© 2008 © 2010 the continuum of pred: guiding diagnosis & treatment of progression to diabetes...

© 2008© 2010

The Continuum of PreD:

Guiding Diagnosis & Treatment of

Progression to DiabetesAndrea M Girman, MD,

MPHVOMA

27 April 2012

The Continuum of PreD: Guiding Diagnosis & Treatment of Progression to Diabetes

Andrea M. Girman, MD, MPH The following potential conflict of interest relationships are germane

to my presentation:Equipment: None

Speakers Bureau: NoneStock Shareholder: None

Grant/Research Support: NoneConsultant: None

Employment: Genova Diagnostics

Status of FDA devices used for the material being presented: NA/Non-Clinical

Status of off-label use of devices, drugs or other materials that constitute the subject of this presentation:

NA/Non-Clinical

© 2010© 2010 3

Continuum of PreD: Conversation Goals

• Examine the focus on obesity as major identifier of people at risk for Type 2 DM

• Identify an underlying driver of progression to Type 2 Diabetes: Inflammation

• Define the Stages of Pre-Diabetes progression

• Consider Stage-specific Therapeutic Interventions ~ Lifestyle +/- Meds

© 2010© 2010 4

Obesity: Challenging Assumptions

• Many clinicians assume that they can accurately predict patient risk for diabetes based on obesity.

• If this is true, are tests designed to assess risk of diabetes really needed?

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Defining Overweight/Obesity

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Overweight/Obesity Worldwide% Population (2007)

New Zealand 62.6%

United Kingdom 61.0%

Iceland 60.2%

Luxembourg 54.8%

Ireland 51%

Finland 48.9%

Canada 46.8%

Slovak Republic 46.2%

Italy 45.5%

Netherlands 45.5%

Sweden 44.0%

Switzerland 37.3%

© 2010© 2010 7

2000

Obesity Trends* Among U.S. AdultsBRFSS, 1990, 2000, 2010

2010

1990

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

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Rates of CardioMetabolic Syndrome

BMI < 25 BMI 25-30 BMI >30

MEN 30% 51% 71%

WOMEN 21% 43% 65%

TOTAL 26% 46% 68%

© 2010© 2010 9

CDC: Only 40% of the risk of developing diabetes occurs in people who are obese.

How do we find the 60% of people at risk for developing diabetes who are NOT obese?

© 2010© 2010 10

PreD Assessment & Clinical Utility

• Identify patients who are at risk for diabetes & who are not obese

• Define that individual’s stage of progression to Type 2 Diabetes (i.e. Insulin Resistance/Cardio-Metabolic Syndrome)

• Provide stage-specific therapeutic interventions.

© 2010© 2010 11

The Significance of Type 2 Diabetes Mellitus

• According to the CDC, 10% of the US population has diabetes today.

• By the year 2050, the CDC projects that 21-33 % will be diagnosed with diabetes.

• This will lead to a 2-4x increase in health care costs, or approximately $171 billion per year.

© 2010© 2010 13

Type 2 DM Pathophysiology • Initial compensation of IR by increased

pancreatic β-cell insulin secretion– Lifestyle considerations leading to IR

• Insulin drives differentiation of mesenchymal stem cells into pre-adipocytes and adipose tissue

• Concomitant qualitative β-cell dysfunction as cellular cleavage capacity of proinsulin

to insulin exhausted– Added adipogenic effect of proinsulin

© 2010© 2010 14

Type 2 DM Pathophysiology • Increased hormonal secretion & increased

caloric intake = increased production of visceral adipose tissue

• Visceral adipose tissue is metabolically active– Cytokines (adipokines) which negatively

influence IR– Supression of adiponectin secretion by mature

adipose tissue = increased visceral adipose production, increased IR, decreased vasoprotective and anti-atherosclerotic effects

© 2010© 2010 15

Pfutzner A, et al A Biomarker Concept for Assessment of Insulin Resistance , β-Cell Function and Chronic Systemic Inflammation in Type 2 Diabetes Mellitus. Clin Lab 2008; 54:486-490.

© 2010© 2010 16

.

PreD Guide

Inflammation is an underlying driver of the progression to

diabetes.

