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Diabetes Management in the Safety Net: Making Sense of Medication Choices UCSF CME: Medical Care of Vulnerable and Underserved Populations March 1, 2019 Suneil K. Koliwad, MD, PhD Gerold Grodsky, PhD/JAB Chair in Diabetes Research Associate Professor of Medicine Diabetes Center University of California, San Francisco Division of Endocrinology San Francisco General Hospital DISCLOSURES Gilead Sciences (Grant Recipient) Eli Lilly & Co (Grant Recipient) Suggestic (Equity; Consultant) Yes Health (Equity; Consultant) AMMA Therapeutics (Consultant) 2 1

Overview Environmental Factors- The dietary abyss Ethnicity- Putting trends into practice Medications- Oral Agents Insulin Self Care- To check, or not to check Environmental Factors ”Anyone can out-eat their medications” Ken Feingold, MD, PhD UCSF/VAMC 2

Lifestyle Modification for Diabetes Risk Reduction Lifestyle is a powerful “medicine” The Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393. 3

Relative Price Changes for Fresh Fruits and Vegetables, Sugars and Sweets, and Carbonated Drinks, 1978–2009 From: Bronwell KD, Frieden TR. Ounces of Prevention — The Public Policy Case for Taxes on Sugared Beverages. N Engl J Med. 2009 Apr 30;360(18):1805-8. Epub 2009 Apr 8. 4

SODA EXPENDITURES Percent of Total Expenditures, National Rank by Tract (2011) TENDERLOIN MISSION BAYVIEW EXCELSIOR VISITACION VALLEY 5

Ethnicity Diabetes Risk is Not Evenly Spread Across the Population 6

Leptin-deficient patients are severely obese but obesity can be reversed by leptin replacement O’Rahilly et al. Endocrinology, 2003 GWAS Meta-Analysis: Heritable Component of BMI is Dominated by “Brain Genes” Locke, et al. 2015. Nature. 518(7538): 197-206. DEPICT analysis 7

Obesity is Not a Highly Penetrant Diabetes Risk Factor Two Individuals with POMC Mutations Variable Patient 1 Patient 2 Glucose (mg/dl) 65 76 Insulin (mU/L) 26.7 9.8 Triglycerides (mg/dl) 99 63 HbA1C 5% 5.4% Kuhnen, et al., NEJM 2016 Obesity and T2DM In the United States Among people diagnosed with 15% Type 2 diabetes, 55% are BMI ≥ 30 (obese), 55% 30% are BMI ≥ 25 or ≤30 30% (overweight) 15 percent have a BMI ≤ 25 (classified as normal weight). BMI < 25 ~70% of Overweight and BMI > 25 or BMI < 30 Obese People do not develop T2DM Adapted from: http://www.obesityinamerica.org/trends.html 8

Obesity and T2DM In the United States Among people diagnosed with 15% Type 2 diabetes, 55% are BMI ≥ 30 (obese), 55% 30% are BMI ≥ 25 or ≤30 30% (overweight) 15 percent have a BMI ≤ 25 (classified as normal weight). BMI < 25 ~70% of Overweight and BMI > 25 or BMI < 30 Obese People do not develop T2DM Adapted from: http://www.obesityinamerica.org/trends.html DEPICT: Heritable Component of Insulin Resistance is Dominated by White AdiposeTissue and its Peripheral Storage Capacity Lotta, et al. Nature Genetics 49, 17–26 (2017); Involved Two Large Cohorts and a PFLD1 Cohort 9

What is the prevalence of type 2 diabetes?  A. 10% of all diabetes in ages 5-18  B. 5% of all diabetes in ages 5-18  C. It is ethnicity dependent  D. It can be greater than the prevalence of type 1 diabetes 10

Understanding Ethnicity-Associated T2DM Risk: Clinical Impact China and Japan : overweight BMI of 24, obesity BMI > 28. India: overweight BMI of 23, and obesity BMI > 27 Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet . 2004; http://screenat23.org Ethnicity Impacts T2DM Risk Nurse’s Health Study Shai I et al. Diabetes Care 2006;29:1585-1590 11

Distribution of Diabetes Types by Age at Diagnosis and Race/Ethnicity Case 55 yow w/ HTN, BMI 32, DM2 for 3 years. On metformin but in past year A1C has increased to 8.2%. What do you do next? a) Encourage improved diet and exercise b) Start a sulfonylurea c) Start a TZD d) Start a DPPIV-inhibitor e) Start an SLGT-2 inhibitor f) Start a GLP-1 analogue g) Start insulin h) Start an α-glucosidase inhibitor, bromocriptine or colesevelam 24 12

A1C Goal Cardiovascular Efficacy Benefit/Harm Comorbidities Cost Complications Adverse Effects Patient Acceptance Risks/Hypoglycemia Case 55 yow w/ HTN, BMI 32, DM2 for 3 years. On metformin but in past year A1C has increased to 8.2%. What should her A1C target be? a) < 6% b) < 6.5% c) < 7% d) 7-8% e) < 8% 26 13

What I Know about Lowering Glucose in Diabetes 27 I THINK What I Know about Lowering Glucose in Diabetes 28 14

