DIABETESDIABETES

THE NEW EPIDEMICTHE NEW EPIDEMIC3rd June 20143rd June 2014

Professor Paolo PozzilliProfessor Paolo Pozzilli

In collaboration with Rocky Strollo and Valentina Greto

Number of people with diabetes Number of people with diabetes (20-79 years), 2013(20-79 years), 2013

IDF Diabetes Atlas, 6th Edition, 2013

Tot: 382,000,000 in 2013Tot: 471,000,000 in 2035

Trends in age-standardized diabetes prevalence by Trends in age-standardized diabetes prevalence by

regions in regions in MALESMALES (1980-2008) (1980-2008)

Danaei et al.Lancet 2011

High income regionsEurope/North America

Central/Eastern Europe Sub-Saharan Africa Oceania

Central Asia, NorthAfrica, Middle-East

South Asia East Asia and SE Asia World

Southern America Central/Andean America

High income Asia

Dia

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%)

20

16

128

4

20

16

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4

20

16

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4

1985 1995 2005 1985 1995 2005 1985 1995 2005

1985 1995 2005

Trends in age-standardized diabetes prevalence by Trends in age-standardized diabetes prevalence by regions in regions in FEMALES FEMALES (1980-2008)(1980-2008)

Danaei et al.Lancet 2011

High income regionsEurope/North America

Central/Eastern Europe Sub-Saharan Africa Oceania

Central Asia, NorthAfrica, Middle-East

South Asia East Asia and SE Asia World

Southern America Central/Andean America

High income Asia

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%)

20

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4

20

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20

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1985 1995 2005 1985 1995 2005 1985 1995 2005

1985 1995 2005

Overall prevalence of antidiabetic drug use in children and adolescents by age on IMS, 1998-2005 inclusive girls boys and overall

Hsia Y et al., British Journal of Clinical Pharmacology, 2008

Increased prevalence of diabetes in Increased prevalence of diabetes in

children and adolescentschildren and adolescentsResults from prescription data from a UK general practice databaseResults from prescription data from a UK general practice database

Prevalence of insulin, oral antidiabetic and oral antidiabetic drugs with a diabetes indication amongst

children and adolescents aged 0-18 (with 95% CIs), insulin oral antidiabetic drugs

oral antidiabetic drugs with diabetes indication ; *a significant trend for increasing use (p< 0.001).

*

*

*

Increasing use of antidiabetic drugs among Increasing use of antidiabetic drugs among

children and adolescentschildren and adolescents

Hsia Y et al., British Journal of Clinical Pharmacology, 2008

Type 1 diabetes (15%)

It is caused by an autoimmune reaction, where the body’s defence system attacks the insulin-producing beta cells in the pancreas. The body can no longer produce the insulin that it needs.

Type 2 diabetes (85%)

It is the most common type of diabetes. It usually occurs in adults, but it is increasingly seen in children and adolescents. The body is able to produce insulin but either this is not sufficient or the body is unable to respond to its effects.

Projections of the number of individuals aged <20 years Projections of the number of individuals aged <20 years

with type 1 diabetes –2010 to 2050 in the US populationwith type 1 diabetes –2010 to 2050 in the US population

Imperatore et al. Diabetes Care 2012

2010 2050

TOT = 179,388 TOT = 587,488

A global increase of 23%

Projections of the number of individuals aged <20 years Projections of the number of individuals aged <20 years

with type 2 diabetes –2010 to 2050 in the US populationwith type 2 diabetes –2010 to 2050 in the US population

2010 2050

TOT = 22,820 TOT = 84,131

A global increase of 49%

Imperatore et al. Diabetes Care 2012

Prevalence of type 2 diabetes in urban and rural Prevalence of type 2 diabetes in urban and rural

areas in the Arabic-speaking countries, 2011areas in the Arabic-speaking countries, 2011

Badran M and Laher I, International Journal of Endocrinology, 2012

Type 2 diabetes prevalence in South Africa, 2009Type 2 diabetes prevalence in South Africa, 2009

Betram MY et al., Global Health Action 2013

Prevalence of type 2 diabetes in Asian countries in 2013

data source: http://www.idf.org/diabetesatlas/data-visualisations

Abdullah N et al., International Journal of Endocrinology, 2014

Worldwide prevalence of obesityWorldwide prevalence of obesity

Source: World Health Organization (WHO), 2012

Obesity prevalence is high in developing countriesObesity prevalence is high in developing countriesPrevalence of obesity in Arabian countries in adult males and females Prevalence of obesity in Arabian countries in adult males and females

aged between 15 and 100 years, WHO estimates, 2010.aged between 15 and 100 years, WHO estimates, 2010.

