Evidence‐based Synthesis Progr

(ESP)

Predictors and Consequences of Se

Hypoglycemia Hypoglycemia in Adults with Diabe

Diabe

A S t ys ematic R i ev ew of the E id v ence

Hanna E. Bloomfi ld e , MD, MPH

Staff Physician

Minneapolis VA H th ea Care S t ys em

June 25,2012
Evidence‐based Synthesis Progr

(ESP)

Acknowledgements

Co‐Authors/Collaborators Expert Panel/Reviewers

o Nancy Greer, PhD o David C. Aron, MD, 

o David Newman, MD o Stephen Davis, MB

o Timothy Wilt, MD,MPH o William Duckworth, 

o Devan Kansagara, 

o Debbie Khachikian Khachikian, o Leonard Pogach, Mo Matthew Riddle, MD 
Evidence‐based Synthesis Progr

(ESP)

Disclosure

This report is based on research research conducted conducted by the Evidence Evidence‐based 

Program (ESP) Center located at the Minneapolis VA HealthCare Sy

Minneapolis Minnesota funded by the Department of Veterans Aff

Health Administration Administration, Office of Research Research and Development Development, Qualit

Qualit

Enhancement Research Initiative. The findings and conclusions in tare those of the author(s) who are responsible for its contents; the 

conclusions conclusions do not necessarily necessarily represent represent the views of the Departm

Departm

Affairs or the United States government. Therefore, no statement 

should be construed as an official position of the Department of Ve

No investigators estigators have any affiliations affiliations or financial financial involvement (e.g., 

consultancies, honoraria, stock ownership or options, expert testimpatents received or pending, or royalties) that conflict with materia

the report.
Evidence‐based Synthesis Progr

(ESP)

VA Evidence‐based Synthesis (ESP)

Program Overview

VA E id b d S h i (ESP)

• Sponsored by VA Office of Research & Development, Quality 

Research Initiative (QUERI).

• Established Established to provide provide timely and accurate accurate syntheses/reviews syntheses/reviews 

topics identified by VA clinicians, managers and policy‐maker

work to improve the health and healthcare of Veterans.

• Builds on staff and expertise already in place at the Evidence‐

Practice Centers (EPC) designated by AHRQ. Four of these EP

ESP Centers:

o Durham VA Medical Center; VA Greater Los Angeles Healt

System; Portland VA Medical Center; and Minneapolis VA 

Center.
Evidence‐based Synthesis Progr

(ESP)

• Provides evidence syntheses on important clinical practice to

to Veterans, and these reports help:

o develop cli i l n ca poli i c es i f n ormed by evidence,o the implementation of effective services to improve 

outcomes and to support VA clinical practice guidelin

performance measures, and

o guide the direction for future research to address gap

knowledge.

• Broad topic nomination process – e.g. VACO, VISNs, field – fa

ESP Coordinating Center (Portland) through online process:

http://www.hsrd.research.va.gov/publications/esp/TopicNomin
;

Evidence‐based Synthesis Progr

(ESP)

• Steering Committee representing research and operations (PC

and VISN) provides oversight and guides program direction.

• Technical Expert Panel (TEP)

o Recruited for each topic to provide content expertise

o Guides topic development; refines the key questions

o Reviews data/draft report.

• External Peer Reviewers & Policy Partners

o Reviews Reviews and comments comments on draft report

• Final reports posted on VA HSR&D website and disseminated 

through the VA.

http://www.hsrd.research.va.gov/publications/esp/reports
‐

Evidence‐based Synthesis Progr

(ESP)

Predictors and Consequences of Se

Hypoglycemia Hypoglycemia in Adults with Diabe

Diabe

(June 25 2012)

Full‐length report available available on ESP website: website:

http://www.hsrd.research.va.gov/publications/esp/reports
Background

• Prevalence of Type 2 Diabetes increasin

Prevalence of Type 2 Diabetes increasin

– Estimated at 25% in VA 

• Associated with increased risk of CVD 

• National guidelines have emphasized ve

glucose control 

• Prevent microvascular complications 

• Tight control associated with hypoglycem
Key Questions

• What is the incidence of severe hypoglycemia in ad

Type 2 Diabetes on one or more hypoglycemic age

• What are the risk factors for severe hypoglycemia i

population?