1 2

0%0%

1. Strongly Agree

2. Agree

3. Disagree

4. Strongly Disagree

Answer

Now Countdown

4

© 2008© 2010

Inflammation:Driving the

Progression 2 Diabetes

© 2010© 2010 20

Inflammation & Chronic Disease

© 2008© 2010

Abdominal

Obesity

DysglycemiaDyslipidemi

aHypertensio

n

Diabetes MellitusHeart Disease

© 2008© 2010

Insulin Resistanc

e

Abdominal

Obesity


aHypertensio

n


© 2008© 2010

Insulin Resistanc

e

Abdominal

Obesity


aHypertensio

n


InflammationInflammation

© 2010© 2010 24

Causes of Inflammation

• Diet– Sugar– Trans & saturated fats– Polyunsaturated omega 6 oils (except GLA)

• Allergens (food & environmental)• Stress• Lack of exercise• Toxins (metals, petrochemicals)• Infections (especially dental/gingivitis)• Obesity & Insulin Resistance

© 2010© 2010 25

Inflammation: A Critical Underlying Driver• Inflammation is a major driver of the

progression to diabetes through each stage.

• “Inflammation causes insulin resistance . . .” – Jerrald M. Olefsky, MD

• The use of multiple inflammatory markers provides greater insight into the effects of inflammation -> one marker for inflammation may not provide a full clinical picture.

© 2010© 2010 26

Markers of Inflammation

• hs-CRP– Acute phase response protein/IR

• Interleukin IL-6– Inflammatory cytokine/abdominal obesity

• Interleukin IL-8– Inflammatory cytokine/abdominal obesity

• Tumor Necrosis Factor Alpha (TNFα)– Inflammatory cytokine/abdominal obesity

• Plasminogen Activator Inhibitor 1 (PAI-1)– Acute phase response protein/visceral obesity

© 2010© 2010 27

Kuller MRFIT1996 CHD deathRidker PHS 1997 MIRidker PHS1997 StrokeTracy CHS/RHPP1997 CHDRidker PHS1998,2001 PADRidker WHS 1998,2000,2002 CVDKoenig MONICA1999 CHDRoivainen HELSINKI 2000 CHDMendall CAERPHILLY 2000 CHDDanesh BRITAIN 2000 CHDGussekloo LEIDEN 2001 Fatal StrokeLowe SPEEDWELL 2001 CHDPackard WOSCOPS 2001 CV EventsRidker AFCAPS 2001 CV EventsRost FHS 2001 StrokePradhan WHI 2002 MI, CVD death Albert PHS 2002 Sudden Death

0 1.0 2.0 3.0 4.0 5.0 6.0Relative Risk (upper versus lower quartile)

Ridker PM. Circulation 2003;107:363-369

hs-CRP: Risk Factor for CVD

© 2010© 2010 28

C-Reactive Protein• Marker of inflammation, infection and injury

– Aspirin’s reduction of MI risk appears to be related to CRP levels

– CRP activates complement which injures the inner layer of blood vessels constriction of vessels, arrhythmia

• Strong predictor of the risk of future MIJUPITER Study – November, 2008• 49% decrease in CAD end-points• 20% decrease in ‘all cause’ mortality• ‘40% of participants had insulin resistance’

© 2010© 2010 29

Inflammation & Risk of T2DM

© 2008© 2010

Stages ofProgression 2

Diabetes

© 2010© 2010 32

Progression of Pre-Diabetes

© 2010© 2010 33

Optimal Function

Intervention = Maintenance of healthy diet & lifestyle

© 2010© 2010 34

Stage 1: Early Insulin Resistance

© 2010© 2010 35

Adiponectin

• Protective adipose-derived protein

• Plays an important role in regulating glucose and lipid metabolism–Moderates fat tissue–Promotes insulin sensitivity– Is inversely related to glucose & insulin–Decreases hepatic glucose & lipid production–Protects against atherosclerosis by

suppressing vascular inflammation (anti-inflammatory)

© 2010© 2010 36

Low Adiponectin associated with:

• Insulin resistance

• Glucose intolerance

• Dyslipidemia

• Increased risk of vascular injury &

atherosclerosis

• Increased risk of diabetes mellitus

• Inflammation

© 2010© 2010 37

• Pattern recognition:– LOW Adiponectin– ‘Normal’ Glucose, HbA1C, Insulin, and Proinsulin– Normal or slightly high HOMA-IR

• Treat with diet, lifestyle, supplementation.

Stage 1: Early Insulin Resistance

• “Normal” fasting blood sugar = < 100 mg/dL

• Blood sugar >87 mg/dL = progressive increase of type 2 DM.

• Blood sugar < 81 mg/dL = low risk of DM NEJM 2005;353:1454-62.

Medication considerationsSupplement considerations

Reduce excess weight;

Increase physical activity;

Reduce stress ;

Treat inflammatory disorders (TNF-α

inhibits adiponectin)

Meds are not usually needed at this stage if

dietary and lifestyle

measures are followed.

