Transcript TYPE II DIABETES MANAGEMENT

Prior to the start of the program, please check your syllabus
to ensure you have the following printed program materials:
• Pre-activity Survey
– Located at the front of your syllabus
• CME Evaluation with Post-activity Survey
– Located at the back of your syllabus
Disclosures
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Off-label Discussion Disclosure
This educational activity may contain discussion of published and/or
investigational uses of agents that are not indicated by the Food and
Drug Administration. PCME does not recommend the use of any agent
outside of the labeled indications. Please refer to the official
prescribing information for each product for discussion of approved
indications, contraindications and warnings. The opinions expressed
are those of the presenters and are not to be construed as those of the
publisher or grantors.
Educational Objectives
At the conclusion of this activity, participants should be able to
demonstrate the ability to:
• Consider the risk of hypoglycemia associated with current therapeutic
agents when determining treatment and re-evaluate the impact of
hypoglycemia on patient outcomes throughout the ongoing
management of T2DM patients
• Integrate the most recent evidence with current guidelines to provide
a multifaceted, individualized approach to patients with T2DM to
maintain glycemic control and reduce vascular complications
• Empower patients through individualized patient education and
collaboration with the care team to address the breakdown of barriers
for optimal outcomes
Polling Question
Pre-activity Survey
• Please take out the Pre-activity Survey from your packet
• Fill out the demographic information at the top of the form;
as questions are asked, please take a moment to select
your answer to the corresponding question on this form
• Your answers are important and will help us shape and
improve future CME activities
Polling Question
Pre-activity Survey
Please rate your confidence in integrating guidelines to
individualize the management of T2DM patients:
A. Expert
B. Very confident
C. Confident
D. Somewhat confident
E. Not confident
Polling Question
Pre-activity Survey
Please rate your confidence in managing T2DM in patients
with multiple prevalent macro- and/or microvascular
comorbidities:
A. Expert
B. Very confident
C. Confident
D. Somewhat confident
E. Not confident
Polling Question
Pre-activity Survey
Please rate your confidence in using GLP-1 receptor
agonists, DPP-4 inhibitors, and SGLT2 inhibitors to reduce
HbA1C in your T2DM patients:
A. Expert
B. Very confident
C. Confident
D. Somewhat confident
E. Not confident
Polling Question
Pre-activity Survey
How often do you incorporate a shared decision-making
(SDM) approach to T2DM management?
A. Always
B. Frequently
C. Sometimes
D. Never
E. I do not know the definition of SDM
Polling Question
Pre-activity Survey
How often do you evaluate the risk of hypoglycemia in your
T2DM patients and adjust management as necessary to
avoid hypoglycemic episodes?
A. Always
B. Frequently
C. Sometimes
D. Never
Polling Question
Pre-activity Survey
Do you participate in quality reporting initiatives, such as
PQRS from CMS?
A. Yes
B. No
C. I don’t know what PQRS is
Polling Question
Pre-activity Survey
NS is a 64-year-old man who had been taking metformin 1000 mg BID
for 3 years. Four months ago, he added glyburide 10 mg QD to his
treatment regimen to gain better control of his hyperglycemia. His A1c
dropped from 7.9% on metformin alone to 7.4% today. However, he
has noted an increase in episodes of hypoglycemia since adding
glyburide. Which of the following strategies might you recommend in
order to reduce his risk of hypoglycemia?
A. Discontinue glyburide and stay on metformin 1000 mg BID
B. Reduce the dose of metformin to 500 mg BID
C. Switch to metformin plus basal insulin
D. Switch to metformin plus a SGLT2 inhibitor
Polling Question
Pre-activity Survey
Which of the following characteristics might prevent you from
prescribing an SGLT2 inhibitor for a patient?
A. Renal insufficiency, GFR 43 mL/min
B. A history of recurrent UTIs
C. Orthostatic hypotension
D. All of the above
E. None of the above
Polling Question
Pre-activity Survey
MK is a 60-year-old woman who was diagnosed 3 years ago with
T2DM. She is currently taking metformin 1000 mg BID. Her A1C is
7.9%. She has gained 14 lbs in the past 9 months, and is very
unhappy about her weight (current BMI, 28.2 kg/m2). Which of the
following changes to her treatment regimen do you expect to result in
the greatest reduction in body weight?
A. Addition of a sulfonylurea
B. Addition of a DPP-4 inhibitor
C. Addition of a GLP-1 receptor agonist
D. Switch to basal insulin
Polling Question
Pre-activity Survey
RL is a 52-year-old husband and father of 3 children aged 11 to 19
years. He was diagnosed 4 years ago with T2DM. He takes metformin,
although he admits to skipping a few doses per week. His A1c is 7.6%.
He is a smoker and drinks socially. He is obese (BMI, 31.4 kg/m2), and
his wife and children are also overweight. Which of the following is an
example of shared decision-making?
A.
Refer the patient to a smoking cessation program
B.
Involve a certified diabetes educator to coach the patient on selfmanagement techniques
C.
Ask the patient to identify 3 lifestyle changes that he is willing to adopt
for the next month
D.
Invite the patient’s family to attend a community diabetes education and
screening event
CASE
Hypoglycemia in an Elderly
T2DM Patient with Heart Failure
CASE: Introduction
• Sophie is 87 years old and has had type 2 diabetes for 15 years
– Initially diagnosed when she had an acute MI at the age of 62
– Managed with glipizide 10mg BID since then with fairly good HbA1C levels
• Current concerns
– Recent episodes of confusion/dizziness
– Occasionally forgets medication and meals
– Home glucose monitoring shows multiple hypoglycemic episodes throughout day;
? wrong dose of medication, ? missing meals
• Physical examination
– Frail appearance (BMI: 19.0 kg/m2)
– Rales at both lung bases posteriorly
– Bilateral 1+ pitting pedal edema
• Laboratory evaluation
– Random glucose: 68 mg/dL; HgbA1C: 6.1%
– SCr 1.7; eGFR: 28 mL/min/1.73 m2
– CXR: Mild CHF
CASE: Key Patient Features and
Considerations for Individualized Therapy
• Hypoglycemia
– Risk factors?