Badran M et al., Journal of Obesity, 2011

Obesity prevalence in adults (Italy), 2011Obesity prevalence in adults (Italy), 2011

Valle d’Aosta

8,3%Piemonte9.1%

Umbria11.2%

Liguria8.3%

Toscana

8.7%

Lazio9.2%

Calabria

11.4%

Lombardia

8.9%

Trentino

7.5%Friuli-V.G.

11.8%

Basilicata

13.1%

Puglia12.6%

Abruzzo

8.7%

E.Romagna12.0%

Molise13.5%

Campania

10.9%Sardegna

10.2%

Marche9.6%

Veneto9.9%

Sicilia9.8%

Source: ISTAT 2013

Percentage of US adults who were obese Percentage of US adults who were obese or diagnosed with diabetesor diagnosed with diabetes

Centre for Disease Control and Prevention: National Diabetes Surveillance Systemhttp://apps.nccf.cdc.gov/DDTSTRS/default.aspx. Accessed March 2013

DiabetesDiabetes

Obesity (BMIObesity (BMI 30 KG/m 30 KG/m22))

Obesity prevalence remains high altough no Obesity prevalence remains high altough no

significant changes between 2003-2012 significant changes between 2003-2012

9120 participants in the 2011-2012 nationally representative 9120 participants in the 2011-2012 nationally representative

National Health and Nutrition National Health and Nutrition Examination SurveyExamination Survey

Ogden et al. JAMA 2014

Childhood obesity (2-19 years)

Adult obesity (>20 years)

the prevention windowthe prevention window

Natural history of type 2 diabetesNatural history of type 2 diabetes

Progression of disease

Impaired Glucose Tolerance

Insulin level

Insulin resistance

Hepatic glucose production

Diabetes Diagnosis

Post-prandial glucose

Fasting glucose

β-cell function

Frank Diabetes

4–7 years

Combined impaired fasting glucose (IFG) + Combined impaired fasting glucose (IFG) + impaired glucose tolerance (IGT) confers the impaired glucose tolerance (IGT) confers the

highest risk of diabetes progressionhighest risk of diabetes progression

Metanalysis of total risk of pre-diabetes and diabetes progression, Metanalysis of total risk of pre-diabetes and diabetes progression, based on 21 cohort studies and 9 RCT based on 21 cohort studies and 9 RCT

(follow-up: 1-17 years)(follow-up: 1-17 years)Gerstein HC et al. Diabetes Research and Clinical Practice 2007

Isolated IGT

Isolated IFG

Rel

ati

ve

Ris

k (9

5% C

I)

Prediabetes increases the risk for Prediabetes increases the risk for

cardiovascular events and deathcardiovascular events and death

DECODE study group. Lancet 1999

Relative risk of death is linear by 2h-PG – DECODE studyRelative risk of death is linear by 2h-PG – DECODE study

Pathophysiological defects Pathophysiological defects

in type 2 diabetesin type 2 diabetesβ-Cell

dysfunctionInsulin

resistance

Kahn CR et al. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005

Increased glucose production by liver

Loss of first phase insulin secretion Loss of first phase insulin secretion

in type 2 diabetesin type 2 diabetes

Polonsky KS et al. N Engl J Med, 1988

time

0

200

400

600

800

6.00 10.00 14.00 18.00 22.00 2.00 6.00

breakfast lunch dinner

normal

Type 2 diabetes

Insu

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tio

n(p

mo

l/min

)

--cell mass: decline over diabetes cell mass: decline over diabetes continuumcontinuum

Holman RR et al. Diabetes Res Clin Pract 1998

100

80

60

40

P < 0.0001

Timing to diagnosis Timing to diagnosis (years)(years)

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(%

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0–10 –9 –8 –7 –6 –5 –4 –3 –2 –1 1 2 3 4 5 6

0

1

2 Insu

lin resistan

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sulin

resistance

The United Kingdom Prospective Diabetes Study (UKPDS)The United Kingdom Prospective Diabetes Study (UKPDS)

-cell function-cell functionInsulin resistanceInsulin resistance

HOMA model, diet-treated n = 376

0

0,5

1

1,5

2

2,5

3

NGT IFG Diabetetipo 2

NGT Diabetetipo 2

LADA

ObeseObese LeanLean

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ll m

ass

-c

ell

mas

s

(%)

(%)

-50%

-63%

-cell mass is already impaired at the

diagnosis of type 2 diabetes

Butler AE et al. Diabetes 2003; Leslie RD e Pozzilli P, J Clin Endocrinol Metab 2006

Type 2 diabetes

Type 2 diabetes

Oral hypoglycemic agents targeting the Oral hypoglycemic agents targeting the

pathophysiologic defects in type 2 diabetespathophysiologic defects in type 2 diabetes

