10/11/19 Disclosure New Frontiers in Diabetes Management: - - PDF document

10/11/19 1

New Frontiers in Diabetes Management: Challenges in the care of Asian Patients

UCSF 8th Annual Asian Health Symposium 2019 T ejaswi Kompala, MD UCSF Division of Endocrinology

1 Disclosure

I have no relevant financial relationships with any company related to the content of this course

2 Roadmap

• Diabetes epidemiology
• Pathophysiology differs in Asians
• Metabolic Phenotype
• Diagnosis and T

esting

• Treatment: Lifestyle Interventions

3

Asia is considered as the epicenter of recent worldwide epidemic of diabetes

IDF Diabetes Atlas 8e

Number of People with Diabetes in 2017 and 2049 (20-70 years old)

• In China, diabetes prevalence

increased from 1% in 1980 to 9.7% in 2010.

• In Korea, rates increased

from 0.9% in 1971 to 9.9% in 2009. These prevalence rates equal that of the US: CDC report estimates that 9.4% of Americans have diabetes.

4

10/11/19 2

IDF Diabetes Atlas 8e

Undiagnosed percentage and undiagnosed cases of diabetes (20-79 years) per region

Half of people with diabetes don’t know they have it

5

352 million people are at risk

• f developing type

2 diabetes

IDF Diabetes Atlas 8e

Number of adults (20-79 years) with Impaired Glucose T

• lerance in 2017

6

Incidence of Diabetes Among US Ethnic Subgroups

DISTANCE: 15,357 new cases of medically diagnosed diabetes in 2010

Karter AJ et al. Dia Care 2013

7

Under-Recognition of Diabetes Among Asian Americans

• JAMA. 2015;314(10):1021-1029

32.3 36.8 49 50.9 Whites Blacks Hispanics Asians

% of NHANES participants UNAWARE of Diabetes Diagnosis

8

10/11/19 3

How Does Diabetes Differs In The Asian Patient: Implications For Diagnosis And Treatment

9

The Pathophysiology Of Diabetes Differs In Asian Patients

• Proposed mechanism: insulin resistance, initial pancreatic beta cell

compensatory response, and eventual beta cell exhaustion.

Yabe D., eat al. Current Diab Reports. 2015; Qian L., et al. Diabetes Metab Res Revi 2009; Kim DJ et al. Metabolism. 2001, Fukushima M. et al. Diabetes Res Clin Pract. 2004

Reduced insulin secretory capacity, especially in the early phase, has been reported not only in Japanese but also in other East Asians such as Korean and Chinese.

Normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (DM).

10

The insulinogenic index, a marker of beta cell function that measures insulin and glucose levels, was lower for Japanese subjects with normal glucose tolerance

Fukushima M. et al. Diabetes Res Clin Pract. 2004

11

HOMA-IR Is Lower In Japanese Throughout NGT , IGT , And T2DM in Comparison With that of Caucasian

Fukushima M. et al. Diabetes Res Clin Pract. 2004

12

10/11/19 4

DM2 Physiology: Take Home Points

• 1. Counterbalance between insulin secretion and insulin

resistance is critical for T2DM pathogenesis

• 2. Why Asians show a low reserve capacity of insulin secretion?
• 3. GWAS studies are trying to answer this question:

several T2DM-susceptible genes in East Asians but it is difficult to know how these genes might affect β cell function.

Yasuda K, et al. Nat Genet. 2008; Cho YS, et al. Nat Genet. 2012

13

Diabetes in Asians

• Younger Age
• Lower body-mass

index (BMI)

• But…INCREASED

visceral adiposity

14

BMI is lower in Asians vs. Non-Asians with Diabetes

Karter AJ et al. Dia Care 2013

BMI of Asians with diabetes

• utside of US is < 25

15

Lower BMI, Higher Body Fat In Asians

• NYC healthy volunteers: 445 Whites, 243 Asians (mostly Chinese and foreign

born)

• Skinfold measurements: Significantly higher fat in trunk and arms in Asians

compared to whites

White Males Asian Males White Females Asian Females BMI kg/m2 25.1 23.4 23.9 22.5** Body Fat (DXA) 19.3% 21.4%* 30.1% 31.6%

Wang J. eta l. Am J Clin Nutr 1994

*p=0.006 white vs. Asian males; **p=0.002 white vs Asian females

16

10/11/19 5

17

BODY FAT DISTRIBUTION MIGHT ACCOUNT FOR THE DIFFERENCES IN T2DM RISK IN ASIAN GROUPS.

