycemia FPG / preprandial glucose PPG A1C mg/dl <180 mg/dl <7%, or lowest possible without unacceptable hypoglycemia Hypertension Blood pressure <140/80 mmhg, or further lowering if tolerated by patients Dyslipidemia LDL HDL Triglycerides <100 mg/dl, patients with diabetes <70 mg/dl, very high risk patients with diabetes and CVD >40 mg/dl, men; >50 mg/dl, women <150 mg/dl A1C = glycated hemoglobin; CVD = cardiovascular disease; FPG = fasting plasma glucose; HDL = high density lipoprotein; LDL = low density lipoprotein; PPG = postprandial plasma glucose. AACE Algorithm 2016 American Diabetes Association, Diabetes Care 2016;39 (Suppl 1).

18 The Steno-2 Study: Synergy in Care Treating Glucose, Blood Pressure, and Lipids A follow-up study, conducted 21 years after the original trial, found a median gain of 7.9 years of life in Steno-2 patients originally provided with intensive treatment. CABG = coronary artery bypass graft; PCI = percutaneous coronary intervention. Gæde P, et al. Diabetologia. 2016;59: Gæde P, et al. NEMJ. 2003;348(5):