Smoldering Insulin Resistance: Strategies to Optimize Cardiometabolic Health

Smoldering Insulin Resistance: Strategies to Optimize Cardiometabolic Health Thomas Dayspring, MD, FACP, FNLA, NCMP Chief Academic Officer True Health Diagnostics Richmond, VA Disclosures (Last 12 months) Employment True Health Diagnostics Lecture Bureau Sanofi Regeneron As diabetes develops, we currently waste the first 10 years of the natural history If we found prediabetes and early diabetes when they first presented and treated them more effectively, we could prevent or delay the progression of hyperglycemia and the development of complications 1

The earliest stage of type 2 diabetes is prediabetes (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]), where glucose levels are higher than normal but not in the diabetes range Prediabetes tends to progress to diabetes, and over time, persistent hyperglycemia leads to the complications that are the major source of morbidity, mortality, and cost This natural history reflects underlying loss of β-cell function due in part to factors such as elevated glucose and lipid levels, inflammation, amyloid, and oxidative and endoplasmic reticulum stress Unfortunately, we waste the first 10 years of the natural history when the disorder is easiest to treat There are 79 million Americans with prediabetes and 7 million with early T2DM who are largely unrecognized because we do not screen to find these states of dysglycemia Moreover, when we do make the diagnosis, we do not treat in a way that lowers glucose levels to normal and as a consequence, the disease tends to progress, and patients need more and more medications Development of Diabetes, Diabetes Complications Prediabetes Diabetes Complications Prediabetes is glucose > normal but not as high as diabetes Underlying loss of β-cell function and mass (apoptosis) due to high glucose and lipids, inflammation and oxidative and ER stress Diagram illustrating the natural history of diabetes from progression from prediabetes to diabetes and development of diabetes complications over time without interventions Years 2

Development of Diabetes, Diabetes Complications Prediabetes Diabetes Complications Prediabetes is glucose > normal but not as high as diabetes Start Rx, diet, exercise Stop progression with interventions that glucose Benefit persists after treatments stop Legacy effect Diagram illustrating the natural history of diabetes from progression from prediabetes to diabetes and development of diabetes complications with interventions such as lifestyle change or a glucose-lowering medication that are successful in decreasing progression from prediabetes to diabetes, but then are stopped Development of Diabetes, Diabetes Complications Prediabetes Diabetes Complications Prediabetes is glucose > normal but not as high as diabetes Rx, diet, exercise, Rx -? More Rx progression and complications by glucose Obtain benefit for years Systematic treatment Diagram illustrating the natural history of diabetes from progression from prediabetes to diabetes and development of diabetes complications over time with interventions that are titrated to keep glucose and A1C levels in the normal range and are not stopped Start Don t stop Continue Cumulative Diabetes Incidence 0.8 0.6 0.4 0.2 Control Rosiglitazone Study ended, drug stopped Benefit sustained Cumulative diabetes incidence in the DREAM study, where subjects with prediabetes were given rosiglitazone or placebo, including time points before and after the primary study was stopped 0.0 0 1 2 3 4 5 6 Years DREAM = Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication 3

16 14 12 10 8 6 4 2 Incident severe retinopathy (%)18 Control Study ended Diet + exercise Benefit sustained 0 0 2 4 6 8 10 12 14 16 18 20 Follow Up (Years) Cumulative incidence of severe diabetic retinopathy in the Da Qing IGT & Diabetes study, showing subjects with prediabetes who were randomized to receive instruction in diet/exercise or to be control subjects, including time points before and after the primary study was stopped In the Diabetes Prevention Project subject population, achieving normal glucose levels appeared to be particularly beneficial Among subjects who had not developed diabetes at the end of the primary study, those who achieved normal fasting and 2-h oral glucose tolerance test (OGTT) glucose levels at least once during the average 3.2 years of the primary study had a 56% decrease in development of diabetes during follow-up after the primary study ended It did not matter how normal glucose was achieved, as the reduction in the tendency to develop diabetes was comparable among subjects in the lifestyle change, metformin, and control groups who achieved normal glucose levels at least once Cumulative Diabetes Incidence (%) 40 30 20 10 0 0 0.0 Control - Drug stopped at 0.9 years - Study ended (for these subjects) Troglitazone Benefit sustained 1.0 2.0 3.0 4.0 Years since randomization During 0.9 years of treatment Cumulative with troglitazone, the diabetes incidence diabetes incidence rate in the was U.S. 3.0 cases/100 Diabetes personyears, considerably Project Prevention lower study, than showing the rate of 12.0 subjects cases/100 with person prediabetes years with who were placebo given However, troglitazone during or the placebo, 3 years including after time troglitazone points before was stopped, and after the diabetes the incidence was virtually primary study was identical to that of the placebo stopped group without evidence of catch-up 4