– Drug classes to avoid?
• Comorbid cardiovascular disease (heart failure)
– Drug classes to avoid?
• Renal insufficiency
– Drug classes to avoid?
– Required dose adjustments?
Hypoglycemia Risk Factors in Elderly
Patients with T2DM
• Advanced age
• Alcohol ingestion
• Polypharmacy
• Endocrine deficiencies
(thyroid, adrenal, pituitary)
• Sulfonylurea or insulin use
• Poor nutrition or fasting
• Intercurrent illness
• Chronic renal disease
• Chronic liver disease
• Prolonged physical exercise
Mathieu C et al. Int J Clin Pract. 2007;61(suppl 154):29-37.
• Loss of normal counterregulation
• Hypoglycemic unawareness
The Association Between Medication-related
Hypoglycemia and Vascular Risk
Cumulative 3-Year Incidence (%)
40%
35%
30%
Hypoglycemia group
P < 0.0001
Control group
P < 0.0001
34.46%
30.65%
25%
22.03%
20%
17.48%
15%
10%
5%
0%
n=761
CVD
Zhao Y et al. Diabetes Care. 2012;35:1126-1132.
Microvascular complications
ADA/EASD General Recommendations for
Hyperglycemia Management
Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379. Inzucchi SE et al. Diabetologia 2012;55:1577-1596.
ADA/EASD Adapted Recommendations:
When Goal is to Avoid Hypoglycemia
SGLT2-i’s
?
Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379. Inzucchi SE et al. Diabetologia 2012;55:1577-1596.
Adverse Events Associated with
Thiazolidinedione Treatment
• Weight gain
– Averages 1-5 kg (2-11 lbs)
– Correlates with improved A1C; attenuates when A1C stabilizes
– Greatest in combination with insulin and SU
• Fluid retention
– Rarely severe; most common when used in combination with insulin
– In patients with heart failure, more likely peripheral than pulmonary
– Likely PPAR-gamma effect on Na+ handling by the distal renal tubule
Asnani S et al. Curr Med Res Opin. 2003;19:609-613.
Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411.
Tang WHW et al. J Am Coll Cardiol. 2003;41:1394-1398.
Hussein Z et al. Med J Aust. 2004;181:536-539.
Nesto RW et al. Diabetes Care. 2004;27:256-263.
Zhang H et al. PNAS. 2005;102:9406-9411.
PROactive: Heart Failure Events with
Pioglitazone vs Placebo in T2DM
Endpoint
Any report of HF
(nonadjudicated)
Pioglitazone
Placebo (n=2633)
(n=2605)
No. Patients (%)
No. Patients (%)
P Value
281 (11)
198 (8)
<0.0001
149 (6)
108 (4)
0.007
25 (1)
22 (1)
0.634
HF leading to
hospitalization
HF leading to
death
HF = heart failure; PROactive = Prospective Pioglitazone Clinical Trial in Macrovascular Events.
Dormandy JA et al. Lancet. 2005;366:1279-1289.
What About SGLT2 Inhibitors?
•
•
•
•
•
Insulin-independent action (can be
used regardless of DM duration)
Complement action of other
anti-diabetic agents
Weight loss
Decreased BP
Low hypoglycemia rates
•
•
•
•
•
•
Recurrent UTI
Genital fungal infection
Dehydration/hypotension
Worsening of renal function#
Increased hematocrit*
Increased LDL-C*
# Specific considerations for individuals with existing renal insufficiency, the elderly, and those receiving loop diuretics
* Significance on patient outcomes is unclear at this time
Kim Y et al. Diabetes Metab Syndr Obes. 2012;5:313-327.
Dose Adjustments and Contraindications in
T2DM Patients with Renal Impairment
• Metformin: Contraindicated when SCr ≥1.5 • SGLT-2 inhibitors
(men), ≥1.4 women
– Canagliflozin (100-300mg QD): 100 mg QD
for eGFR 45-<60; discontinue (or do not
• SU: dose reduction for renal insufficiency; do
initiate) when eGFR <45; contraindicated
not use glyburide
when eGFR<30
• Insulin: dose reduction for renal insufficiency
– Dapagliflozin (10 mg QD): do not initiate when
• GLP-1 receptor agonists
– Exenatide: do not use if eGFR <30
– Others: use with caution
• DPP-4 inhibitors
– Sitagliptin (100 mg QD): 50 mg for eGFR <50,
25 mg for eGFR <30
– Saxagliptin (5 mg QD): 2.5 mg QD when
eGFR <50
– Linagliptin (5 mg QD): no dose adjustment
needed
– Alogliptin (12.5 mg QD): 6.25 mg QD for CrCl
<30 mL/min
Physicians' Desk Reference. Montvale, NJ: PDR Network; 2014.
eGFR <60; discontinue when eGFR
persistently <60; contraindicated in severe
renal impairment, ESRD, dialysis
– Empagliflozin (10-25 mg QD): do not initiate
when eGFR <450; discontinue when eGFR
persistently <45; contraindicated in severe
renal impairment, ESRD, dialysis
Profiles of Antidiabetic Medications
Of the recommended options for this
patient, the DPP-4i class is
associated with the fewest cautions.
HbA1C lowering 0.5 – 0.9%
Copyright © 2013 AACE May not be reproduced in any form without express written permission from AACE.