Alba, D. et al., JECM 2018; John Shepherd; UCSF Nutrition and Obesity Research Center (NORC)

19

Shai et al., Diabetes Care 2006; Thorpe et al., Diabetes Care 2009

Fat Distribution Is A More Precise Predictor Of T2D

Those who expand both visceral and subcutaneous fat mass develop T2D at relatively high BMI Those who preferentially expand visceral adipose tissue (VAT) mass, develop T2D at a lower BMI

VAT accrual is tightly linked to T2D risk

Normal weight Overweight Obese Percent with T2D White Black Asian Hispanic

20

Asians Have High Visceral Adiposity

Obesity Research Volume 13, Issue 8, pages 1458-1465, 6 SEP 2012 DOI: 10.1038/oby.2005.176 http://onlinelibrary.wiley.com/doi/10.1038/oby.2005.176/full#f1

Filipino (n=181) White (n=196) African American (n=193) BMI, kg/m2 25.5* 26.0 29.7† Type 2 Diabetes 32.1%*‡ 5.8% 12.1% Waist-hip ratio 0.84*‡ 0.78 0.82† VAT by CT (cm3) 69.1* 62.3 57.5†

*p<0.05 Filipino vs. African American †p<0.05 African American vs. white ‡p<0.08 Filipino vs. white

21

10/11/19 6

T wo Possible Mechanisms Could Drive Visceral White Adipose Tissue (Wat) Expansion And Consequent Insulin Resistance And T2D

Subcutaneous WAT (scWAT):

• Minimal inflammation
• Relatively insulin sensitive
• Highly thermogenic “Beige”.

Visceral WAT (vWAT):

• Prone to inflammation
• Drives insulin resistance
• Increases risk for T2D,

cardiovascular disease, and mortality

23

Type 2 diabetes Insulin Resistance

( (

Determining How Fat Tissue Accumulation Affects Metabolic Disease Requires Understanding How Fat Mass is Regulated

Genetics + lifestyle

26

Diagnosis and T esting in Asian Patients

28

Fasting blood glucose and HbA1c are the primary tests in the diagnosis of diabetes

• Gold standard oral glucose tolerance test (OGTT) is not traditionally

recommended by the ADA.

• In 2010 in China: 44% of men and 50.1% of women with diabetes had

normal fasting glucose (implying normal insulin sensitivity) but isolated increased two-hour blood glucose (from beta-cell dysfunction)

Yang W. et al. N Engl J Med. 2010; Bao Y. et al. Br. Med. J. 2010

29

10/11/19 7

Characteristics Curve Of Hba1c For Detecting Diabetes At Each Possible Hba1c Threshold.

Yuqian Bao et al. BMJ 2010;340:bmj.c2249

HbA1C threshold of 6.3% was highly specific for detecting undiagnosed diabetes

30

Diagnosis and T esting in Asian Patients

The selection of diagnostic tests and cutoff values used in the US should be modified for Asian patients, especially given that normal fasting glucose levels may mask diabetes that would be found using an oral glucose challenge test.

31

Implications For Treatment in Asian Patients

32

The Cornerstone Of Treatment For T ype 2 Diabetes Is Lifestyle Intervention, Including Dietary Modifications: Diabetes Risk According T

• Dietary Intake

Hu F. Dia Care 2011

33

10/11/19 8

The Cornerstone Of Treatment For T ype 2 Diabetes Is Lifestyle Intervention, Including Dietary Modifications: Diabetes Risk According T

• Dietary Intake

Hu F. Dia Care 2011

Risk adjusted for:

• BMI
• Exercise
• Family history
• Alcohol

Fiber Unsaturated: Saturated Fat Trans Fat Glycemic Load

34

Hsu W C at al. PLOS ONE 2014

Effect of transitioning Asian Americans and Caucasian Americans from a traditional Asian diet to a traditional Western diet (TWD)

Asian Diet: 70% CHO, 15% protein, 15% fat, and 15 grams of fiber/1000 kcal TWD: 50% carbohydrate, 18% protein, 34% fat, and 6 grams of fiber/1000 kcal.

37

Weight Loss And Improved Insulin Sensitivity In Both Groups On Traditional Asian Diet

Hsu W C at al. PLOS ONE 2014

38

AA Transitioned to Western Diet: Elevated Body Fat And Trunk Fat With A Rise In Insulin, Despite Insignificant Weight Gain

Hsu W C at al. PLOS ONE 2014

39

10/11/19 9

CA transitioned to TWD: significantly increased weight, body fat, and trunk fat with no significant change in insulin resistance

Hsu W C at al. PLOS ONE 2014

Macronutrient composition of Asian diet improved insulin sensitivity in both AA and CA. In contrast, TWD may have impaired the insulin sensitivity in AA, but not CA with normal BMI, raising the possibility that diets may elicit different effects in different ethnic groups.

