Diabetes Management Today - api.ning.comapi.ning.com/files/-*rf1dO92wxkeN5UxCxYXFnwTAcCdyV3tJ3uUQ3rL…Minnesota Department of Family Practice ... Describe priorities of care for adults

©2015 International Diabetes Center

Diabetes Management Today

Gregg Simonson, PhDDirector, Professional Training and Consulting International Diabetes Center; Adjunct Assistant Professor, University of Minnesota Department of Family Practice

Overview

Discuss diabetes epidemiology, cost classifications, and diagnosis

Describe the pathophysiology and natural history of type 1 diabetes, gestational diabetes and type 2 diabetes

Describe priorities of care for adults with diabetes


Epidemiology of Diabetes

29.1 million people in U.S. have diabetes (2012)

– 9.3% of U.S. population

1.7 million new cases diagnosed in 2012

1 in 3 children will develop diabetes

7th leading cause of death

Type 1: ~1,300,000 GDM: ~250,000

Undiagnosed~8.1 millionType 2: ~19.5 million

National Diabetes Statistics Report, 2014

www.cdc.gov/diabetes

County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years: United States 2009Diabetes by County in 2011

Age-adjusted percent

0 - 6.3

6.4 - 7.5

7.6 - 8.8

8.9 - 10.5

> 10.6


Inpatient($76.0 billion)50%

Diabetes Medications and Supplies ($21.6 billion))

Nursing Home, HomeHealth and Hospice($19.2 billion)

Medications forComplications($31.7 billion)

Outpatient: Office Visits, ER, Podiatry ($27.3 billion)

Estimated Economic Cost of Diabetes in the United States for 2012 Total cost of diagnosed diabetes is $245 billion; includes $176

billion direct medical costs and $69 billion in reduced productivity 13% of all U.S. healthcare dollars attributed to diabetes

American Diabetes Association. Diab Care 2013; 36:1033-1046.

2%

11.5%

43.1%18.1%

15.5%

12.3%

11.0%

Distribution of Direct Medical Costs

Diabetes = siphon or flow, Mellitus = sweet

Chronic disorder of carbohydrate metabolism

Hyperglycemia and glycosuria

Defects in insulin secretion, action or both

Chronic hyperglycemia results in complications: eyes, kidneys, heart nerves and blood vessels

Definition and Description

ADA, Clinical Practice Recommendations,Diabetes Care 37:Suppl.1, 2014


Criteria for Diagnosis of Diabetes

Must be confirmed on subsequent day unless unequivocal symptoms of hyperglycemia

No “gold standard” but A1C has advantage of preanalytical stability, less variability with stress or illness, and convenience of not requiring fasting

A1C (lab only) >6.5 %

Fasting Plasma Glucose

>126 mg/dL

Random Plasma Glucose

>200 mg/dL and symptoms (polyuria, polydipsia, weight loss)

2-hour OGTT >200 mg/dL

ADA Clinical Practice Recommendations 2015 Suppl.1; ADA , EASD, IDF International

Expert Committee Report on A1C for Diagnosis of Diabetes.

Blood Glucose and A1C Levels

Fasting

Diabetes>126 mg/dL

Normal70-99 mg/dL

Impaired fasting glucose

100-125 mg/dL

Diabetes>200 mg/dL

Normal<140 mg/dL

Impaired glucosetolerance

140-199 mg/dL

OGTT

Diabetes>6.5%

Normal<5.7%???

High risk for diabetes5.7-6.4%

A1C

ADA Clinical Practice Recommendations 2014; Suppl.1; ADA , EASD, IDF International

Expert Committee Report on A1C for Diagnosis of Diabetes; National Diabetes Statistics Report, 2014

Prediabetes(86 million)

“IncreasedRisk for

Diabetes”


Type 1 Diabetes

What Autoimmune destruction of the pancreatic beta cells

Genetic Predisposition

50% concordance in identical twins

Environmental Triggers

Virus? Cows milk allergy?

Symptoms Increased thirst, urination, appetite; unexplained weight loss

Ketones Usually positive; ketoacidosis

Age Usually < 30 years old; peaks at adolescence

Routine Screening

Not recommended

Natural History of Type 1 Diabetes

Time (Age Dependent)

Glu

cose

(m

g/d

L)

Rel

ativ

e F

un

ctio

n

-4 -2 0 2 4 6 8 10

50

100

150

200

250

300

350

Insulin level

0

25

75

100

125

-6

Post-meal glucose

Fasting glucose

50

Autoimmune B cell destruction begins

Islet cell antibodies appear

Genetic backgroundat risk for type 1 diabetes

© 2014 International Diabetes Center, Minneapolis, MN


Diabetes Control and Complications TrialIntensive Insulin Therapy in Type 1 Diabetes

DCCT Study Group. N Engl J Med 329:977, 1993.