CASE: Key Patient Features and
Considerations for Individualized Therapy
• Hypoglycemia
– Risk factors: older age, concurrent medications (SUs, insulin), comorbidities
– Drug classes to avoid (?): SUs, insulin
• Comorbidity: Heart Failure
– TZD contraindicated
– ? New data on DPP-4 inhibitors (specifically, saxagliptin in SAVOR-TIMI)
• Renal Insufficiency
–
–
–
–
Metformin contraindicated
SGLT2-inhibitors not effective
DPP-4 inhibitors: most require dose adjustment (linagliptin exception)
GLP-1-RAs acceptable but use cautiously
• What is the optimal treatment choice for this patient?
Clinical Tips for Preventing Hypoglycemia
•
•
•
•
•
•
•
•
•
•
•
Address at each visit
Individualize A1C goals – avoid aggressive targets in advanced disease
Employ flexible, physiological insulin regimens
Avoid long-acting secretagogues when possible
Track renal function
Consider hypo risk factors (age, disease duration, diet changes, CKD)
Review and apply diabetes self-management
Request frequent SMBG – reevaluate skills periodically
Limit alcohol intake (≤1 drink/day in women, ≤2 drinks/day in men)
Add carbohydrate before exercising if BG <140 mg/dL
Strict avoidance of hypoglycemia for several weeks may partly resolve
hypoglycemia unawareness
Seaquist E et al. Diabetes Care. 2013;36:1384-1395.
Garber A et al. Endocr Pract. 2013 (suppl 2):1-48.
Cryer PE et al. J Clin Endocrinol Metab. 2009;94:709-728.
American Diabetes Association. Diabetes Care. 2013;36(suppl 1):S11-S66.
Inzucchi S et al. Diabetes Care. 2012;35:1364-1379.
CASE
Managing Between-meal
Hypoglycemia
CASE: Introduction
• Mathilda is a 50-year-old woman who has had T2DM since gaining a great deal of
weight in her 30s
– Diabetes currently managed with metformin 1,000 mg BID and glimepiride 4mg QD
• Current concerns
– Patient is motivated to lose weight
•
Daughter is getting married next year; patient wants to wear a nice dress
•
History of multiple diets; currently on her own variation of the “South Beach Diet,” limiting carbs
especially at lunchtime
– Recent episodes of feeling lightheaded and shaky in the mid-afternoon
– Home glucose monitoring reveals multiple episodes of hypoglycemia between meals that
correlate with her symptoms
• Physical examination
– Height: 5’4”; BP: 160/90; Body weight: 150 pounds; BMI: 25.7 kg/m2
– Random glucose: 110 mg/dL
– HgbA1C: 8.1%
– eGFR: >90
CASE: Key Patient Features and
Considerations for Individualized Therapy
• Glycemic control: current A1C is 8.1%
– What is her target? Can she do better?
• Hypoglycemia
– Why is she experiencing hypoglycemia?
• Desire to lose weight
– Considerations for T2DM treatment?
• Hypertension
– Any considerations re T2DM management?
• Normal renal function
ADA/EASD General Recommendations for
Hyperglycemia Management
Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379. Inzucchi SE et al. Diabetologia 2012;55:1577-1596.
ADA/EASD Adapted Recommendations:
When Goal is to Avoid Hypoglycemia and Weight Gain
SGLT2-i’s
?
Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379. Inzucchi SE et al. Diabetologia 2012;55:1577-1596.
Deciding about First Injectable Drug for
Patients Not Controlled by Oral Agents
• DURATION-3 trial of once-weekly exenatide vs insulin
glargine as first injectable therapy
3-year endpoint
Exenatide
(n=233)
Insulin glargine
(n=223)
P Value
Change in A1C
-1.01%
-0.81%
0.03
Change in body weight
-5.5 lbs
+4.4 lbs
<0.001
0.3 events per
patient-year
0.9 events per
patient-year
NR
Hypoglycemia (exposureadjusted events)
NR = not reported.
Diamant M et al. Lancet. 2014:2:464-473.
What About SGLT2 Inhibitors?
•
•
•
•
•
Insulin-independent action (can be
used regardless of DM duration)
Complement action of other
anti-diabetic agents
Weight loss
Decreased BP
Low hypoglycemia rates
•
•
•
•
•
•
Recurrent UTI
Genital fungal infection
Dehydration/hypotension
Worsening of renal function#
Increased hematocrit*
Increased LDL-C*
# Specific considerations for individuals with existing renal insufficiency, the elderly, and those receiving loop diuretics
* Significance on patient outcomes is unclear at this time
Kim Y et al. Diabetes Metab Syndr Obes. 2012;5:313-327.
SGLT2 Inhibitors and Body Weight
Mean Body Weight Reduction
Canagliflozin 300 mg
Mean change from baseline in
body weight (kg)
Dapagliflozin 10mg
Mean Body Fat Loss
Control
Data presented are not from head-to-head studies
Ferrannini E et al. Diabetes Care. 2010;33:2217-2224.
Bailey CJ et al. Lancet. 2010;375:2223-2233.
Stenlof K et al. Diabetes Obes Metab. 2013;15:372-382.
Rosenstock J et al. Diabetes Care. 2012;35:1232-1238.
Wilding JP et al. Int J Clin Pract. 2013;67:1267-1282.
Bolinder J et al. Diabetes Obes Metab. 2014;16:159-169.
Pressure change from baseline (mmHg)
SGLT2 Inhibitors and Blood Pressure
Dapagliflozin 10 mg
Canagliflozin 300 mg
*
**
* P<0.001 vs PBO
** P<0.001 vs sitagliptin
a Comparison not specified
Ferrannini E et al. Diabetes Care. 2010;33:2217-2224.
