Dace Trence, MD April, 2015

Type 1 DM, 2015-

No Longer a Disease of Youth

Dace Trence, MD

April, 2015

Type I Diabetes (Trence), NWGEC Spring 2015 1

Epidemiological Data

Type 2 diabetes mellitus remains dominant formOverall incidence of type 1 diabetes increasing by 2–5% per year worldwide As a result of improved diabetes management, an increased proportion of individuals with type1 diabetes are living into later decades of life

Diabet Med 2006;26:857–86.Lancet 2009;373:2027–2033.International Diabetes Federation: Diabetes Atlas. 5th ed. Brussels, Belgium, International

Diabetes Federation, 2011

Incidence of diabetes in children under age 10 years in Norway, 1925–1995.

Gale EM. Diabetes 51:3353-3361, 2002


Cumulative incidence of diabetes from three U.K. birth cohorts. Progressive left shift in age of onset of the disease

Gale EM. Diabetes 51:3353-3361, 2002

Type 1 diabetes is commonly diagnosed in childhood~ 25% of people with type 1 diabetes are

diagnosed as adults Some even as late as the ninth decade of life

Thunander M, et al Diabetes Res Clin Pract 2008;82:247-255,


Three Year Follow-Up in Kronenberg, Sweden

Thunander M, et al Diabetes Res Clin Pract 2008;82:247-255


Type 1 Diabetes: What have we learned?

Can occur at any age (NOT “juvenile-onset”)Can occur in overweight peopleBest identified using immune and genetic markers

Immune markers: GAD, ICA-512, IAA, ZnT8Genetic markers: high-risk, no-risk and low-risk HLA types

Long pre-clinical period

Normalislet

function

Onsetclinical

diabetes

TIME (months or years)

Genetic risk Environmental Insult

“preclinical period”

Autoimmune attack

Natural History of Type 1 DM


22 y/o: brother type 1 DMserial testing with

glucose load1980-1986

C-peptide

Commonly present early in course of Type 1 In adulthood, better clinical outcomes and can achieve lower A1C levels with less serious hypoglycemia thanwithout detectable C-peptide concentrations

Diabetes 2004 53:250–264.Ann Intern Med 1998;128:517–523,


Predictive Value of Developing Type 1 DM

Diabetes Care. 2012; 35: 1213–1218.

Goals of TreatmentShort Term:

Symptom control-Fatigue, weight loss, polyuria, polydipsiaFrequent infections: Yeast, UTI, skin

Metabolic stability-Diabetic ketoacidosisSensorium changesComa

Long term: Prevent complications

Microvascular: eye, kidney, nerveMacrovascular: CVD


A1C Targets Suggested by Different Organizations

AACE target: A1C <6.5%EASD target: A1C <6.5%ADA target: A1C <7% (general)

A1C <6%* (individual patient)

Optimal target: A1C <6% (normal range)

*As close to normal (<6%) without significant hypoglycemia.ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes, AACE = American Association of Clinical Endccriologists.

Barrier: hypoglycemia!!!!!

Diabetes Complications and Control Trial:

DCCT. NEJM 1993;29:977-86


Intensive Therapy ReducesRisk of Retinopathy and NephropathyDCCT Retinopathy MicroalbuminuriaCumulative

percent progressing

DCCT Research Group. N Engl J Med. 1993;329:977-986

00

6050403020100

-76%P<0.001

605040302010

0 1 2 3 4 5 6 7 8 9

Secondary Intervention-54%P<0.001

302520151050

-34%P<0.04

50403020

100

1 2 34 5 6 7 8

Secondary Intervention

-43%P=0.001

Conventioal treatmentherapyIntensive therapy

Years9

Primary PreventionPrimary Prevention



Therapy and Cardiovascular Complications

N Engl J Med 2005; 353:2643-2653


Swedish Registry 1998-2011: Type 1 DM, mean age 36 at entry

N Engl J Med 2014;371:1972-8


DCCT/EDIC Study mortality data

27 year follow-up dataRelatively few deathsBetter glycemic control protects- “metabolic memory”Most deaths due to CVD, with added risk if smoking, diabetes dx a later age, renal dysfunction

JAMA. 2015;313:45-53.