Glucose absorption

Hepatic glucoseoverproduction

Impaired insulinsecretion

Insulinresistance

Pancreas

↓Glucose level

Muscle and fatLiver

Metformin TZDsDPP-4 inhibitorsGLP1 analogues

SulfonylureasMeglitinidesDPP-4 inhibitors GLP1 analogues

TZDsMetformin

α-Glucosidase inhibitorsMetformin

Gut

Lifestyle intervention can prevent Lifestyle intervention can prevent

type 2 diabetes developmenttype 2 diabetes development

Trial n Population Follow-up(years) Interventions RR

(95% CI)

Da Qing

577IGT (China)

61. Diet2. Exercise3. Diet & Exercise

0.66 (0.53-0.81)0.56 (0.44-0.70)0.49 (0.33-0.73)

DPS 522 IGT overweight (Finland)

3.2 Diet & Exercise 0.42 (0.3-0.7)

DPP 3,234IGT(USA)

21. Diet & Exercise2. Metformin

0.42 (0.34-0.52)0.69 (0.57-0.83)

IDPP 531IGT(India)

2.5

1. Diet & Exercise2. Metformin3. Metformin + Diet & Exercise

0.72 (0.62-0.80)0.74 (0.65-0.81)0.72 (0.62-0.80)

DPS, Finnish Diabetes Prevention Study; DPP, Diabetes Prevention Program; IDPP, Indian Diabetes Prevention Program

0 1 2 3 4

0

10

20

30

40Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )

Percent developing diabetes

All participants

All participants

Years from randomization

Cum

ulat

ive

inci

denc

e (%

)

Placebo (n=1082)

Metformin (n=1073, p<0.001 vs. Placebo)

Lifestyle (n=1079, p<0.001 vs. Metformin , p<0.001 vs. Placebo)

Incidence of Diabetes in the DPP trial Incidence of Diabetes in the DPP trial

Risk reductionRisk reduction31% by metformin31% by metformin58% by lifestyle58% by lifestyle

The DPP Research Group, NEJM 346:393-403, 2002

Pharmacological intervention to Pharmacological intervention to

prevent type 2 diabetesprevent type 2 diabetes

Trial Subjects(n) Population Drug Follow-up

(years)RR

(95% CI) Weight Adverse events

DPP 3,234 IGR overweight

Metformin(850mg bid) 2.8 0.69

(0.57-0.83) ↓ GI symptoms

STOP-NIDDM 1,419 IGT Acarbose(100mg tid) 3.9 0.75

(0.63-0.90) GI symptoms

Voglibose 1,780 IGT Voglibose(0.2mg tid) 3 0.59

(0.43-0.81) GI symptoms

DREAM 5,269 IGR Rosiglitazone (8mg/day) 3 0.40

(0.35-0.46) ↑ Edema

ACT-NOW 602 IGT Pioglitazone (30-45mg/day) 2.4 0.28

(0.16-0.49) ↑ Edema, Dyslipidemia

XENDOS 3,277 IGT obese Orlistat(120mg tid) 4 0.72

(0.58-0.91) ↓ GI symptoms

ORIGIN 1,456 IGR Glargine 6 0.80*(0.64-1.00) ↑ Hypoglycemia

* Odds Ratio; IGR, Impaired glucose regulation; GI, Gastro-intestinal.

The STOP-NIDDM: AcarboseThe STOP-NIDDM: Acarbose

Acarbose reduced risk of new• Hypertension

>140/90; 5.3% absolute risk reduction (P=0.006)

• Myocardial infarction (P=0.02)

• Any CVD event: CHD, CV death or stroke, CHF, PVD (P=0.03)

Acarbose100 mg TID

n=682

Placebon=686

25% Relative Risk Reduction P=0.0022

Chiasson JL, et al. Lancet. 2002;359(9323): 2072-2077;Chiasson JL, et al. JAMA. 2003;290(4):486-494.

ACT NOW: Pioglitazone

• Pioglitazone reduced risk of type 2 diabetes by 72% vs. placebo (HR 0.28; 95% CI 0.16–0.49 P<0.001)

• Conversion to normal glucose tolerance: 48% of patients with pioglitazone vs 28% with placebo (P<0.001)

• Pioglitazone reduced fasting glucose,2-hour glucose, HbA1c

• Weight gain, edema observed in the pioglitazone arm

DeFronzo RA, et al, for the ACT NOW Study. N Engl J Med. 2011

ORIGIN: Insulin glargine

Gernstein et al. NEJM 2012

Sustained effect of lifestyle intervention

Diabetes Prevention Study3-years post-intervention follow-up

DaQing 20-years post-intervention follow-up study

Li G et al. Lancet 2008Lindstrom J et al. Lancet 2006

DPP: Metformin had sustained effect after drug washout

• Brief (1-2 week) drug washout study at end of Diabetes Prevention Program trial

• After washout, diabetes was more frequently diagnosed in metformin vs. placebo (1.49; 0.93, 2.38; P=0.098)

• DPP primary analysis: metformin decreased diabetes risk by 31%

• Washout: 26% accounted for by pharmacological effect of metformin

• Postwashout: diabetes reduced by 25%

Diabetes Prevention Program Research Group. Diabetes Care. 2003;26:977-980.