Stenlof K et al. Diabetes Obes Metab. 2013;15:372-382.
Bailey CJ et al. Lancet. 2010;375:2223-2233.
Rosenstock J et al. Diabetes Care. 2012;35:1232-1238.
Strojek K et al. Diabetes Obes Metab. 2011;13:928-938.
Schernthaner G et al. Diabetes Care. 2013;36:2508-2515.
Profiles of Antidiabetic Medications
Comparison of DDP-4i,
GLP-1 RA, and SGLT-2 profiles
Copyright © 2013 AACE May not be reproduced in any form without express written permission from AACE.
Case: Key Patient Features and
Considerations for Individualized Therapy
• Hypoglycemia
– Discontinue glimepiride; avoid insulin
• Desire to lose weight
– Metformin as foundation therapy
– If needs other agent, avoid insulin and TZD
– Consider DPP-4 inhibitors, GLP-1 agonist, or SGLT2 inhibitor
• Normal renal function
– Can safely use any drug from a renal standpoint
• Hypertension
– Blood pressure reduction with SGLT2 inhibition, GLP-1?
• What is the optimal treatment choice for this patient?
CASE
Newly Diagnosed T2DM in
Patient with Prior MI
CASE: Introduction
• George is a 54-year-old accountant admitted to the hospital with
acute MI
– In-hospital laboratory panels:
•
Morning glucose levels: 138-163 mg/dL
•
HbA1C: 6.7%
• Current concerns
– Is anti-hyperglycemic therapy warranted upon discharge?
• Medical history
– Well-controlled hypertension, dyslipidemia, gout, obesity, and OSA
– Patient does not smoke; no polyuria, polydipsia, blurred vision, or
non-healing wounds
– Father has T2DM and is currently on dialysis
CASE: Key Patient Features and
Considerations for Individualized Therapy
• T2DM is commonly revealed during acute cardiovascular
events
– In an AMI population: 1/3 of patients have established DM, 1/3 have
newly diagnosed T2D or ‘pre-diabetes’; the remainder are euglycemic
(but may have metabolic syndrome)
• T2D therapy in the context of CVD should attempt to avoid
drugs that lead to substantial risk of hypoglycemia (i.e.
activates adrenergic nervous system)
– Sulfonylureas may also decrease the body’s ability to adapt to
myocardial ischemia through ischemic preconditioning
– Heart failure when present can also affect drug choices (e.g. no TZDs,
? DPP-4 inhibitors)
Impact of Intensive Therapy for Diabetes:
Summary of Major Clinical Trials
Study
Microvasc
UKPDS





DCCT/EDIC*




 
(7.0 vs 7.9%)
(7.2 vs 9.1%)
CVD
Mortality

ACCORD



ADVANCE



VADT



(6.4% vs 7.5%)
(6.3% vs 7.0%)
(6.9% vs 8.4%)
Kendall DM, Bergenstal RM. © International Diabetes Center, 2009.
UKPDS Group. Lancet. 1998;352:854.
Holman RR. N Engl J Med. 2008;359:1577.
DCCT Group. N Engl J Med. 1993;329;977. Nathan DM. N Engl J Med. 2005;353:2643.
Gerstein HC. N Engl J Med. 2008;358:2545. Patel A. N Engl J Med. 2008;358:2560.
Duckworth W. N Engl J Med. 2009;360:129 (erratum: N Engl J Med. 2009;361:1024).
Initial Trial
* in T1DM
Long Term Follow-up
Non-Insulin T2DM Therapies
Class
CV ‘Advantages’
?  CVD events
ischemic preconditioning
SUs
Biguanides
CV ‘Disadvantages’
LDL,  CRP, insulin
 HDL;  TG,  insulin, CRP,
CVD events (pio)
 HF,  LDL,
?CVD events (rosi)
 weight,  BP,  TG,  CRP,
? direct cardiac effect
 HR
DPP-4 inhibitors
? direct cardiac effect (via GLP-1)
?  HF
SGLT-2 inhibitors
 BP,  weight
 LDL
TZDs
GLP-1 RAs
All-cause Mortality and MACE with SU vs
Metformin Monotherapy
• Retrospective analysis of patients prescribed metformin
monotherapy (n=76,811) or SU monotherapy (n=15,687) as first-line
glucose-lowering therapy from 2000-2012
• Median follow-up: 2.9 years with metformin; 3.1 years with SU
Hazard Ratio (95% CI) for SU vs. Metformin
Endpoint
Main Analysis
Propensity-Matched
Cohort*
Directly Matched
Cohort†
All-cause mortality
1.58 (1.48-1.68)
1.90 (1.73-2.09)
1.27 (1.02-1.58)
MACE
1.20 (1.09-1.31)
1.20 (1.00-1.44)
0.81 (0.58-1.15)
*n = 8,836 in each arm; †n = 2,604 in each arm.
MACE = major adverse cardiovascular events (MI or stroke)
Morgan CL et al. Diabetes Obes Metab. 2014;16:957-962.
SUs and Ischemic Preconditioning
Brady PA, Terzic A. J Am Coll Cardiol. 1998;31:950-956.
Hypoglycemia and Cardiovascular Risk
Desouza CV et al. Diabetes Care. 2010;33:1389-1394.
UKPDS: Metformin Improves CVD Outcomes
Myocardial Infarction
20
Coronary Deaths
10
P=0.01
P=0.02
Incidence per 1000 patient years
NS
8
15
39%
50%
6
10
4
5
0
2
Conventional
Diet
Insulin
or
SUs
Metformin
0
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 199812;352:854-865.
