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
bet
es P
reva
len
ce (
%)
20
16
128
4
20
16
128
4
20
16
128
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
Dia
bet
es P
reva
len
ce (
%)
20
16
128
4
20
16
128
4
20
16
128
4
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
lin s
ecre
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)
Bet
a ce
ll f
un
ctio
nB
eta
cell
fu
nct
ion
(%
) (
%)
20
0–10 –9 –8 –7 –6 –5 –4 –3 –2 –1 1 2 3 4 5 6
0
1
2 Insu
lin resistan
ceIn
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
-ce
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
styl
ePh
arm
acol
ogic
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
Ch
ang
e i
n w
eig
ht
fro
m b
asel
ine
(lb
)
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