“Lowering blood glucose significantly reduced the risk of complications.”

Sustained retinopathy 63%

Laser therapy 54%

Microalbuminuria 39%

Proteinuria 54%

Neuropathy 60%

Diabetes Control and Complication Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications Study (EDIC)

Nathan for DCCT/EDIC Research Group. Diab Care 2014;37:9-16.

(eAG 215 mg/dL)

(eAG 160 mg/dL) (eAG 183 mg/dL)

(eAG 183 mg/dL)


Summary of Risk Reduction in DCCT and EDIC

Nathan for DCCT/EDIC Research Group. Diab Care 2014;37:9-16.

Gestational Diabetes

Cause Insulin resistance and insulin deficiency

Genetic

Predisposition

High

Environmental

Factors

Over nutrition, obesity, inactivity

Symptoms Usually none, rarely increased urination thirst,

and appetite

Ketones Usually negative, under-eating may cause ketone

production (starvation ketosis)

Age Risk increases with age

Routine

Screening

ADA recommends universal screening between

24-28 weeks of gestation with 75 gram OGTT

(FPG ≥92 mg/dL; 1 hr ≥180 mg/dL; 2 hr ≥153 mg/dL)


Definition of GDM

“Gestational diabetes is defined as glucose intolerance of variable severity with onset or first recognition during pregnancy”

First through Fifth International GDM Conference

Gestational Diabetes: Caring for Yourself and Your Baby, IDC Publishing

Insulin Resistance

Relative Insulin Deficiency

Pathophysiology of GDM


Type 2 Diabetes

Cause Insulin resistance and insulin deficiency

Genetic Predisposition

High, 80-90% concordance in identical twins

Environmental Factors

Over nutrition, obesity, inactivity

Symptoms Often none; fatigue; dry/itchy skin; urinary/vaginal infections; blurred vision

Ketones Usually negative

Age Adult, adolescents, and children

Routine Screening

>45 yrs of age (especially W. BMI >25 kg/m2)<45 yrs of age, overweight plus other risk factorsEvery 3 years

Risk Factors for Type 2 Diabetes

Overweight (BMI >25 mg/m2)

Family history (1st degree relative)

Physical inactivity

Race/ethnicity: Native American, African American, Latino, Asian American and Pacific Islanders

Prediabetes (A1C 5.7-6.4%, FPG 100-125 mg/dL)

Hypertension >140/90 mmHg in adults

HDL <35 mg/dL and/or triglycerides >250 mg/dL

History of CVD

History of GDM or delivery of baby >9 pounds

Polycystic ovary syndrome

Acanthosis nigricans

ADA Standards of Care. Diabetes Care, 2014; Suppl.1


United Kingdom Prospective Diabetes Study (UKPDS)

02468

1012

1

2

3

4

A1C

BP

Mic

ro-

and

Mac

rova

scu

lar

Co

mp

licat

ion

s R

isk

Based on:UKPDS 35: Lancet. 1998, 352:837-53.UKPDS 38: BMJ 317, 703-13, 1998.UKPDS 32: BMJ 316:823-28, 1998.

Overall Results

The Ominous Octet: Pathophysiology of Type 2 Diabetes

Adipose Muscle

GI TractLiver

↑Glucose Production

Pancreatic -Cells

↑Glucagon

Kidney

↑Glucose Reabsorption↓Glucose Uptake

↑FFA Release

Brain

Neurotransmitter Dysfunction

Decreased Incretin Effect

Pancreatic -Cells

↓Insulin

DeFronzo Diabetes 2009; 58:773-795.


Natural History of Type 2 Diabetes

Years

Glu

cose

(m

g/d

L)

Rel

ativ

e F

un

ctio

n

-10 -5 0 5 10 15 20 25 30

50

100

150

200

250

300

350

Insulin resistance

Insulin level

Fasting glucose

Post-meal glucose

OnsetDiabetes

OnsetDiabetes

Pre-diabetesmetabolic syndrome

0

50

100

150

200

250

-15

Incretin action

Adapted from: UKPDS 33: Lancet 1998; 352, 837-853 ; DeFronzo RA. Diabetes. 37:667, 1988; Saltiel J. Diabetes. 45:1661-1669, 1996. Robertson RP. Diabetes. 43:1085, 1994; Tokuyama Y. Diabetes 44:1447, 1995. Polonsky KS. N Engl J Med 1996;334:777.

What is the relationship between gaining weight and developing insulin resistance?


Role of Obesity in Development of Insulin Resistance

Central obesity is critical factor:

Waist to hip ratio >1

Waist >40 inches in men

Waist >35 inches in women

Abdominal adipose tissue is more metabolically active than subcutaneous fat.