Conventional
Diet
Metformin
UKPDS 10-year Follow-up: MI Hazard Ratio
(fatal or non-fatal myocardial infarction or sudden death)
Intensive (metformin) vs conventional glucose control
Conventional
Intensive
Δ
73
39
34
Holman R et al. N Engl J Med. 2008;359:1577-1589.
83
45
38
92
55
37
106
64
42
118
68
50
126
81
45
ProACTIVE: Time to Principal 2 Endpoint
0.1
5
Kaplan-Meier event rate
n events:
3-year estimate:
Placebo
358 / 2,633
14.4%
Pioglitazone
301 / 2,605
12.3%
0.1
0
0.0
5
0.
N at 0
risk:
Pioglitazone
vs placebo
5,238
0
HR
95% CI
P value
0.84
0.72, 0.98
0.027
5,102
4,991
4,877
4,752
4,651
6
12
18
24
30
786 (256)
36
Time from randomization (months)
( Primary Endpoint: HR 0.90 P=0.095 )
Dormandy JA et al. Lancet. 2005;366:1279-1289.
Large CV Outcomes Trials in Diabetes
Study
SAVOR
EXAMINE
CAROLINA
CARMELINA
DPP4-i
saxagliptin
✓
TECOS
✓
alogliptin
sitagliptin
linagliptin
linagliptin
Comparator
placebo
placebo
placebo
sulfonylurea
placebo
n
16,500
5,400
14,000
6,000
8,300
Results
2013
2013
2015
2017
2017
Study
LEADER
ELIXA
SUSTAIN 6
EXSCEL
REWIND
GLP1-RA
liraglutide
lixisenatide
semaglutide
exenatide LR
dulaglutide
Comparator
placebo
placebo
placebo
placebo
placebo
n
16,500
14,000
6,000
5,400
8,300
Results
2015
2015
2016
2018
2019
Study
EMPA-REG
CANVAS
DECLARE
NCT01986881
SGLT-2-i
empagliflozin
canagliflozin
dapagliflozin
ertugliflozin
Comparator
placebo
placebo
placebo
placebo
n
7300
4300
22,200
3900
Results
2015
2017
2019
2020
Profiles of Antidiabetic Medications
Cardiovascular safety profiles
and considerations
Copyright © 2013 AACE May not be reproduced in any form without express written permission from AACE.
Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379. Inzucchi SE et al. Diabetologia 2012;55:1577-1596.
CASE: Key Patient Features and
Considerations for Individualized Therapy
• Trial of therapeutic lifestyle change
• Metformin monotherapy is ideal first-line drug so long as no CKD
-
-
Should reduce his A1C to <7%
If 2nd agent is needed, unclear which is best drug as add-on
Consider avoiding SUs due to hypoglycemia risk and ? ischemic
preconditioning
Consider avoiding insulin due to hypoglycemia risk (but may be
necessary at some point if other agents fail to control glucose)
Don’t forget about global CVD risk reduction!
Reasonable options: DPP-4 inhibitors, GLP-1 RAs, TZD or SGLT-2
inhibitors
What is the optimal treatment choice for this patient?
CASE
Renal Impairment in Patient
with T2DM
CASE: Introduction
• Roberta is a 55-year-old African American woman with slowly
progressive CKD
• Current concerns
– Does she need to start antihyperglycemic therapy?
• Laboratory evaluation
–
–
–
–
Random blood glucose: 245 mg/dL
HbA1C: 8.1%
Serum creatinine: 1.6 mg/dL (eGFR: 46 mL/min/1.73 m2)
Urine albumin : Cr ratio = 158 mcg/mg
• Medical history
– Poorly controlled HTN for 5 years and pre-diabetes for 3 years
– COPD with a recent exacerbation that required oral steroids, during which
she developed polyuria and polydipsia
• Medications: HCTZ, metoprolol, amlodipine
CASE: Key Patient Considerations for
Individualized Treatment
• What is the HbA1C target for this patient?
• Reduced renal function
– Drug choice?
– Dose modifications due to eGFR?
• Risk of hypoglycemia and other adverse events?
Estimated Glomerular Filtration and
Normal Aging
200
Estimated GFR (mL/min/1.73m2)
180
160
140
120
100
80
60
40
Insulin (Davies and Shock, 1950)
20
NHANES III Estimated GFR (median, 5th, 95th percentiles)
0
0
20
40
60
80
Age (years)
Uremia, Ca-PO4 imbalance, volume overload, oxidative stress, inflammation, anemia incident CVD, CVD death
100
Natural History of Renal Measures and
Impairment in Diabetic Kidney Disease
eGFR
Albumin
600
120
500
100
400
Albuminuria
80
300
60
200
40
Microalbuminuria
20
0
0
Courtesy of Mark E. Molitch, MD.
5
10
15
20
Duration of Diabetes (years)
100
25
30
0
Urinary Albumin (mg/24 h)
eGFR (mL/min/1.73 m2)
140
Chronic Kidney Disease and T2DM
10.4%
No CKD
13.4%
39.6%
60.4%
14.1%
Stage 1, GFR ≥ 90 + kidney damage*
Stage 2, GFR 60-89 + kidney damage*
Stage 3, GFR 30-59
Stage 4, GFR 15-29
1.1%
NHANES: 41.7% with undiagnosed diabetes and 17.7% with prediabetes had CKD1
USRDS (2007): 166,674 patients (0.6%) with T2DM have end-stage renal disease2
Glomerular filtration rate (GFR) = mL/min/1.73 m2
*Albumin-creatinine ratio >30 or other abnormalities in blood or urine tests or imaging studies
1. Plantinga LC et al. Clin J Am Soc Nephrol. 2010;5:673-682.
2. USRDS. 2009 Annual Data Report. Volume 3: Reference Tables on ESRD in the United States. Bethesda, MD: NIH, NIDDK;
2009:453-468. Available at: www.usrds.org/2009/ref B_Ref_09.pdf. Accessed February 23, 2011.