• What are the consequences of severe hypoglycem
Methods

• Medline search for trials, observational studies and 

reviews (1950 to November 2011) of adults with type 2 d

diabetes medication

• Severe hypoglycemia defined as an episode with ty

symptoms resolving after treatment (IV glucose, IM glu

carbohydrate) administered by another person

• For KQ1 and 2, studies with < 500 subjects or < 6 m

duration were excluded
353 abs ac s

MEDLINE Search

(n=2353 abstracts)

Excluded Abstracts (n=1914)

ll i

Excluded Articles (n=320)

Population = 4Publication type = 46Outcomes of Interest= 131Study < 6 months or < 500 pts = 135

=

=

=

Non FDA meds = 2

KQ3 Specific Excludes:No association between severe

hypoglycemia and outcomes ofinterest = 2

=

=

Hand Search (n=8)

KQ1 Included

Articles (n=72)

KQ3 Included

Articles (n=59)

KQ2 Included

Articles (n=31)

Literature Search

MEDLINE Search

(n=2353 abstracts)

Excluded Abstracts (n=1914)

Full Text Review

Excluded Articles (n=320) (n=439 articles)

Population 4Publication type 46Outcomes of Interest= 131

Study < 6 months or < 500 pts 135

Non FDA meds 2KQ3 Specific Excludes:

No association between severe

hypoglycemia and outcomes ofinterest 2

Included Articles

(n=119)

Total Included

Hand Search (n=8)

Total Included

Articles (n=127)

KQ1 Included

Articles (n=72)

KQ3 Included

Articles (n=59)

KQ2 Included

Articles (n=31)
–

KQ1: Incidence

• 60 studies (72 articles)

most were RCTS (46) & funded by drug commost were RCTS (46) & funded by drug com

– 5 intensive vs. standard control 

• O l n y 12/46 RCTS were rat de as good quality• Severe hypoglycemia seen infrequently in st

– Metformin, Glinides, Detemir – TZDs, GLP-1 Analogs – DPP-4 inhibitors 4 inhibitors 
KQ1: Incidence

• Highest rates for...• Insulins

– NPH monotherapy 9.3% over 3.5 yrs* (95% CI 7.3 to 11.8, N– Glargine 

• > 2 years: 4.1% (95% CI 1.9 to 8.4%, N=1223, 3 studies• < 1 yr: 1.6% (95% CI 1.6%, 95% 0.8 to 3.2%, N=13,088, 

– Lispro 3.6% over 1.3 yrs* (95% CI 2.3 to 5.4,N=1198, 2 studi– Glulisine + NPH 1.0% over 0.5 years* (95% CI 0.5 to 2.1%, N

• Sulfonylureas 1 2% 2 3 * 1.2% over 2.3 yrs* (95% CI 0 9 t 1 4 N 908

(95% CI 0.9 to 1.4, N=908

* weighted mean average duration 
KQ1: Intensive Control

Stud

y Standard Intensive 

Average 

Follow-u

p 

(Years) 

Definition 

G

(st(st

ACCORD3 261/5123 

(5.1%) 

830/5128 

(16.2%) 

3.5 HA 

ADVANCE4 81/5569 (1.5%) 150/5571 

(2 7%). 

5.0 HA L

VA-DT5 28/899 (3.1%) 76/892 (8.5%) 5.6 ** 

VA-CSDM30 2/78 (2.6%) 5/75 (6.6%) 2.3 HA 

UKPDS

#21 29, 8/1138 (0 %) 8/1138 (0.7%) 33/30 1 (1 1%) 33/30

71 (1.1%) 10 0. HA FPG 

FPG 

F

POOLED 

3.1% 

7.6% 5.2 yrs 

RR 2.4 

(95% CI 1.8 to 

# ** life threatening or resulted in death, hospitalization, disability or incapacity, data fo

studies are combined as per Hemmingsen 2011, HA—episode of hypoglycemia requiring another person 
KQ1: Population-Based

• In order to

gain

a more

p po

pulation

‐based

per

on hypoglycemia incidence

• We re

‐reviewed reviewed all the abstracts abstracts to find articl

articl

data from more representative groups...

– Population or clinic based (no drug RCTs) 

• ...using more liberal inclusion criteria

– <500 people, duration < 6 months – Definition of severe hypoglycemia not as rigorous – Lack of true incidence data 

(cross sectional surve

y

s
353 abs ac s

Excluded Abstracts (n=1914)

ll i

Excluded Articles (n=320)

Population = 4Publication type = 46Outcomes of Interest= 131Study < 6 months or < 500 pts = 135

=

=

=

Non FDA meds = 2

KQ3 Specific Excludes:No association between severe

hypoglycemia and outcomes ofinterest = 2

=

=

Re‐reviewed for KQ1

Extension

‐      

Total Included

Articles (n=127)

KQ1 Extension

Included Articles

KQ1 Included

Articles (n=72)