Summary of lifestyle/ pharmacological interventions

Lifestyle intervention continues to have an effect; most drugs do not

Study N Intervention Treatment Risk Reduction

DPP IGT 3,324 Metformin 3 years 31%

DREAM IGT 5,269 Rosiglitazone 3 years 60%

STOP-NIDDM IGT 1,429 Acarbose 3 years 21%

ACT NOW IGT ~600 Pioglitazone 3 years 81%

ORIGIN IGR 1,456 Glargine 6 years 20%

Study N Intervention Treatment Risk Reduction

Da Qing IGT 577 Lifestyle 6 years20 years

34% - 69%

Finnish DPS IGT 523 Lifestyle3 years7 years 58%

DPP IGT 3,324 Lifestyle 3 years 58%

Life

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Dietary intake keep increasing…

Grains and fats account for nearly all of the increasein daily calorie consumption since 1970

Source: Food and Agriculture Organization of the United Nations

… while price of food, adjusted for inflation, has dropped

Source: USDA's Economic Research Service

-50%

+30%

-38%

-38%

-29%

-50%

0%

The price of added sugars has dropped significantly more than the price of healthful foods

Taxing unhealthy food and drinks to improve health?

Examples of Health-related food taxes

Mytton et al. BMJ 2012

Junk food taxes might reduce energy intake, weight and insulin levels over time 20 years longitudinal study (CARDIA study) on 5,115 young adults

* and e, P<0.05 Duffey et al. Arch Intern Med 2010

Financial Incentive–Based Approaches for Weight Loss

57 healthy subject 30-70 years, BMI 30-40, were randomized to 3 weight loss plans:

1) Monthly weigh-ins,

2) LOTTERY incentive program: participants played a lottery and received the earnings if they achieved or lost more than the target weight

3) DEPOSIT incentive: participantsinvested their own money, which theylost if they failed to achieve weightgoals.

16 weeks follow-up

The use of economic incentives produced significant weight loss (more than the control group) during the 16 weeks of intervention that was not

fully sustained (Volpp et al. JAMA 2008)

Financial incentives for weight loss: group-based incentives are more effective than

individual incentives

Control groupIndividual-incentive group*

Group-incentive group**

105 obese employers (BMI 30-40) randomized to and followed up to 24 weeks: *INDIVIDUAL INCENTIVE: $100 per person per month for meeting or exceeding weight-loss goals**GROUP INCENTIVE: $500 per month split among participants within groups of 5 who met or exceeded weight-loss goals CONTROL GROUP

Kullgren et al. Ann Intern Med 2013

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ht

fro

m b

asel

ine

(lb

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Week

Peer mentoring and financial incentives for blood glucose control

118 African Americans veterans assinged to the following three groups and followed-up to 6 months:

1) USUAL CARE

2) PEER MENTOR Patients were assigned a mentor who formerly had poor glycemic control but now had good control (HbA1c level 7.5%). The mentor was asked to talk with the patient at least once per week. Peer mentors were matched by race, sex, and age.

3) FINANCIAL INCENTIVES- $100 by decreasing HbA1c by 1% - $200 by decreasing HbA2c by 2% or to an HbA1c 6.5%.

Peer mentorship improved glucose control in a cohort of African American veterans with diabetes. (Long et al. Annals of Int Med 2012)

Call for Action• We must identify patients at highest risk

(prediabetes)

• Modest lifestyle changes are most effective

• Sustain interventions

• Increase opportunities for community programs to support prevention

• Delaying or preventing type 2 diabetes is cost-effective and will help turn the tide on the diabetes epidemic

• “Health-taxes” for improving adherence to healthy lifestyle or reducing calorie intake might be considered

Obesity

A possible approach to tackle the diabetes epidemic

Lifestyle

Genetic background

Normal blood glucose Pre-diabetes Diabetes

Lifestyle intervention

Easy to deliverSustained effectLow cost

Junkfood taxes

“BMI taxes”or

“BMI prize”

“Blood glucose taxes”or

“Blood glucose prize”

Good Adherence

Detect and tackle barriersLow Adherence