ADA Standards of Care for Renal Disease in
Patients with T2DM
• Monitoring recommendations
– Assess urine albumin excretion annually beginning at diagnosis
– Measure serum creatinine at least annually to estimate GFR and stage
level of CKD, if present (use MDRD equation)
• Consult nephrologist when stage 4 CKD (eGFR <30) develops
• Non-renal specialists should educate patients
– Progressive nature of diabetic kidney disease
– Renal preservation benefits of aggressive blood pressure, blood glucose,
and hyperlipidemia control
– Potential need for renal replacement therapy
ADA. Standards of medical care in diabetes – 2013. Diabetes Care. 2013;36(Suppl 1):S11-S66.
Least
Intensive
Less Intensive
A1C: Most
Intensive
6.0%
7.0%
8.0%
Psychosocioeconomic Considerations
Highly Motivated, Adherent,
Knowledgeable,
Excellent Self-Care Capacities,
& Comprehensive Support Systems
Less motivated, Non-adherent,
Limited insight,
Poor Self-Care Capacities,
& Weak Support Systems
Hypoglycemia Risk
Moderate
Low
High
Patient Age
45
40
55
50
60
65
70
75
Disease Duration
5
20
15
10
Other Comorbidities
None
Few/Mild
Multiple/Severe
Established Vascular Complications
None
Ismail-Beigi F et al. Ann Intern Med. 2011;154:554-559.
Early Micro
Cardiovascular
Advanced Micro
Profiles of Antidiabetic Medications
Renal safety profiles and
considerations
Copyright © 2013 AACE May not be reproduced in any form without express written permission from AACE.
Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379. Inzucchi SE et al. Diabetologia 2012;55:1577-1596.
Metformin in Patients with Mild Renal
Impairment
• Precautions/contraindications in the US
– Metformin contraindicated in women with SrCr >1.4 mg/dL
– Metformin contraindicated in AACE guidelines in stage 3B,
4, 5 CKD
• NICE guidelines (UK)
– Metformin permitted when eGFR <60 mL/min/1.73 m2, with
dose adjustment (half) when <45 mL/min/1.73 m2,
discontinuation when <30 mL/min/1.73 m2 (or Cr ≥1.7 )
Physicians' Desk Reference. 66th ed. Montvale, NJ: PDR Network; 2012; NICE Clinical Guideline 87. Management of Type 2 Diabetes. 2009.
Dose Adjustments and Contraindications in
T2DM Patients with Renal Impairment
• Metformin: Contraindicated when SCr ≥1.5 • SGLT-2 inhibitors
(men), ≥1.4 women
– Canagliflozin (100-300mg QD): 100 mg
• SU: dose reduction for renal insufficiency; do
QD for eGFR 45-<60; discontinue (or do
not use glyburide
not initiate) when eGFR <45;
• Insulin: dose reduction for renal insufficiency
contraindicated when eGFR <30
• GLP-1 receptor agonists
– Dapagliflozin (10 mg QD): do not initiate
– Exenatide: do not use if eGFR <30
when eGFR <60; discontinue when eGFR
– Others: use with caution
persistently <60; contraindicated in severe
• DPP-4 inhibitors
renal impairment, ESRD, dialysis
– Sitagliptin (100 mg QD): 50 mg for eGFR
– Empagliflozin (10-25 mg QD): do not
<50, 25 mg for eGFR <30
initiate when eGFR <450; discontinue
– Saxagliptin (5 mg QD): 2.5 mg QD when
when eGFR persistently <45;
eGFR <50
contraindicated in severe renal
– Linagliptin (5 mg QD): no dose adjustment
impairment, ESRD, dialysis
needed
– Alogliptin (12.5 mg QD): 6.25 mg QD for
CrCl <30 mL/min
Physicians' Desk Reference. Montvale, NJ: PDR Network; 2014.
Sulfonylureas in Patients with Renal
Impairment
• SUs are a leading cause of ER evaluations for adverse drug
reactions
• Some SUs have prolonged half-life (glyburide, glimepiride)
• Some SUs have active metabolites that are renally excreted
(glyburide)
• Safest may be glipizide (shortest acting and inactive metabolites)
• Consider a glinide (e.g. repaglinide, nateglinide) – rapid-acting
secretagogues.
• Dose any secretagogue cautiously in CKD due to the fact that
insulin itself is renally cleared
Physicians' Desk Reference. 66th ed. Montvale, NJ: PDR Network; 2012.
Estimated Rates of Emergency Hospitalizations
for Adverse Drug Events in Older US Adults,
2007–2009
Medications implicated in 67.0% of
hospitalizations:
-warfarin (33.3%)
-Insulins (13.9%)
-oral antiplatelet agents (13.3%)
-Oral hypoglycemic agents (10.7%)
Data from the National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance project (2007 through
2009) to estimate the frequency and rates of hospitalization after emergency department visits for adverse drug events in older.
Budnitz DS et al. N Engl J Med. 2011;365:2002-2012.
CASE: Key Patient Considerations for
Individualized Treatment
• HbA1C target: 7.0%-7.5%
• First-line treatment options
– Metformin monotherapy contraindicated per package label
– Other alternatives include SUs, but consider risk of hypoglycemia
– Other first-line drugs include TZDs, DPP-4 i’s, GLP-1 RAs, and
SGLT-2 inhibitors
•
SGLT-2 i’s less effective with declining kidney function (do not use if eGFR
<45-60, depending on drug)
– Basal insulin also possible but not popular with patients
– With a modest HbA1C target of 7%-7.5%, any of these treatments
should be able to get her close to goal
What is the optimal treatment choice for this patient?