KQ1 Included KQ2 Included

Included Articles

(n=16)

Literature Search

MEDLINE Search

(n=2353 abstracts)

Excluded Abstracts (n=1914)

Full Text Review

Excluded Articles (n=320) (n=439 articles)Population 4Publication type 46Outcomes of Interest= 131

Study < 6 months or < 500 pts 135

Non FDA meds 2KQ3 Specific Excludes:No association between severe

hypoglycemia and outcomes ofinterest 2

Included Articles

(n=119)

Total Included

Hand Search (n=8)

Re reviewed for KQ1

Extension

KQ1 Extension

Included Articles

Articles (n=72)

KQ3 Included

Articles Articles (n=59) (n=31)

Included Articles

(n=16)
KQ1: Incidence

• 13 survey

st di u es ( ti pa en

t recall)

–

5 six month studies in pts on oral agents on

•

1

‐13% incidence incidence hypoglycemia hypoglycemia requiring requiring any ass

ass

(HA)

• 

1

‐4% incidence hypoglycemia requiring medical 

(HMA)

–

3 one year studies in pts on insulin only

• 12

‐17% HA

• 2% HMA

• 

1

pros

pective stud

y

– 1 month community based in Scotland – 173 adults – 3% incidence of HA 
at o

KQ1: VA Specific Specific Data

• Four of our included studies were of VA pat

• 2 additional VA studies did not meet our in

criteria or were published later

• These studies sugg tes that VA patients pa tien may

experience higher incidence rates than the 

population
KQ1: Limitations

• Data mostly from drug company company sponsored sponsored 

• highly selected pts• ascertainment bias

• Population based data

• patient patient recall

• lack of standard definitions
KQ1: Summary

• Incidence Incidence of severe hypoglycemia: 0‐3%/yr• Highest for

– Insulins

– Sulfonylureas– Regimens targeting tight control

• Prospective Prospective population population based studies studies needed

– VA and non‐VA
KQ2

• What are the risk factors for severe 

hypoglycemia in adults with Type 2

diabetes on one or more hypoglyceagents? agents? 
case co o

KQ2: Risk Factors for 

Hypoglycemia Hypoglycemia 

• 28 studies (31 articles)

• Only the 12 studies that used multivariate a

are reported

– 2 RCTs– 2 cohort

– 4 cross‐sectional

– 4 case control
KQ2: Risk Factors for 

Hypoglycemia Hypoglycemia 

• Transient causes (e.g. missed meal, excess exerc

use, acute infection) were not included

• All studies studies met pre

‐specified specified definition definition of se

hypoglycemia

• Data were unsuitable for pooling

• lengths of f/u

• risk factors• populations
o ce a

KQ2: Independent Risk Factors Consistently Associated wit

of Hypoglycemia

• Demographics

– lower education level

– African American race

• Medical History

– past hypoglycemia

– renal insufficiency

– non‐renal microvascular complications

– dementia

– longer diabetes duration

• Treatment

– intensive diabetes control
KQ2: Independent Risk Factors NOT Consistently

Associated with Risk of Hypoglycemia

• Gender, Age and BMI

• In the two largest studies, higher age and lower 

significantly associated with higher risk
KQ2: Inadequately Studied Ris

Factors

• h/ h i oypoglycemia unawareness

• genetic markers • mari l ta status 

• smoking • alcohol consumption • p yp ol harmacy• recent discharge from the hospital • congestive heart failure • use of ACE inhibitors 
KQ2: Limitations Limitations and Summa

Summa

• Publication Bias • Risk Factors

– Negative – lower education le

studies

– African American 

unlikely to be

– past hyp ogy l cemia report de– renal insufficiency – non-renal microva

complications complications 

– dementia – longer diabetes du– intensive diabetes – ?higher age – ?lower BMI ?lower BMI 
KQ3

• What are the consequences of severe

hypog yl cemia?
KQ3: Ideal Study Design

Complications (e.g Death, MI, coma, 

P l ith 

Hypoglycemic 

, , , 

ER visit) 

People with diabetes on medications 

Event No complications 

No Hypoglycemic Event 

Cohort 

assembled 

Complications 

assessed 

Follow-up over Time
Features Features of an Ideal Study

• Population based• Prospective• Controlled

– People with diabetes diabetes on medications medications who 

have hypoglycemia

• Most studies studies were far from this ideal
KQ3: Consequences of

Hypoglycemia

• 59 articles on 53 studies • Consequences Consequences 

– Complications at Presentation– Long-Term Ot u comes

– All-cause mortality – Cognitive Impairment 

– Quality of Life 
Complications Complications at Presentatio

Presentatio

• Retrospective cohort study of 19,932 Tenesse

medicaid medicaid enrollees enrollees, age >65, on oral hypogly

hypogly

insulin

Population‐based

+/‐ Prospective

Control Group

Schorr et al Arch Intern Me
Study Design

Complications (e.g Death, MI, coma, 

P l ith 

Hypoglycemic 

, , , 

ER visit) 