As the natural history of diabetes the tendency for the disease to get worse and for complications to develop reflects underlying loss of β-cell function, which is due in part to glucotoxicity, treatment that normalizes glucose levels should help preserve β-cell function Indeed studies have shown that attaining normal glucose levels was predicted somewhat more strongly by better β-cell function than by better insulin sensitivity, although both were statistically significant Changing the Natural History of Diabetes How Medical Practice Should Change Screening to identify early diabetes and prediabetes should become routine Oral glucose tolerance tests - most sensitive, least convenient Fasting plasma glucose - lowest cost, intermediate sensitivity and convenience A1C - most convenient, least sensitive Patients who are at high risk and have health prospects justifying improved glucose control should have management aimed to keep glucose levels as close to normal as possible without causing hypoglycemia Begin with lifestyle change Changing the Natural History of Diabetes How Medical Practice Should Change Include medications if appropriate Begin with metformin for patients with diabetes Consider metformin for patients with prediabetes if there is: IFG and IGT and No FDA Indications At least one risk factor for progression to diabetes (age < 60 years, BMI 35 kg/m 2, a family history of diabetes, elevated triglycerides, reduced HDL-cholesterol, hypertension, or A1C > 6.0%) Other medications that may be appropriate (DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 analogs, α-glucosidase inhibitors, and possibly basal insulin and thiazolidinediones) 5

Changing the Natural History of Diabetes Stepped Care Strategy Insulin is typically added relatively late in the natural history Use of home glucose monitoring to guide management varies and often is not initiated until patients are treated with insulin relatively late in the natural history All patients with prediabetes and early diabetes should have management of cardiovascular risk factors, use of aspirin (if appropriate), screening for eye and renal complications, and education in medical nutrition management CONCLUSIONS We believe we are at a time when we can change the natural history of type 2 diabetes Doing so should benefit the health of millions of patients and might also benefit health care systems, by reducing resource use and costs The prevalence of diabetes is increasing in all industrialized countries and its prevention has become a public health priority, however, the predictors of diabetes risk are insufficiently understood We identified novel biomarkers that were associated with the risk of clinically incident diabetes over and above the classic risk factors This gives new insights into the pathogenesis of diabetes and may help with targeting prevention and treatment PLOS one 2014 5(4): e10100 6

Biomarker Testing for Clinically Incident Diabetes A score consisting of adiponectin, apolipoprotein B, C-reactive protein and ferritin almost doubled the relative risk of diabetes in the validation cohort (HR per one standard deviation increase 1.88, p = 2.8 e-5) It also improved discrimination of the model (IDI = 0.0149, p < 0.0001) and reclassification of diabetes risk [Net reclassification Index (NRI) = 11.8%, p = 0.006] Gender-specific analyses suggested that the best score differed between men and women Among men, the best results were obtained with the score of four biomarkers: adiponectin, apolipoprotein B, ferritin and interleukin-1 receptor antagonist, which gave an NRI of 25.4% (p<0.0001) Among women, the best score included adiponectin, apolipoprotein B, C-reactive protein and insulin which gave an NRI of 13.6% (p = 0.041) Salomaa V et al. PLOS one 2014 5(4): e10100 Biomarker Testing for Clinically Incident Diabetes The biomarker score, composed as a linear combination of four biomarkers, was associated with doubling of the relative hazard of diabetes in the independent validation cohort The prediction of absolute risk of diabetes produced a significantly improved net reclassification and discrimination, especially in gender-specific analyses, with the model including the biomarker score This information may help with identifying individuals at high risk of developing diabetes Salomaa V et al. PLOS one 5(4): e10100 Progression of Insulin Resistance Beta-Cell Strain Beta-Cell Function Beta-Cell Dysfunction Fasting Insulin LDL-P (apob) small LDL-P sdldl-c Large VLDL-P HDL-P HDL 2-C Lipoprotein Abnormalities Insulin Resistance TIME (months to decades) Fasting Glucose & HbA1c Prediabetes FG = 100-125 Diabetes FG > 125 (mg/dl) Beta-Cell Failure Bergenstal R et al. Diabetes Endocrinol 2005;7(2) Lipoproteins in Diabetes Mellitus Jenkins, Toth, Lyons. Humana Press 2014 7

