Extending The Healthspan Of Those With Diabetes And Prediabetes - - PowerPoint PPT Presentation

Extending The Healthspan Of Those With Diabetes And Prediabetes

Anne Peters, MD Professor, USC Keck School of Medicine Director, USC Clinical Diabetes Programs

Disclosure

Advisory Boards

• Abbott Diabetes Care
• Astra Zeneca
• Bigfoot Biomedical
• BD, BI
• Lexicon, Lilly, Livongo
• Medscape, Merck
• NovoNordisk (also

Speaker’s Bureau)

• Omada Health
• Sanofi, Science37

Research Funding

• Dexcom
• Mannkind

Objectives

• 1. Review burden of diabetes
• 2. Discuss diabetes prevention in 2018
• 3. Analyze CVOT outcome data in T2DM
• 4. Look at outcomes beyond A1C

Years of Life Lost Due to Diabetes by Age of Onset

Age at Diabetes Onset Narayan et al JAMA 2003;290:1884-1890

Complications in T2D and the Metabolic Syndrome

Diabetic Retinopathy Macrovascular Disease

Risk Relative To General Population

1 2 3 4

• 15
• 10
• 5

5 10 15

• 20

20

5 6

Years of Diabetes

Insulin Resistance Dyslipidemia Hypertension Hyperglycemia

Adapted from: Kendall DM. Am J Manag Care 7S327-S343, 2001.

Diabetes Prevention Program: Incidence of T2D

Cumulative incidence

• f diabetes (%)

Years

40 30 20 10 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Placebo Metformin Lifestyle

Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

P<0.001 for each comparison. N = 3324

14.4% 21.7% 28.9%

Medicare Diabetes Prevention Program

https://innovation.cms.gov/initiatives/medicare-diabetes-prevention- program/

LDL Cholesterol Targets in Diabetes

Residual Risk of CVD

? Role of other lipid and non-lipid factors

Risk Attributable to LDL-C 60 80 100 120 140 160 180 200 220

LDL Cholesterol (mg/dl)

Clinical Event Rate

4S CARE HPS LIPID CARDS Post CABG ASCOT PROVE IT

Severe Hypoglycemia and Mortality Risk

ACCORD ADVANCE VADT

Severe Hypo Intensive Standard Intensive Standard Intensive Standard (%/ year) 3.1% 1.1% 0.7% 0.4% 12.0% 4.0%

0.0% 1.0% 2.0% 3.0% 4.0% 5.0% Intensive Standard 1.3% 1.0% 2.8% 4.9%

Annual mortality

Bonds et al. BMJ 2010;340:b4909

Yellow = +severe hypo

Study

SAVOR EXAMINE TECOS CAROLINA CARMELINA

DPP4-I

saxagliptin alogliptin sitagliptin linagliptin linagliptin

Comparator

placebo placebo placebo SU placebo

N

16,492 5,380 14,735 6,072 7,003

Reported

2013 2013 2015 2018 2018

CVOT Outcome

Neutral Neutral Neutral

Other

Increased CHF Increased CHF

CV Outcomes Trials in Diabetes: DPP-IV I

• CHF warning on all DPP-IV I’s in patients at risk for heart failure

N Engl J Med 2013; 369:1317-1326 N Engl J Med 2013; 369:1327-1335 N Engl J Med 2015; 373:232-242

Study ELIXA FREEDOM

• CVO

LEADER SUSTAIN 6 EXSCEL GLP1-RA

lixisenatide ITCA-650 exenatide liraglutide semaglutide exenatide LR

N

6068 ~4,000 9,340 3,297 14,752

Reported

2015 2016 2016 2016 2017

CVOT Outcome

Neutral Neutral Benefit In label Benefit Neutral

Other

Renal benefit Worsening retinopathy N Engl J Med 2016; 375:1834-1844, N Engl J Med 2016;375:311-322, Diab Obes Metab 2018;20:42-49, N Engl J Med 2017;377:1228-1239, NEJM 2015;373:2247-2257

CV Outcomes Trials in Diabetes: GLP1-RA

Ongoing = REWIND Dulaglutide n = 9901

Primary outcome

CV death, non-fatal myocardial infarction, or non-fatal stroke

The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

CV death

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

Hospitalization for heart failure

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional- hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54

• months. CI: confidence interval; HR: hazard ratio.

Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

Time to first renal event

Macroalbuminuria, doubling of serum creatinine, ESRD, renal death

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional- hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54

• months. CI: confidence interval; ESRD: end-stage renal disease; HR: hazard ratio.

Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

CV Outcomes Trials in Diabetes: SGLT-2 I

Study EMPA-REG CANVAS Program DECLARE- TIMI VERTIS-CV SGLT-2 I

empagliflozin canagliflozin dapagliflozin ertugliflozin

N

7028 10,142 17,276 ~8,000

Reported

2015 2017 2018 2019

CVOT Outcome

Benefit In label Benefit Pending Pending

Other

Reduction in CHF Renal Benefit Increased risk

• f amputation

and fracture

N Engl J Med 2015; 373:2117-2128, N Engl J Med 2017; 377:644-657,

EMPA-REG CV death

HR 0.62 (95% CI 0.49, 0.77) p<0.0001

N Engl J Med 2015; 373:2117-2128

EMPA-REG Heart Failure Hospitalization

HR 0.65 (95% CI 0.50, 0.85) p=0.0017

N Engl J Med 2015; 373:2117-2128

EMPA-REG Renal Function over Time

Wanner C et al. N Engl J Med 2016;375:323-334

The Many Paths to an A1C = 7%

Brown A, Close K. Close Concerns FDA briefing

T1DM: A1C =6.8%, low variability

180 80

T1DM: A1C = 6.9%, high variability

Standardizing Clinically Meaningful Outcome Measures Beyond HbA1c for Type 1 Diabetes

A Consensus Statement of AACE, AADE, ADA, Endo Society, JDRF International, Helmsley Charitable Trust, Pediatric Endo Soc and the T1D Exchange

Hypoglycemia

Level Definition Level 1 Glucose <70 mg/dl (3.9 mmol/L) and >54 mg/dl (3.0 mmol/L) Level 2 Glucose <54 mg/dl (3.0 mmol/L) Level 3 A severe event characterized by altered mental and/or physical status requiring assistance

American Diabetes Association Standards of Medical Care in Diabetes. Glycemic targets. Diabetes Care 2017; 40 (Suppl. 1): S48-S56

Hyperglycemia

Level Definition Level 1 Glucose >180 mg/dl (10 mmol/L) and <250 mg/dl (13.9 mmol/L) Level 2 Glucose >250 mg/dl (13.9 mmol/L)

Time in Range/DKA

Outcome Definition Time in Range Percentage of readings in the range of 70 mg/dl (3.9 mmol/L) - 180 mg/dl (10 mmol/L) per unit of time DKA

• Elevated serum ketones (above ULN)

and

• Serum bicarbonate <15 mmol/L or blood pH

<7.3

The Value of Continuous Glucose Monitoring

Flash Glucose Monitoring

Nondiabetes

Nondiabetes

Approaching Prediabetes

PreDiabetes

Almost Diabetes

A1C Over 7%

T2DM: On Metformin alone

“Normal” Fasting Blood Sugar Levels

150

“Normal” Fasting Blood Sugar Levels

“Do I Really Need Insulin?”

77 yo on metformin + nateglinide

77 yo on metformin + nateglinide + basal insulin

Knowledge ≠ Adherence: Middle Aged Pharmacist

Real World: Impact of Adherence

Diabetes Care 2017 Aug 11. pii: dc162725. doi: 10.2337/dc16-2725. [Epub ahead of print]

JP—On SU/lira/empa/glargine/met, not working

JP on met/dula/degludec

T1DM: Twice daily NPH and Reg, ELA

Stepp-Up Project

ADA 2018: Treatment of Adults with T2DM

Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85

Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85

ADA 2018: Treatment of Adults with T2DM

Thank You

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