People with diabetes on medications 

Event No complications 

No Hypoglycemic Event 

Cohort 

assembled 

Complications 

assessed 

Follow-up over Time Schorr et al Arch Intern Me
Complications Complications at Presentatio

Presentatio

• 586 persons with a first episode of serious hypoglyc

occurring outside the hospital that resulted in an ER 

hospitalization or death

• 5% of these episodes were associated with

‘catastrophic complications’ including

– Stroke (1.2%) or TIA (0.6%)– MI (0.5%)– Injury (1.7%)

– Death (0.3%

Schorr et al Arch Intern Me
Long Term Outcomes:

Mortality

ACCORD and ADVANCE

+/‐ Population‐based

• RCTs, but liberal entrance criteria

Prospective

• With long follow‐up

Control Group

• With no episodes of hypoglycemia
Mortality

• Severe hypoglycemia was associa

an increased risk of death in both ACCORD and ADVANCE 
Mortality

in people without a h/o severe hypoglyc

Study Mortality

Intensive Standar

Hypoglycemia Yes No Yes ACCORD

(annual)

2.8% 1.2% 3.7% 1.

ADVANCE

(annual)

3.6% 1.8% 5.1% 1.

UKPDS(10 yr)

12.5% NR 0% N
Mortality

in people with a h/o severe hypoglyc

Study Mortality

Intensive Standar

Hypoglycemia Yes No Yes ACCORD

(annual)

2.8% 1.2% 3.7% 1.

ADVANCE

(annual)

3.6% 1.8% 5.1% 1.

UKPDS(10 yr)

12.5% NR 0% N
Long term Outcomes:

Cognitive Impairment

• 2 high quality quality cohort studies studies (Whitmer Whitmer 2009, Bruce 200

– Population‐based (both)– Prospective (Bruce)– Control Group (both)

• However Bruce 2009 was grossly grossly underpowered underpowered

– N=205 followed for < 2 years
Cognitive Impairment

Whitmer

– 16,667 pts with diabetes from a healthcare plan i– 3 8. years of follow‐up for incident incident dementia dementia (retrosp

(retrosp

– 1465 (8.8%) with one or more episodes of hypogl

identified retrospectively

– Increased risk of dementia in those with 1 or mo

(HR 1.68, 95% CI 1.47 to 1.93)

JAMA 200
Long term Outcomes:

Quality of Life

• 8 cross‐sectional studies

– 5 had 1/3 quality indicators*– 2 had 2/3 quality indicators– 1 had 0/3

*Population Population based, prospective prospective, control control group
Quality of Life

Study Quality

Indicators

HRQoL Worry/

Fear

Other

Marrett, USA, 2009 2/3Labad, Scotland, 2010 2/3 ‐ ‐ Increased Petterson, Sweden, 2011 1/3Hermanns, Germany, 2005 1/3 ‐ ‐ Increased aAlvarez, Europe, 2010 1/3 ‐Vexiau, France, 2008 1/3Davis, UK, 2005 1/3 ‐ ‐ Decreased 

In diabetics reporting severe hypoglycemia compared to those reporhypoglycemia All results are significant at p<0.05 
Accidents Accidents / Trauma

• No high quality studies

• ACCORD

– No difference in # of MVAs in which pt w

driver between between intense intense and standard standard con

con
KQ3 Summary

• There is evidence that severe hypoglyce

– Decreases quality of life

– Is associated with increased mortality

– May lead to cognitive impairment

– Increases Increases hospital hospital and ER utilization utilization (data not s

• Limitations

– Few high quality studies (population based, prospective, co
Conclusions

In patients with diabetes on medications...• Incidence Incidence of severe hypoglycemia hypoglycemia is difficult difficult to quan

quan

not negligible

• Several Several co‐morbidities, morbidities, demographic demographic and treatment treatment 

factors increase the risk

• Severe hypoglycemia has a negative effect on QoL an

to serious outcomes including death

• Intensity of glucose control is the risk factor most am

intervention
National Recommendation

Goal A1C: “< 7% in most patients patients

ADA Standards of Medical Care (2011)

Patient centered approach

Less stringent goal (7.5 to 8 0) . appropriate fo

ADA and EASD (2012)
Patient‐centered Approach

ADA and EASD (2012)

Glycemic Control 

Patient attitude Patient attitude 

Risks associated with hypoglycemia Disease Duration 

Life expectancy Comorbidities Comorbidities Established vascular complications Resources, support system 

More stringent 

More Motivated, adhere

Low

 Hi

New LoLong Absent Few Absent Few Readily Available 
VA‐DoD Guidelines 2010

• Individualized goal based on...