CASE: Key Patient Considerations for
Individualized Treatment
• Other considerations
– HCTZ and beta blockers tend to increase BGs
– ACEI or ARB may provide renal protection, although mainly
in the setting of albuminuria
– Given lack of protein in her urine, whether her CKD relates
to DM is debatable
CASE
Team Approach for Overcoming
Barriers to Optimal T2DM
Management
CASE: Introduction
• Luis is a 79-year-old Hispanic man with a 20-year history of T2DM
• Current concerns
– Difficulty managing an increasingly complex T2DM regimen, which now
includes metformin/saxagliptin 5mg/1000mg and premixed insulin as
part 70/30 35 units BID
• Medical history: HTN, hyperlipidemia, GERD, OA, depression,
diabetic neuropathy; A1C 7.6% - 8.7% over the past few years
• Other medications: valsartan, amlodipine, HCTZ; rosuvastatin,
fenofibrate; omeprazole; gabapentin; baby aspirin
• Laboratory results: HbA1C 9.1%; Cr 1.2 mg/dL; eGFR 58 mL/min
• Blood glucose logs: 58-324 mg/dL over the past month
• Physical evaluation suggests mild cognitive dysfunction
CASE: Key Patient Considerations for
Individualized Treatment
• Patient appears to be on a reasonable, aggressive combination
therapy, yet his A1C is 9.1%. What are the barriers to better
glycemic control?
– Language barriers, health literacy, and other cultural
considerations
– Advancing age and infirmity
– Decreasing cognitive function
– Polypharmacy
– Nonadherence to medication
• Other considerations for management
– Treatment cost?
ADA-EASD Guideline: Considerations for
Hyperglycemia Management in Older Adults
• Reduced life expectancy
Less ambitious targets
• Higher CVD burden
HbA1C <7.5%–8.0% if
tighter targets not
easily achieved
• Reduced GFR
• At risk for adverse events
from polypharmacy
Focus on drug safety
• More likely to be
compromised from
hypoglycemic episodes
Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379. Inzucchi SE et al. Diabetologia 2012;55:1577-1596.
SDM in Patients with T2DM
• Goal of SDM: ensure that treatment
decisions align with patient’s
preferences
– Often includes patient education and
decision-support tools
• Potential benefits of SDM in T2D
– Increased patient knowledge and
adherence
– Less anxiety over the process of care
– Improved health outcomes
– Reductions in inappropriate care and costs
Lee EO et al. N Engl J Med. 2013;368:6-8.
VA. Shared Decision Making with the Patient with Diabetes. 2012.
Decision-Support Tools for SDM in T2D
Mayo Clinic “Diabetes Medication Choice” Decision Aid
• Decision-support tool for comparing T2DM medications by several factors of
interest to patients; available in English and Spanish
Mayo Clinic. Available at: http://diabetesdecisionaid.mayoclinic.org.
T2DM in the Hispanic Population
• Risk of T2DM is 66% higher among
Hispanic/Latino Americans than nonHispanic white Americans
• Wide variations of T2DM rates within
Hispanic populations
– 8.5% for Central and South Americans
– 9.3% for Cubans
– 13.9% for Mexican Americans
– 14.8% for Puerto Ricans
• Compared with non-Hispanic whites,
Hispanic patients are:
– 1.7 times more likely to start treatment
for diabetes-related ESRD
– 1.5 times more likely to die from
diabetes
American Diabetes Association (ADA). National Diabetes Statistics Report, 2014.
Enhancing Patient Engagement
• Increase patient comfort with welcoming atmosphere
– Employ Spanish speakers in clinic or office, provide Spanish-language
reading material, videos
– Include materials for various literacy levels that include illustrations,
idiomatic expressions
• Build trust
– Shake hands, make eye contact
• Engage family or other surrogates to ensure medications are taken
properly and provide help/support encouragement (cognitive impairment)
• Identify reasons for nonadherence; reduce pill burden, discuss cost issues,
use reminder tool (pill box)
Lipton RB et al. Diabetes Educ. 1998;24-67-70.
Oomen JS et al. Diabetes Educ. 1999;25:220-225.
Tips for Enhancing Patient Understanding
(For All Backgrounds)
• Use plain language
• Break it down into short
statements
• Focus on the 2 or 3 most
important concepts
• Check for understanding
using the teach-back method
• Try to get patient to be a
partner in his/her care
• Discuss side effects
Teach Back
1. Explain to the patient.
2. Have patient explain it back to
you.
Those who can: Success!
Those who can’t: Explain again,
using appropriate communication
and terms.
3. Repeat as necessary until goal
achieved.
Can also help identify terms and strategies
that are most commonly understood (and
misunderstood)
Beyond the Doctor
Enhancing Patient Engagement in Diabetes Care
• Help
overcome
social, cultural,
linguistic
barriers
Community
Health
Workers
Pharmacistled Medication
Management
Non-Physician
Providers
• Act as
powerful
change agents
Case
Managers
Baig AA et al. Med Care Res Rev. 2010;67(5 Suppl):163S-197S.
Medical (or
Medication)
Assistance
Programs
Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379. Inzucchi SE et al. Diabetologia 2012;55:1577-1596.
CASE: Key Patient Features and
Considerations for Individualized Therapy
• Difficult situation
• ? Loosen A1C target (around 8%)
• Simplify regimen
• Once daily meds (metformin XR – renal function acceptable)
• Once daily DPP4; consider once weekly GLP1-RA?
• Once daily insulin (basal insulin)
• Family supervision
• ? Visiting nurse
What is the optimal strategy for this patient?