Stage 1 of metabolic dysglycemia represents early insulin resistance, with adequate pancreatic beta cell compensation to maintain normal glucose. Insulin level may be normal or high. Adiponectin, which provides protection against insulin resistance, diabetes and cardiovascular disease, is typically low. Dyslipidemia may or may not be present, including elevated triglycerides and LDL-C, and/or low HDL-C. At this stage, dietary and lifestyle measures are usually adequate for improving insulin sensitivity and preventing progression to Stage 2.

Nutritional: B vitamins, vitamin D, biotin,

magnesium, zinc, chromium, alpha-lipoic acid & other

antioxidants, fish oils;

Herbal: Green tea, cinnamon, fenugreek;

Hormonal: DHEA (if low)

Stage 1 – Early Insulin Resistance

Lifestyle considerations Dietary considerations

Minimize sugar and refined carbohydrates, fructose, soft drinks, and saturated fats. Avoid trans fats.

Emphasize a low-saturated fat, Mediterranean-type diet (complex

carbohydrates, fresh fruits and vegetables, nuts & other

monounsaturates, foods rich in omega-3 fats, such as cold water

fish).

Treatment recommendations for Stage 1:

© 2010© 2010 39

Stage 2: Elevated Fasting Insulin

© 2010© 2010 40

• Pattern recognition:– LOW Adiponectin– HIGH or high-normal HOMA-IR – HIGH Insulin, but normal Proinsulin– Mildly elevated glucose and/or HbA1C

• Fasting glucose 100-126 mg/dl and/or 2-hr pp glucose 140-200 mg/dl and/or HbA1C 5.5-6.0%

• Usually due to a combination of insulin resistance & early beta-cell impairment

• 24 million cases of type 2 DM in the U.S., but 57 million cases of ‘pre-diabetes’

• Treat with diet, lifestyle, supplementation, possible pharmacotherapy.

Stage 2: Elevated Fasting Insulin

Stage 2 – Elevated Fasting Insulin

Treatment recommendations for Stage 2

Stage 2 represents impaired glucose tolerance, usually due to combination of insulin resistance and early pancreatic beta-cell impairment. In most cases of insulin resistance, compensatory increased insulin secretion is sufficient to prevent hyperglycemia. However, in combination with beta-cell dysfunction, hyperglycemia can develop.1

Adiponectin is usually low, and glucose and/or HbA1C are elevated, although not yet to a diabetic level. Insulin is usually elevated. Dyslipidemia may or may not be present, including elevated triglycerides and LDL-C, and/or low HDL-C. At this stage, diet and lifestyle measures, along with supplementation can help improve insulin sensitivity, restore proper glucose regulation, and prevent progression to diabetes (Stage 3).


Insulin sensitizers: Biguanides (e.g.,

metformin); Dual PPAR agonists (e.g., aleglitazar);

Inhibitors of starch digestion: α-Glucosidase inhibitors (e.g., acarbose);Improvement of HbA1C:

DPP-4 Inhibitors (e.g., sitagliptin) or Pramlintide


Reduce weight;

Increase physical activity (esp. aerobic);

Reduce stress;

Treat any inflammatory disorders

Avoid sugar and refined carbohydrates, fructose, soft

drinks, alcohol, and trans fats. Minimize saturated fats.

Emphasize a high-fiber, low-saturated fat, Mediterranean-type

diet (e.g., legumes and whole grains, fresh fruits and

vegetables, nuts & other monounsaturates, foods rich in

omega-3 fats, such as cold water fish).

Nutritional: B vitamins, vitamin D, biotin, Mg, Zn, Cr, α-lipoic acid & other antioxidants, flavonoids

(e.g., grape seed extract), fish oils, fiber supplement;

Herbal: Gymnema sylvestre, green tea,

cinnamon, fenugreek;Hormonal: DHEA (if low)

© 2010© 2010 43

Proinsulin• Produced by pancreatic β-cells

• Precursor to insulin

• Serves as a marker of later stage β-cell dysfunction & insulin resistance

• Has been used in trials (proinsulin/insulin ratio) to describe improved β-cell function resulting from β-cell sensitizing meds (ie, biguanides/Metformin, TZDs/Actose)

© 2010© 2010 44

Proinsulin

• β-cell dysfunction impaired cleavage of proinsulin to insulin levels of proinsulin increase

• Higher circulating levels of circulating proinsulin (compared to insulin) indicate advancing β-cell dysfunction & increased risk or presence of diabetes.

• With advancing pre-diabetes, levels of both insulin & proinsulin decline.

© 2010© 2010 45

Stage 3: Elevated Proinsulin

• Pattern recognition:– LOW Adiponectin– HIGH Insulin & Elevated Proinsulin– HIGH HOMA-IR – HIGH Glucose & HbA1C

May or may not meet ADA definition for Type 2 Diabetes Mellitus – Fasting Glucose > 125 mg/dL– HgbA1c > 6.5%

• Treat with diet, lifestyle, supplementation, and pharmacotherapy.