1. Lowering A1C prevents microvascular complications. The lower the better. The earlier in the disease the better. 2. Lowering A1C early in the disease prevents macrovascular complications many years later. 3. The effects of improved glycemic control early in the disease last decades after. 4. Aggressive A1C lowering results in more hypoglycemia and the elderly are more prone to severe hypoglycemia. DCCT/EDIC - Cumulative Incidence CVD Outcomes 42% reduction in CVD risk 57% reduction in risk of nonfatal MI, stroke or CVD death 8.0 v 8.1 % A1C [----------------------------------------------] At 30 y Follow up 30% reduction in CVD risk 32% reduction in risk of nonfatal MI, stroke or CVD death 7.2 v 9.1 % A1C N Engl J Med 2005;353:2643-2653 15

UKPDS - HbA 1c Progression 7% v 7.9% A1C Conventional Intensive 0 3 6 9 12 15 Time from Randomization (years) Lancet, 1998; 352:837-853. 31 UKPDS - 20 y follow-up Intensive Glucose Control RR = 0.67* RR = 0.85* NEJM, 2008; 359:1577-89. 16

UKPDS - 20 y follow-up Intensive Glucose Control RR = 0.87* RR = 0.73* NEJM, 2008; 359:1577-89. Risk Factors for Mortality and CV Outcomes in DM2 • 271,174 patients with DM2 in Sweden • Assessed 5 risk factors out of target range – A1C > 7%, SBP > 140, smoking, LDL > 97 mg/dL, albuminuria – Explored CV outcomes and mortality • Hazard Ratio for patients with all variables in target range – death 1.06 (1.00‐1.12) – acute MI 0.84 (0.75‐0.93) – stroke 0.95 (0.84‐1.07) Rawshani et al. N Engl J Med 2018;379:633‐644. 17

Which risk factor outside the target range was the strongest predictor of acute MI and stroke? a) elevated A1C b) elevated SBP c) smoking d) elevated LDL e) albuminuria 0 A B C D E A Rawshani et al. N Engl J Med 2018;379:633‐644. 18

Which risk factor outside the target range was the strongest predictor of death? a) elevated A1C b) elevated SBP c) smoking d) elevated LDL e) albuminuria A Rawshani et al. N Engl J Med 2018;379:633‐644. 19

UKPDS ADVANCE ACCORD VADT # subjects 4,209 11,140 10,251 1,791 Age (y) 54 66 62 60 BMI 28 28 32 31 CVD 7.5% 32% 35% 40% Dx (y) New 8 10 12 A1C % 7.1 7.5 8.3 9.4 Duration of 10+10= 5.0 3.4+5.6= 5.6+4.4= Follow-up 20 9 10 39 Summary of Major Tight Control Trials Study Microvasc CVD Mortality         UKPDS DCCT / EDIC                 ACCORD      ADVANCE         VADT Initial Trial Long Term Follow‐up Modified from Kendall and Bergenstal 20

Take Home Points  Lowering A1C prevents microvascular complications. The lower the better. The earlier in the disease the better.  Lowering A1C early in the disease prevents macrovascular complications many years later.  Effects of early A1C lowering last decades after tight control is done.  Tight control late in T2DM in patients with established CV disease o Has more modest effects on microvascular disease o Has unclear CV benefit 41 Case 55 yow w/ HTN, BMI 32, DM2 for 3 years. On metformin but in past year A1C has increased to 8.2%. What should her A1C target be? a) < 6% b) < 6.5% c) < 7% d) 7-8% e) < 8% 0 A B C D E 42 21

Guidelines for Glycemic Targets  American Association of Clinical Endocrinologists  American Diabetes Association  VA/DOD  NICE – UK  American College of Physicians 43 Glycemic targets - < 7.0% for many adults - < 6.5 % for selected patients if this can be achieved without hypo or other adverse effects - < 8% for patients with history of severe hypoglycemia, limited life expectancy, advanced macro/microvascular disease, longstanding DM without attaining the goal Diabetes Care 2018;41(Suppl. 1):S55–S64 | https://doi.org/10.2337/dc18-S006 22

ACP Guidance for A1C Targets in DM2  Clinicians should aim to achieve A1C of 7-8% in most patients o ACHIEVE - NOT “AIM TO ACHIEVE”  Clinicians should consider cutting back on medical therapy with A1C < 6.5% Qaseem et al for Guildine Committee, Ann Intern Med March, 2018 45 ACP Guidance for A1C Targets in DM2  Clinicians should aim to achieve A1C of 7-8% in most patients o ACHIEVE - NOT “AIM TO ACHIEVE”  Clinicians should consider cutting back on medical therapy with A1C < 6.5% o NOT FOR FOLKS ON METFORMIN/DRUGS WITHOUT HYPOGLYCEMIA OR YOUNG FOLKS WITHOUT LOWS  Life expectancy < 10 years (e.g. 80+, nursing home, dementia, ESRD, COPD, CHF etc) goal is to minimize symptoms without A1C target o – NEED AN A1C TO KNOW SE – Big difference between 8 and 12  Personalize goals based on all those things we are talking about o YES!!! Qaseem et al for Guildine Committee, Ann Intern Med March, 2018 46 23