40

A little weight loss and exercise = big benefits

• U.S. Diabetes Prevention Program
• 2000+ Pre-diabetic subjects with BMI >24 (or >22 if Asian)
• Randomized to Metformin, Intensive Lifestyle, or Routine Care
• Intensive lifestyle:
• 7% Body weight loss (low fat, low calorie diet)
• 150 minutes per week of moderately strenuous activity

N Engl J Med 346:393-403, 2002

44 Diabetes Prevention Program

N Engl J Med 2002

NNT Lifestyle: 6.9 people x 3 yrs NNT Metformin 13.9 people x 3 yrs N=3234 92% completion rate Lost 7% body weight with diet and moderate exercise

45

Chinese Diabetes Prevention Study

• 577 Chinese adults with pre-diabetes, mean age of 40 and BMI of 26
• Randomized to:
• Diet (Consume more vegetables and less sugar and alcohol. If overweight, eat

less)

• Exercise (increase leisure physical activity)
• Diet + Exercise
• Control

46

10/11/19 10

Chinese Diabetes Prevention Study: Cumulative incidence of DM during follow-up

2 4 6 8 10 12 14 16 18 20 Years of follow-up Number at risk Control Intervention 10 20 30 40 50 60 70 80 90 100 Percentage 114 136 147 161 192 206 230 250 314 387 428 14 23 27 27 34 37 40 48 69 105 135 6-year intervention hazard rate ratio 0·49 (95% CI 0·33–0·73) 20-year follow-up hazard rate ratio 0·57 (95% CI 0·41–0·81) Control Intervention Figure 2: Cumulative incidence of diabetes mellitus during follow-up in China Da Qing Diabetes Prevention Gi L. Et al. Lancet 2008

1 kg weight difference at 6 yrs 0.5 kg weight difference at 20 yrs

The annual incidence

• f diabetes was 7%

for intervention vs 11% in control

47

Intensive Lifestyle to Treat Diabetes

• Randomized control trial comparing a 5 year intensive lifestyle

intervention (ILI) vs. diabetes support and education (DSE) for the prevention of major cardiovascular events in T2DM over 11.5 year follow up

• Intervention: 7% weight loss with a reduced calorie diet and

175 min of mod-strenuous exercise per week

• Primary endpoint was major CV event (ultimately, the event

rate was too low in both arms to show difference)

https://www.lookaheadtrial.org/public/LookAHEADProtocol.pdf

48

Weight Loss + A1c Reduction with Intensive Lifestyle

Year The Look AHEAD Research Group. Ann Intern Med. 2010:170:1566-75 Year

49

Lifestyle Intervention/Prevention DM Asian Studies

Knowler W et al, N Engl J Med 2002; Pan XR et al, Diabetes Care 1997; Kosaka Diabetes Res Clin Pract 2005; Saito T et al Arch Intern Med 2011

52

10/11/19 11

Challenges in Patient care

• Awareness
• Despite the marked increase in diabetes prevalence in Asia and the US, recent

studies have highlighted a lack of awareness in many Asian patients.

• Cultural Attitudes & Beliefs
• Older Chinese Americans more likely to hold negative perceptions of and

attitudes toward diabetes in relation to pharmaceutical companies and health insurance policies

• Social-economic Differences
• Education
• Language barriers

Lee H. et al. J Am Osteopath Assoc. 2018.

54

Impact of Language Barriers in Chinese Americans with Diabetes

Patients had comparable diabetes care and self-management behaviors Hsu WC et al. Diabetes Care. 2006.

55 Take Home Points

• Despite its global presence, T2D is not universally the same
• In Asians, it presents with more
• β cell dysfunction
• increased visceral adiposity
• Lifestyle interventions work, alongside pharmacologic therapy

56 Take Home Points- for our patients

• Continue to raise awareness, facilitate early diagnosis, and encourage

preventive strategies to combat T2D

• Diabetes is preventable and treatable with lifestyle changes!!
• Healthy diet and exercise is beneficial even in normal weight patients

with type 2 diabetes

• Asian patients have an increase risk for T2D, despite lower BMI ( but

higher % fat and visceral adiposity)

• Given increase adiposity and early β cell dysfunction, implementation
• f therapeutics might need to occur earlier

57

10/11/19 12

Roadmap

• Diabetes epidemiology
• Pathophysiology differs in Asians
• Metabolic Phenotype
• Diagnosis and T

esting

• Treatment: Lifestyle Interventions

58 59