Cholesterol Synthesis and Absorption Markers Lipoprotein Dynamics in Insulin Resistant States TG-rich VLDL Large LDL CE Apo A-V There is now less cholesterol per LDL & HDL particle than previously apocii (CETP) apoe TG apob Lipoprotein Lipase Smaller TG-depleted, cholesterol-rich cholesterol-rich VLDL remnants VLDL TG-enriched Cholesterol-depleted particles CE (CETP) LDL-C & HDL-C TG Large HDL Dayspring T. Chapter 4 Lipoproteins in Diabetes Mellitus Jenkins, Toth, Lyons. Humana Press 2014 VLDL-C Triglyceride Cholesteryl ester Lipoprotein Dynamics in Insulin Resistant States Large TG-rich LDL TG-rich VLDL Small LDL CE Hepatic Lipase (CETP) ~ LDL-C, sdldl-c TG CE Lipoprotein Lipase Smaller cholesterol-rich VLDL remnants TG-enriched Cholesterol-depleted particles (CETP) TG Large HDL Small & total LDL-P Triglyceride Dayspring T. Chapter 4 Lipoproteins in Diabetes Mellitus Jenkins, Toth, Lyons. Humana Press 2014 Cholesteryl ester Lipoprotein Dynamics in Insulin Resistant States Large TG-rich LDL TG-rich VLDL Small LDL CE Hepatic Lipase (CETP) HDL-P HDL-C TG HDL2-C TG-enriched cholesterol-depleted HDL particles Free apoa-i CE Lipoprotein Lipase Smaller cholesterol-rich VLDL remnants (CETP) TG Dayspring T. Chapter 4 Lipoproteins in Diabetes Mellitus Jenkins, Toth, Lyons. Humana Press 2014 ApoA-I Hepatic Lipase Large TG-rich HDL Triglyceride Smaller HDL Renal catabolism of apoa-i Cholesteryl ester 8

Lipoprotein Biomarkers: Insulin Resistance 25 Insulin resistance leads to hepatic VLDL overproduction Elevated TG, VLDL-C, non-hdl-c, VLDL-TG Elevated VLDL-P and large VLDL-P Increased VLDL size Increased remnants and remnant-cholesterol Increased apoc-iii Abnormal Remodeling of apob particles Variable LDL-C Increased small and total LDL-P Increased sd-ldl-c Increased LDL-TG Abnormal remodeling of apoa-i particles Low HDL-C Decreased large and total HDL-P Decreased HDL 2 -C Dayspring T. Chapter 4 Lipoproteins in Diabetes Mellitus Jenkins, Toth, Lyons. Humana Press 2014 Incident Diabetes Biomarkers Alphahydroxybutyrate Insulin Resistance Ferritin Adiponectin Linoleoylglycerophosphocholine Leptin Leptin/BMI Oleic Acid Pancreatic Beta-Cell Proinsulin Dysfunction C-peptide Insulin Initial hyperinsulinemia Later hypoinsulinemia Proinsulin: C-peptide Ratio Hyperglycemia Dyslipidemia Glucose HbA1c Fructosamine Trigs HDL-C HDL-P 1,5-Anhydroglucitol Apo B LDL-P Incident Diabetes and Beta-Cell Function Proinsulin Enzymes cleave proinsulin into C-Peptide and Insulin An elevated proinsulin/c-peptide ratio is a marker related to beta-cell strain* Pre-Insulin Proinsulin Insulin inactive insulin precursor (110 amino acids) A-chain C-Peptide B-chain A-chain B-chain Mature insulin 51 amino acids 70 amino acids C-Peptide With increasing demand for insulin (insulin resistance), cleavage capacity becomes exhausted, resulting in increased levels of proinsulin *Diabetologica 2011;54(12):3047-54 Holt R. Essential Endocrinology & Diabetes 6 th Ed 2012 Swiley Blackwell 9