Risk of Hypoglycemia among Frequently Used Conventional Agents

SU = sulfonylurea.Wright AD, et al. J Diabetes Complicat. 2006;20:395-401 (UKPDS 73).

For All Therapies, the Significance of Differences between Levels Is p<0.0001

Perc

enta

ge o

f Pat

ient

s R

epor

ting

1 H

ypog

lyce

mic

Eve

nt p

er Y

ear (

%)

15

25

35

0

5

DietAlone

0.8% 1.7%

32.6%

10

20

30

7.9%

21.2%

Metformin SU BasalInsulin

only

Basal +BolusInsulin

Hypoglycemia Is Common inPatients Treated with Insulin

Patients aged >15 years reporting hypoglycemia to a general practitioner or specialist in Spain (N=630). BBT = basal-bolus insulin therapy; BT = basal insulin therapy; Other = other insulin regimen (eg, premixed insulin therapy).Orozco-Beltran D, et al. Diabetes. 2013;62(suppl 1):A101 [abstract 397-P].

Freq

uenc

y of

Hyp

ogly

cem

icEp

isod

es, E

vent

s / y

10

100

0.1T1DM

(N=294)

1.0

T2DM BT(N=179)

T2DM BBT(N=95)

T2DM Other(N=62)

0.9

87.9

0.3

18.2

0.3

42.1

0.4

29.6

Severe Hypoglycemia Non-severe Hypoglycemia


Classification of HypoglycemiaTerm Description

Severe hypoglycemia

Assistance required from another person to administer CHO, glucagon, or other resuscitative measureIn the absence of measured plasma glucose, neurological recovery following resuscitative measures is considered sufficient evidence that the event was induced by hypoglycemia

Documentedsymptomatic hypoglycemia

Typical symptoms of hypoglycemia with measured plasma glucose 70 mg/dL

Asymptomatic hypoglycemia No symptoms of hypoglycemia, but measured plasma glucose 70 mg/dL

Probable symptomatic hypoglycemia

Typical symptoms of hypoglycemia, but no measured plasma glucose available

Relative hypoglycemia Typical symptoms of hypoglycemia, with measured plasma glucose > 70 mg/dL

All degrees of hypoglycemia should be considered as serious.CHO, carbohydrateCryer PE, et al. J Clin Endocrinol Metab. 2009;94:709-728.

Asymptomatic HypoglycemiaMay Go Unreported In a cohort of patients

with diabetes, more than 50% had asymptomatic (unrecognized) hypoglycemia, as identified by continuous glucose monitoring1

Other researchers have reported similar findings2,3

Patie

nts

(%)

20

60

70

80

0

All Patientswith Diabetes

55.7

40

Patients with 1 Unrecognized Hypoglycemic Event (%)

Type 1Diabetes

62.5

Type 2Diabetes

46.6

10

50

30

N=70 N=40 N=30

1 Adapted from Chico A, et al. Diabetes Care. 2003;26:1153-1157. 2 Weber KK, et al. Exp Clin EndocrinolDiabetes. 2007;115:491-494. 3 Zick R et al Diab Technol Ther 2007;9:483-492


How Often Does Hypoglycemia Occur in Diabetes?

Daily to about 1/wkFr

eque

ncy

of N

SHE

(%)

20

60

80

0

40

64.5

T1DM

23.5

12

24.9

T2DM

34.940.2

10

50

70

30

1/mo to several times/moOnly a few times/y or very rarely

Wk, week; mo, month; T1DM, type 1 diabetes; T2DM, type 2 diabetes; NSHE, non-severe hypoglycemic events

Survey 409 US patients with T1DM (n = 200) and with T2DM (n = 209)

Brod M, et al. Value Health. 2011;14:665-671.

Hos

pita

lizat

ions

per

100

,000

PY

(No)

1999Year

2009200720052001 2003

100

450

50

300

200

65-74 Years Old

Hyperglycemia (N=279,937)Hypoglycemia (N=404,467)

Review of hospitalizations for hyper, hypoglycemia for 1999-2011 in Medicare populationOlder with T2DM particularly susceptible to hospitalization for hypoglycemiaAs many hospitalizations for hypo as hyperglycemia1 yr post admit mortality rate approx 20%

Hypoglycemia in the over 65 y/o with T2DM

PY = person years.Lipska KJ, et al. JAMA Intern Med. 2014;174(7):1116-24.