Increased release of FFA, TNF-leading to insulin resistance.

FFA TNF- Resistin

*HOMA = homeostasis model assessment; IGT = impaired glucose tolerance.Dashed line shows extrapolation forward and backward from years 0 to 6 based on HOMA data from UKPDS.Lebovitz. Diabetes Rev. 1999, 7:139-53.UKPDS Group. UKPDS 16 Diabetes 1995, 44:1249-58.

Loss of first-phase insulin secretion

-CellFunction*

(%)

Postprandialhyperglycemia

IGT Type 2diabetesphase I Type 2

diabetesphase II

Type 2 diabetesphase III25

100

75

0

50

-12 -10 -6 -2 0 2 6 10 14

Years from Diagnosis

Relative Insulin DeficiencyDecline In -Cell Function


What is an incretin?

A substance released by the gut in response to food that stimulates insulin secretion

Intestine Secretion Insulin = Incretin

Possible candidates: amino acids, lipids, hormones, peptides (proteins)

Currently two well-described incretins– Glucagon-like peptide-1 (GLP-1)

– Glucose-dependent insulinotropic peptide (GIP)

Incretin Action: Role of Glucagon Like Peptide -1 (GLP-1)Incretin Action: Role of Glucagon Like Peptide -1 (GLP-1)

Ahren B Curr Diab Rep 2003; 3:365-372.Baggio LL and Drucker DJ. Gastroenterology 2007; 132:2131-2157.

STOMACH Slows gastric emptying

CNS Effects: Promotes satiety and reduction of appetite

LIVERLess glucagon = less

hepatic glucose output

ALPHA CELLDecreases post-meal

glucagon secretion

BETA CELLIncreases insulinsecretion


Old School Thinking = GLP-1 Levels Decline in Prediabetes and Type 2 Diabetes

Toft-Nielsen M, et al., J Clin Endocrinol Metab 2001; 86:3717–3723.

* P <0.05 between T2DM and NGT group.

20

15

10

5

00 60 120 180 240

Time (min)

MeanGLP-1 (pmol/L)

* * * **

**

*

NGT subjectsPrediabetes subjects

T2DM patients

Meal

New School Thinking = GLP-1 Secretion Same in Type 2 Diabetes vs. Controls

Meta-analysis of 9 studies

Overall no significant decline in nutrient stimulated GLP-1 secretion

GLP-1 response maybe blunted due to “GLP-1 resistance” or hyperglycemia mediated down regulation of GLP-1 receptors

Nauck MA, et al., Diabetologia 2011; 54:10-18;

Calanna et al. Diabetologia 2013; 56:965-972.


DiMarchi et al., Peptides-Chemistry and Biology 1992:26-28.Howey et al., Diabetes 1994;43:396-402.

Insulin Processing

B-chain

A-chainC-peptide

Proinsulin

1 21

S S

SS

SS

1 30

Mature Insulin C-peptide

+

Endopeptidase

Endopeptidase

Insulin supplied in vial, cartridge or pump

Nauck MA, et al., J Clin Endocrinol Metab 1986; 63:492–498.

Incretin EffectBeta-cell response to isoglycemic glucose challenge

Pla

sma

glu

cose

(m

g/d

L)

0 60 120 180

Time (min)

Incretin effect200

100

0

*

*

*

*

**

*

Oral glucose (50 g)or isoglycemic infusion

IV glucoseOral glucose

C-p

epti

de

(nm

ol/L

)

0 60 120 180

0.0

0.5

1.0

1.5

2.0

Time (min)


Time, minIR

In

sulin

, m

U/L n

mo

l/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

Incretin Effect in Subjects without and with Type 2 Diabetes

Control Subjects (n=8)

Patients with Type 2 Diabetes (n=14)

Time, min

IR I

nsu

lin,

mU

/L nm

ol / L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

Oral glucose load Intravenous (IV) glucose infusion

Incretin Effect

Nauck M et al., Diabetologia 1986; 29:46–52.

Priorities of Care for Adults with Diabetes

Macrovascular ComplicationsMacrovascular ComplicationsASA, tobacco, ACEI/ARB, statin

© 2015 International Diabetes Center.

Diagnosis–PreventionDx A1C ≥6.5%, fasting glucose ≥126 casual ≥ 200 + symptoms

prevent pre-diabetes (IFG-IGT) & metabolic syndrome

Self-Management Knowledge and SkillMonitoring Medication Problem solving Food plan & nutritionRisk reduction Living & coping Physical activity

Hemoglobin A1C Target < 7.0%

SMBGPre 70-130 mg/dL

Post <180 mg/dL(~ 50% of readings)

Blood Pressure(every visit)

Dx and Rx < 140/90

Annual Lipid Profile

LDL < 100HDL > 40

Trigs < 150

DM + CVDLDL < 70

Annual ScreeningNephropathy

Microalbumin screeningCalculated GFR

RetinopathyDilated retinal exam

NeuropathyNeuro and foot exam

Sexual health

Hospital careFoot care

Dental careImmunizations

Glucose HypertensionLipids MicrovascularcomplicationsMicrovascularcomplications

Other essentialsOther essentialsof care

?