Biomarker testing 19 blood-based biomarkers and derived factors organized into three functional categories: (1) glycemic control, (2) insulin resistance, and (3) pancreatic beta cell function can identify IR early, inform treatment, and improve glycemic control in a enable andhigh proportion of patients Biomarker Testing for Prediabetes 40 30 20 10 0 Proportion of normoglycemic patients demonstrating high range values of each biomarker Evidence of insulin resistance and beta cell dysfunction in the normoglycemic patients is prevalent and heterogeneous Of those patients classified as normoglycemic (glucose < 100 mg/dl and HbA1c <5.7, n=929), 82% demonstrated at least one high range biomarker of insulin resistance or beta cell function J Cardiovasc Trans Res 2014;7(6):597-606 Biomarker Associated with Prediabetes 20 15 10 Distribution of the total number of high range biomarker values observed in normoglycemic patients 5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Number of IR and beta cell biomarkers in high range per patient Varvel SA et al. J Cardiovasc Trans Res 2014;7(6):597-606 10

1993 Endocrinology 1993 Endocrinology Cholesterol Synthesis and Absorption Markers Prevention of REnal and Vascular ENd Stage Disease (PREVEND) Urinary Microalbumin and hs-crp in Predicting T2DM Onset 10 Incidence of T2DM (%) 8 6 5 2 0 > 30 UAE (mg/24/hr) 15-30 < 15 < 3 > 3 1-3 CRP (mg/24/hr) Incidence of T2DM after 4.2 years of follow up by category of Urinary Albumin Excretion (UAE) and CRP at baseline Brantsma AH, et al. Diabetes Care 28:2525 2530, 2005 LIFESTYLE THERAPY RISK STRATIFICATION FOR DIABETES COMPLICATIONS ACE Endocrine Practice 2016;22(1):103-113 Nutrition Physical Activity Sleep Behavioral Support INTENSITY STRATIFIED BY BURDEN OF DISEASE AND RELATED COMPLICATIONS Maintain optimal weight Calorie restriction Plant-based diet: high polyunsaturated and monounsaturated fatty acids Avoid trans fatty acids; limit saturated fatty acids 150 min/week moderate exertion (eg. walking, stair climbing) Strength training Increase as tolerated About 7 hours per night Community engagement Screen for mood disorders + Structured counseling Meal replacement + + + ++ Structured program Screen for sleep apnea Medical evaluation/ clearance Medical supervision Refer to mental healthcare professional Behavioral therapy Smoking Cessation No tobacco products Structured programs PREDIABETES ALGORITHM IFG (100-125) IGT (140-199) METABOLIC SYNDROME (NCEP 2001) ACE Endocrine Practice 2016;22(1):103-113 LIFESTYLE THERAPY (including Medically Assisted Weight Loss) TREAT ASCVD RISK FACTORS WEIGHT LOSS THERAPIES ANTIHYPERGLYCEMIC THERAPIES FPG > 100 2 Hour PG > 140 CVD RISK FACTOR MODIFICATIONS ALGORITHM NORMAL GLYCEMIA 1 PRE-DM CRITERION MULTIPLE PRE-DM CRITERIA DYSLIPIDEMIA HYPERTENSION ROUTE ROUTE LEGEND PROGRESSION OVERT DIABETES Intensify Weight Loss Therapies Low-risk Medications Metformin Acarbose Consider with Caution TZD GLP-1 RA Orlistat, lorcaserin, phentermine/topiramate ER, naltrexone/bupropion, liraglutide 3 mg, or bariatric surgery as indicated for obesity treatment PROCEED TO HYPOGLYCEMIA ALGORITHM If glycemia not normalized 11