2011

100

450

50

300

200

Overall


When Does Hypoglycemia Occur with Diabetes?

1/5 of all nonsevere hypoglycemia occurs nocturnally

30%

50%

20%

Awake and at Work

Awake but Not at Work

During Sleep at Night

Survey 409 US patients with T1DM (N=200) and with T2DM (N=209)Brod M, et al. Value Health. 2011;14:665-671. NSHE, non-severe hypoglycemic

events

Economic Consequences of Hypoglycemia

Retrospective analysis of 536,581 patients with type 2 diabetes from 2004 to 2008 showed hypoglycemia cost over $52 million1

Mea

n C

ost p

er Y

ear (

$)2

6,000

18,000

0Adult without

Hypos

$9,00712,000

Adult withHypos

$14,031

Pts >65 YOwithout Hypos

$11,897

3,000

15,000

9,000

21,000 $20,264

Pts >65 YOwith Hypos

YO, years old1 Quilliam BJ, et al. Am J Manag Care. 2011;17:673-680. 2 Bron M, et al. 71st Scientific Sessions of the ADA; 2011 June 24-28; San Diego, CA; Abstract# 1175-P.


Clinical Consequences of Hypoglycemia

Hospital admissions1

In a prospective study of well-controlled elderly T2DM patients, 25% of hospital admissions for diabetes were for severe hypoglycemia

Increased mortality2

9% in a study of severe sulfonylurea-associated hypoglycemia

Road accidents caused by hypoglycemia3

45 serious events per month1 Greco D, et al. Diab Nutr Metab 2004;17:23-26. 2 Campbell IW. Horm Metab Res Suppl. 1985;15:105-111. 3 Hitchen L. BMJ. 2006;332(7545):812.

COSTHASSLE



Physiologic Insulin Secretion

Breakfast Lunch Dinner

Basal Insulin

Prandial Insulin

Adapted with permission from McCall AL. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002:193-222.

Time (h)

Plas

ma

Insu

lin L

evel

s

24:00 4:0012:00 20:0016:008:004:00


Insulin

Basal: backgroundBolus : prandial or combined with correctionCorrection: with prandial or independent

90% food absorbed

INSU

LIN

EFF

ECT

PrandialInsulin

BasalInsulin

NPH

B L

PrandialInsulin

REG

1960s to 1970s: The Evolution of Physiologic Insulin Replacement


INSU

LIN

EFF

ECT

B L S HS BMEALS

Morning Afternoon Evening Night

REG REG REG

NPH

Physiologic Insulin Replacement

prandial

basal

INSU

LIN

EFF

ECT

B L S HS BMEALS


REGLISPRO (aspart, glulys)

NPH/Lente


INSU

LIN

EFF

ECT

B L S HS BMEALS


Lispro/Aspart /GL Lispro/Aspart/GLInsulin Glargine

Lispro/Aspart/glulys

Insulin Pens

More convenient than traditional vial/syringe Easier to use for those with visual/motor skill impairments Less injection pain (Needles not dulled by insertion into vial before insertion into the skin)Most insurance companies covering insulin pensBut more expensive! (2 X)

Asamoah E. J Diabetes Sci Technol. 2008;2(2):292-296.


INSU

LIN

EFF

ECT

B L S HS BMEALS


Basal Infusion

Bolus Bolus Bolus

CSII with LISPRO/ASPART


Continuous glucose monitoring

Moving to a New Era…

0

50

100

150

200

250

300

350

400

9:00 11:00 13:00 15:00 17:00 19:00 21:00 23:00 1:00 3:00 5:00 7:00 9:00

Time

Glu

cose

(mg/

dL)