– Co‐morbidities

– Life expectancy

– Risk of hypoglycemia– Presence of pre‐existing microvascular

complications

– Patient’s preferences
VA‐DoD Guidelines Guidelines 2010

Goal A1C

Microvascular complications complications 

Life Expectancy Absent or Mild Moderate Adv> 10 years <7% <8% 8‐95‐10 years < 8% <8% 8‐9< 5 years 8‐9% 8‐9% 8‐9
Evidence‐based Synthesis Progr

(ESP)

Questions?

If you have further questions,

feel free to contact:

Hanna E. Bloomfield, MD, MPH

Staff Physician, Minneapolis VA

612‐725‐2000

Hanna.Bloomfield@va.gov

The full report and cyberseminar presentation is available on the E

http://www http://www.hsrd.research research.va.gov/publications/esp/ gov/publications/esp/
Key Summary Points Regar

Potential Potential Risk of Hypoglycem

Hypoglycem

Veterans

Leonard Pogach MD, MBA, FACP

National Program Director Endocrinology 

Diabetes 

Bernie Good MD, MPH 

Chair Medication Advisory Panel 
ACCORD

• Increased mortality (2.8%) in intensive

managed patients who had one or mo

severe hypoglycemic episodes compa

those with no episodes episodes (1.2%) (adjust

(adjust

1.41; 95% CI, 1.03‐1.93).

• Trend was also seen in the standard c

group: 3.7% vs. 1.0%, respectively (adHR 2.3; 95% CI, 1.46‐3.6).
ADVANCE

• Severe hypoglycemia was associated wi ht a s

increase in the adjusted risks of major macro

events (hazard (hazard ratio, 2.88; 95% confidence confidence in

in

2.01 to 4.12), major microvascular events (ha

1.81; 95% CI, 1.19 to 2.74), death from a card

cause (hazard ratio, 2.68; 95% CI, 1.72 to 4.19

death from any cause (hazard ratio, 2.69; 95% 

to 3.67) (P<0.001 for all comparisons).

• Similar associations were apparent for a rang

nonvascular outcomes, i l nc uding respi t ra ory, 

and skin conditions (P<0.01 for all compariso
Predictors of CV Death VAD

Death, VAD

Davis, S. ADA 2009

 Hazard Ratio (HR Lower CL, HR Up

Hypoglycemia 4.042 (1.449, 1

HDL 

HbA1c 

0.699 

(0.536, 0

1.213 (1.038, 1

Age 

( , 

2.090 (1.518, 23 116 (1 744 5 

0 2 4 6 8 10 12 

Prior Event 

3.116 (1.744, 5

0 2 4 6 8 10 12 
, 

Risk of Morbidity and Mortality from Severe Hyp

from ACCORD, ADVANCE , VADT

• Association with adverse outcomes gr

with control arms (A1cs achieved 7.5, 

8.4.% respectively.

• Risk greater greater in subjects subjects with chronic chronic c

morbid conditions

• Unlikely that post‐hoc observational d

will disentangle disentangle relationship relationship of hypog

hypog

to outcomes
–

Risk Factors for Serious Hypoglycemia 

Veterans Under-Represented in Tri

• 2004 Risk Factors <65 years (Pogach e

Diabetes Care 2010)

– Complex Glycemic Regimens 30%– Decreased Life Expectancy, 5.4%– Advanced Complications 6.3%– Serious Serious Medical Medical Conditions Conditions 9.0%– Serious Neurological Conditions 4.2%– Serious Serious Mental Health Conditions Conditions 21.5%– Poverty 28%; disability >50% 31.3%
Conclusions:

• The Veteran popul i at on is at high ri ks for seri

hypoglycemia due to age, risk factors (medic

economic)

• Incidence/Prevalence of serious hypoglycem

likely to be known with greater greater certainty certainty with

with

weighted population health surveys.

• Clinicians Clinicians need to balance balance benefits benefits of good g

g

control with potential harms associated with

hypoglycemia, especially in vulnerable vetera

• PBM will address issue of anti‐glycemic safet

those high risk Veterans in near future.