1993 Endocrinology 1993 Endocrinology Cholesterol Synthesis and Absorption Markers GLYCEMIC CONTROL ALGORITHM ACE LIFESTYLE THERAPY (including Medically Assisted Weight Loss) Entry A1c < 7.5% Entry A1c 7.5% Entry A1c 9.0% MONOTHERAPY* DUAL THERAPY* Metformin GLP-1 RA GLP-1 RA SGLT-2i DPP-4i TZD! AGi! SU/GLND MET or other 1 st -line agent SGLT-2i DPP-4i TZD! Basal Insulin! Colesevelam Bromocriptine QR AGi! SU/GLN If not at goal in 3 months proceed to or If not at goal in 3 intensify double therapy months proceed to or intensify triple therapy * Order of medications listed represents a suggested hierarchy of usage: length of line reflects strength of recommendation TRIPLE THERAPY* MET or other 1 st -line agent + 2 nd -line agent If not at goal in 3 months proceed to or intensify insulin therapy GLP-1 RA SGLT-2i TZD! Basal Insulin! DPP4i Colesevelam Bromocriptine QR AGi SU/GLN! SYMPTOMS NO YES Dual Insulin Therapy ± Other OR Agents Triple Therapy ADD OR INTENSIFY INSULLIN Refer to Insulin Algorithm LEGEND Few adverse events and/or possible benefits! Use with caution PROGRESSION OF DISEASE Endocrine Practice 2016;22(1):103-113 ASCVD RISK FACTOR MODIFICATIONS ALGORITHM DYSLIPIDEMIA HYPERTENSION Lifestyle Therapy (Including Medically Assisted Weight Loss) ACE LIPID PANEL; Assess ASCVD Risk GOAL: SYSTOLIC ~ 130, DIASTOLIC ~ 80 mm Hg If statin-intolerant STATIN THERAPY If TG > 500 mg/dl, fibrates, omega 3 ethyl esters, niacin ACEi or ARB For initial blood pressure > 150/100 mm Hg: DUAL THERAPY Try alternate statin, lower statin Repeat lipid panel; Intensify therapies to dose or frequency, or add nonstatin LDL-C lowering therapies tolerance of therapy risk levels assess adequacy, attain goals according to DM but no other major DM + major CVD risk(s) (HTN, Fam RISK LEVELS HIGH risk and/or age <40 VERY HIGH Hx, low HDL-C, smoking) or ASCVD* DESIRABLE LEVELS DESIRABLE LEVELS LDL-C (mg/dl) < 100 < 70 Non-HL-C (mg/dl) < 130 < 100 TG (mg/dl) < 150 < 150 TC/HDL-C (mg/dl) < 3.5 < 3.0 ApoB(mg/dL) < 90 < 80 LDL-P (nmol/l) < 1200 < 1000 Intensify lifestyle therapy (weight loss, physical activity, dietary IF NOT AT DESIRABLE LEVELS changes) and glycemic control; consider additional therapy TO LOWER LDL-C: Intensify statin, add ezetimibe, PCSK9i, &/or colesevelam or niacin TO LOWER Non-HDL-C, TG: Intensify statin and/or add Rx-grade OM3 fatty acid, fibrate and/or niacin Intensify statin and/or add ezetimibe, PCSK9i, colesevelam and/or niacin TO LOWER ApoB, LDL-P: ACEi or ARB + Calcium Channel Blocker β-blocker Thiazide If not at goal (2-3 months) Add calcium channel blocker, β-blocker or or thiazide diuretic If not at goal (2-3 months) Add next agent from above group, repeat If not at goal (2-3 months) Additional choices (α-blockers, central agents, vasodilators, aldosterone antagonists) Assess adequacy & tolerance of therapy with focused laboratory evaluations and patient follow-up Achievement of target blood pressure is critical * EVEN MORE INTENSIVE * EVEN THERAPY MORE INTENSIVE MIGHT BE THERAPY WARRANTED MIGHT ** BE FAMILIAL WARRANTED HYPERCHOLESTEROLEMIA Endocrine Practice 2016;22(1):103-113 Liraglutide (LEADER) and empagliflozin (EMPA-REG) and the novel drug semaglutide (SUSTAIN) reduced CV events Bernard Zinman: who ever thought we'd have a diabetes therapy that reduces cardiovascular death? Christopher Cannon: "that new diabetes mellitus drugs can actually improve cardiovascular outcomes" the top advance of 2016 in cardiology The cardiology, unlike the endocrine community has rapidly embraced the idea of using diabetes drugs for cardiovascular risk reduction Steve Nissen: Greater involvement by cardiologists is essential to translating the benefits observed in clinical trials to the care of individual patients. http://www.medpagetoday.com/cardiology/prevention/62307 accessed 1/26/2017 12

Summary Slide Glycemic indices are the main target goal of insulin resistance therapy Other biomarkers can be used to assess insulin resistance before glycemic abnormalities appear Several lipid/lipoprotein biomarkers associate with IR There is a beneficial legacy effect even with short term treatments AACE guidelines stress lifestyle and pharmacologic algorithms to control weight, glycemia, dyslipidemia and hypertension 13