Stage 3 – Elevated Pro-Insulin

Treatment recommendations for Stage 3

Stage 3 represents the development of diabetes, with insulin resistance and progressive pancreatic beta-cell impairment. Beta-cell dysfunction can result from glucose toxicity, inflammatory cytokines, oxidative stress, and/or lipotoxicity in the presence of excess glucose.1,2

Glucose and HbA1C are significantly elevated, and insulin may or may not be elevated, depending on beta-cell capacity to produce adequate insulin. Sequential measurements can help reveal the degree of beta-cell dysfunction; declining insulin along with increasing proinsulin signifies late-stage impairment. The most important therapeutic goal at this stage is to normalize and maintain normal blood glucose levels.3

At this stage, a comprehensive approach is essential, including diet and lifestyle measures, supplementation, and targeted pharmaceuticals, based on the degree of beta-cell impairment.


Insulin sensitizers: Thiazolidinediones (e.g., pioglitazone); Biguanides (e.g.,

metformin); Dual PPAR agonists (e.g., aleglitazar); Inhibitors of starch

digestion: α-Glucosidase inhibitors (e.g., acarbose); Improvement of

HbA1C: DPP-4 Inhibitors (e.g., sitagliptin) or Pramlintide; AGE

Inhibitor: Aminoguanidine; Insulin secretagogues: Sulfonylureas (e.g.,

glipizide); Meglitinides; exanatide; Insulin & K channel openers


Reduce weight;

Increase physical

activity (esp. aerobic);Reduce stress;

Treat any inflammatory

disorders

Avoid sugar and refined carbohydrates, fructose, soft

drinks, alcohol, and trans fats. Minimize saturated fats.

Emphasize a high-fiber, low-saturated fat, Mediterranean-type diet (e.g., legumes and whole grains, fresh fruits and

veggies, nuts & other monounsaturates, foods rich in

omega-3 fats, such as cold water fish).

Nutritional: B vitamins (esp. niacinamide, B6, B12, folate),

vitamin D, biotin, Mg, Zn, Cr, V, antioxidants (e.g., NAC,

vitamins C, E, α-lipoic acid, Se), flavonoids (e.g., grape

seed, bilberry), fish oils, fiber supplement, carnosine;

Herbal: Gymnema, green tea, cinnamon, fenugreek, maitake,

American or Panax ginseng, rehmannia, scutellaria

© 2010© 2010 49

Hemoglobin A1c (HbA1c)

• Measures the amount of hemoglobin in a red blood cell (RBC) that has been glycated by excess glucose.

• Reflects average glucose concentration

during the previous 3 month period ~ the life cycle of the RBC.

© 2010© 2010 50

HOMA-IR

• Homeostatic Model Assessment- Insulin Resistance

• Calculation based on plasma levels of:– Fasting Glucose & Insulin– Non-invasive, mathematical estimate insulin

resistance

© 2010© 2010 51

C-Peptide

• C-peptide is produced when proinsulin is cleaved to form insulin and C-peptide.

• Increased levels of C-peptide reflect insulin resistance.

© 2010© 2010 53

Leptin

• Leptin is an adipocyte-derived hormone that regulates appetite.

• In a healthy body, overeating induces leptin production which suppresses appetite and controls weight gain.

• Leptin is protective against obesity.

© 2010© 2010 54

Elevation of Leptin

• Indicates leptin resistance (interference with leptin signaling)

• Associated with:– High BMI & abdominal obesity– Pancreatic beta-cell damage– High triglycerides & Low HDL-C

© 2010© 2010 58

Key Points on Progression to Diabetes

• Can be prevented

• Can be reversed

• Can be treated effectively

• Metabolic processes may be present when the patient is not yet symptomatic.

© 2010© 2010 59

Obesity: Final Considerations

• Obesity remains a major clinical concern. Insulin resistance is a major cause of obesity (at least 70%).

• Diabetes Prevention Program trial showed 58% reduction in incidence of T2DM with lifestyle modifications.

• 5-10% reduction in body weight improves insulin sensitivity, lipid profiles, endothelial function, reduces thrombosis and inflammatory markers.

• There is a 3-fold increase in the odds that a patient will attempt weight loss if it is recommended by a trusted health care professional.

© 2008© 2010

The Continuum of PreD:

Guiding Diagnosis & Treatment of

Progression to DiabetesAndrea M Girman, MD,

MPHPAFP

9 March 2012

© 2008 © 2010 the continuum of pred: guiding diagnosis & treatment of progression to diabetes...

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