Glycemic Targets for Type 2 Diabetes

ADA and IDC

A1C <7%*

Fasting and Premeal 80 - 130 mg/dL (ADA)

70 - 130 mg/dL (IDC)

1-2 Hour Postmeal <180 mg/dL**

* A1C goals should be individualized** Note: 2 hour postmeal value should be no more than 40 mg/dLabove premeal value

ADA Standards of Medical Care. Diab Care 2015; 38 Supplement 1


Mean Glucose Levels for Specified A1C

ADA Standards of Medical Care. Diab Care 2015; 38 Supplement 1; Wei et al Diab Care 2014; 37:1048-1051; Nathan et al Diab Care 2008; 31:381-385.

Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials

Study Microvasc CVD Mortality

UKPDS DCCT / EDIC*

ACCORD ADVANCE

VADT

ORIGIN Long Term Follow‐up Initial Trial * in T1DMAdapted Kendall et al. IDC 2009


Inzucchi et al. Diad Care 2015;38:140-149

Add Sulfonylurea(Glimepiride or Glipizide XL)Risk of hypoglycemia Risk of weight gainRapid glucose lowering Long history of use Lowest cost

Add DPP-4 Inhibitor

No hypoglycemia Weight neutralWell tolerated, simple oral dosingHigher cost

Add GLP-1 Agonist(Exenatide, Exenatide XR, Liraglutide, or Albiglutide)

Weight loss, no hypoglycemiaGI side effects – nauseaInjectable (pen)Higher cost

Add Thiazolidinedione(Pioglitazone)

No hypoglycemia Weight gain, edema, CHF, long-term use associated with bone fracture and bladder cancerHigher cost

Titrate to clinically effective dose Advance if not at target in 3 months

Two-Drug Therapy

Incretin DefectInsulin Deficiency Insulin Resistance

© 2014 International Diabetes Center at Park Nicolletinternationaldiabetescenter.com • 1-888-637-2675

Advance if not at target in 3 monthsTitrate to clinically effective dose

Three-Drug Therapy

Add Background Insulin or TZD or SUAdd Background Insulin orTZD, DPP-4, GLP-1

Self-Management• Refer for diabetes education• Monitor BG, food and activity;

titrate medications

Medical Nutrition and Activity Therapy• May lower A1C 1-2%• Refer to Registered Dietitian• Walk 30 min., 5 days/wk, plus some resistance training

Glycemic Targets Premeal 70-130 mg/dL, Postmeal <180 mg/dL A1C <7%†

Emotional Health • Psychosocial support / motivation • Assess for anxiety and/or depression

Advance/initiate drug treatment if not at target

Metformin If not tolerated or if contraindicated select initialtherapy from TWO-DRUG THERAPY below

At Presentationand Ongoing

A1C 7-8.9%FPG 150-200 mg/dL

RPG 200-300 mg/dL

(Strongly consider metformin if A1C ≥6.5%)

A1C 9-11%FPG 201-300 mg/dL

RPG 301-350 mg/dL

Background & Mealtime (main meal) + Noninsulin Agent(s)*

Background & Mealtime (all meals) + Noninsulin Agent(s)*

Premixed Insulin + Noninsulin Agent(s)*

Multi-Dose Insulin Therapy

† Individualize A1C target: consider A1C <8% for those with major medical comorbidities, hypoglycemia unawareness, frail elderly, or those whose therapy has been significantly intensified without seeing an improvement in A1C; consider lower A1C (closer to 6%) for recently diagnosed patients. * Discontinue sulfonylureas; recommend adding or maintaining metformin; consider maintaining DPP-4 inhibitor or GLP-1 agonist if positive response to drug; discontinue thiazolidinedione in most cases.

Add Background Insulin orSU, DPP-4, GLP-1A1C >11%

FPG >300 mg/dL

RPG >350 mg/dL

Start Insulin (Multi-Dose Insulin Therapy preferred)

IDC Type 2 Diabetes Glycemic Control Algorithm

Advance if not at target in 3 monthsTitrate to clinically effective dose

(Sitagliptin, Saxagliptin, Linagliptin or Alogliptin)

Documents

Diabetes Management Today - api.ning.comapi.ning.com/files/-*rf1dO92wxkeN5UxCxYXFnwTAcCdyV3tJ3uUQ3rL…Minnesota Department of Family Practice ... Describe priorities of care for adults