Continuous Glucose Monitoring


DexCom SC Glucose Sensor

Slowly Closing the Loop…


1 month CGM: ave 141/ SD64


6 months CGM: 123/49

Week 1 on sensor-augmented pump

Week 2 on sensor-augmented pump

Mean = 162

Mean = 115


HyperglycemiaChronic

microvascular macrovascular

Complications of Diabetes


Diabetic ketoacidosisInfections: urinary, vaginal, skin

Retinopathy:Most common cause blindness in US

15 yrs DM 1, 50% have more severe form DR20 yrs DM 2, on insulin, 20% have PDR

Screening:DM 1, 5 yrs post diagnosis but after pubertyDM 2, yrly, if photos normal, then q 4yrs

unless proteinuria, severe hyperglycemia


Diabetic retinopathyNeovascularizationHemorrhage

Diabetic retinopathyNeovascularization



Hovind P, et al Diabetes Care 2003; 26:1258–1264


Nephropathy:

30-40% DM 1 will develop5-10% DM 2 developProtein in urine earliest markerMicroalbumin (albumin /creatinine ratio)False positives: exercise

UTIlarge protein intakeHTN

Hovind P, et al Diabetes Care 2003; 26:1258–1264



Challenges in the Management ofType 1 Diabetes in Older Adults

Type 1 Diabetes (T1D) Exchange clinic registry reported characteristics of older adults with type 1 diabetes followed in diabetes centers across US 50 to < 65 years (n = 2,066), mean A1C 7.7% (27% had an A1C < 7.0%, 46% had an A1C < 7.5%, and 11% had an A1C 9.0%), mean self-reported blood glucose testing was

5.5/day 65 years of age(n = 683), mean A1C 7.4% (34% A1C <

7.0%, 52% A1C < 7.5%, and 8% had A1C 9.0%)Mean self-reported blood glucose testing 5.6 times daily.

Dhaliwal R et al Diabetes Spectrum 2014; 27,

Greater frequency of self-monitoring of blood glucose (SMBG) associated with lower A1C levels in both those who used an insulin pump vs insulin via injectionsDiabetic ketoacidosis (DKA) was lower with increasing age and was not associated with duration of diabetes.DKA was more likely in those with higher A1C levels and lower socioeconomic status. No relationship between DKA and pump versusinjection use.


HypoglycemiaSevere hypoglycemia, defined as an episode requiring assistance for treatment, has been associated with cardiac abnormalities including arrhythmias and brain damage. Hypoglycemia unawareness or poor awareness are major risk factors for severe and recurrent hypoglycemia in type 1 diabetes and are of particular concern in the elderly because of increased risk of falls, cognitive impairments, and cardiovascular disease. With aging and long duration of diabetes, there isimpairment of counterregulatory hormone releaseConfusion, dizziness, falling, weakness, difficulty withcommunication, and poor coordination and balance may not be recognized as possible symptoms of hypoglycemia

T1D Exchange: 18.6% with diabetes 40 yearsof age (n = 758) self-reported having had a seizure or loss of consciousness in previous 12 months. Duration of DM associated with occurrence of severe hypoglycemia, also lower education status,lower household income, lack of private insurance,and race (greater in non-Hispanic blacks andHispanics than in non-Hispanic whites). Injection users had more severe hypoglycemia than pump users.

Self-reported severe hypoglycemia lowest with mean A1C 7.0–7.5%.


U.K. Hypoglycemia Study

46% prevalence over 12 months of severe hypoglycemia in adults with type 1 DM of > 15 yrs’ duration (mean age 53 years, A1C 7.8%).Severe hypoglycemia more common in presence of

nephropathy, neuropathy, and depression and with the use of nonselective -blockers and alcohol

Recent study of adults 69 yrs (both type 1 and 2 with an A1C > 8%)72 hours of continuous glucose monitoring (CGM), 65% experienced hypoglycemia at least once.

Arch Intern Med 2011;171:362–364,


Challenges specific to older adults:




Additional Concerns:

LiteracyIncome/coverage (donut hole)Comprehension levelDenial of diseaseTechnology averseSocial isolationFear

“Too often we underestimate the power of a touch, a smile, a kind word, a listening ear, an honest compliment, or the smallest act of caring, all of which have the potential to turn a life around.”

Leo Buscaglia


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Dace Trence, MD April, 2015

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