CASE
Suboptimal Patient Adherence
to Treatment Recommendations:
Use of a Team Approach
CASE: Introduction
• Ralph is a 60-year-old obese man who has had T2DM for 7 years,
now treated with metformin 1000 mg BID and liraglutide 1.2 mg QD
– He is an executive for a large global corporation and travels regularly,
frequently entertaining over business dinners
• Current concerns
– Persistent diarrhea on metformin and GI upset on liraglutide
– While on the road, he does not follow any type of diet or exercise
program and often forgets to take his medications
• Medical history: gout, HTN, HLD; no complications
• Other medications: lisinopril, atorvastatin, allopurinol
– Physical exam: BMI: 38 kg/m2, BP: 138/88 mmHg
• Laboratory results: HbA1C: 8.7 %, LDL-C: 94, eGFR >60
CASE: Key Patient Considerations for
Individualized Treatment
• What are the barriers to better glycemic control?
– Poor adherence to lifestyle advice and medications
•
Lifestyle challenges: eats out a lot; no routine for exercise
•
Medication challenges: GI symptoms with metformin and
GLP-1 RA; also, reluctance to inject daily
• Other health concerns
– Obesity
– Hypertension, hyperlipidemia, and other CV risk factors
– Should he be on prophylactic ASA?
Medication Adherence and Glycemic Control
• Retrospective study of
249 patients who initiated
diabetes therapy with
metformin (46%), SUs
(39%), or TZD (12%)
• Controlling for baseline
A1C and therapy, each
10% decrease in
adherence was
associated with a 0.1%
decrease in A1C
(P = 0.0004)
Rozenfeld Y et al. Am J Manag Care. 2008;14:71-75.
Obesity and T2D: A Common Burden
Obesity Prevalence Among US Adults, 2013
County-Level Estimates of Diagnosed T2D
Among US Adults, 2011
Obesity = BMI ≥30 kg/m2, or ~ 30 lbs. overweight for 5’4” person
CDC Behavioral Risk Factor Surveillance Systems; CDC Diabetes Public Health Resource Center.
Complication-centric Model for Care of the
Overweight/Obese Patient
Copyright © 2013 AACE May not be reproduced in any form without express written permission from AACE.
SDM in Patients with T2D
• Goal of SDM: ensure that treatment
decisions align with patient’s
preferences
– Often includes patient education and
decision-support tools
• Potential benefits of SDM in T2D
– Increased patient knowledge and
adherence
– Less anxiety over the process of care
– Improved health outcomes
– Reductions in inappropriate care and costs
Lee EO et al. N Engl J Med. 2013;368:6-8.
VA. Shared Decision Making with the Patient with Diabetes. 2012.
Decision-support Tools for SDM in T2D
Mayo Clinic “Diabetes Medication Choice” Decision Aid
• Decision-support tool for comparing T2D medications by several factors of interest
to patients; available in English and Spanish
Mayo Clinic. Available at: http://diabetesdecisionaid.mayoclinic.org.
Keys to Facilitating Behavior Change
GOAL-SETTING MODEL
PATIENT-CENTERED
COMMUNICATION
• Focus on the person, not
the disease
• Explore feelings
– Many diabetes patients
feel shock, guilt, anger,
anxiety, depression, and
helplessness
Funnell MM. Fam Pract. 2010;27: i17–i22.
• Explore the problem
• Clarify feelings and meaning
• Develop a plan
• Commit to action
• Experiment with and evaluate the plan
COMMUNICATION MODEL
Ask-Listen-Empathize-Encourage
• Ask open-ended questions
– Reflect on areas of concern or
behaviors
– Identify actions to address the
problem or behavior
Beyond the Doctor
Enhancing Patient Engagement in Diabetes Care
Provide tools for
making better lifestyle
choices
• Food choices when
dining out
• Opportunities for
physical activity
while traveling
Certified
Diabetes
Educator
Pharmacistled Medication
Management
Non-Physician
Providers
Case
Managers
Baig AA et al. Med Care Res Rev. 2010;67(5 Suppl):163S-197S.
Medical (or
Medication)
Assistance
Programs
Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379. Inzucchi SE et al. Diabetologia 2012;55:1577-1596.
CASE: Key Patient Considerations for
Individualized Treatment
• Current treatment priorities
– A1C goal is <6.5% (otherwise healthy)
– Enhance medication adherence
– Identify medication regimen that fits with his lifestyle
•
•
•
•
•
Once weekly GLP-1RA?
SGLT-2 inhibitor?
TZD (weight gain)
Sulfonylurea (hypos)
Basal insulin (not thrilled with injections…?adherence)
– Weight loss medications? Bariatric surgery?
What is the optimal strategy for this patient?
Lipton RB et al. Diabetes Educ. 1998;24-67-70.
Oomen JS et al. Diabetes Educ. 1999;25:220-225.
CASE: Key Patient Considerations for
Individualized Treatment
• Involve the patient in shared decision-making
• Engage a CDE / nutritionist and diabetes care team:
– How can he work physical activity into his daily life?
– How can he optimize diet when traveling?
– Identify realistic lifestyle goals the patient feels he can reach
Lipton RB et al. Diabetes Educ. 1998;24-67-70.
Oomen JS et al. Diabetes Educ. 1999;25:220-225.
Participant CME Evaluation
• Please take out the Participant CME Post-survey and
Evaluation Form from the back of your packet.
• If you are not seeking credit, we ask that you fill out the
information pertaining to your degree and specialty, as well
as the few post-activity survey questions measuring the
knowledge and competence you have garnered from this
program. The post-survey begins on page 1 of the
evaluation form.
• Your participation will help shape future CME activities.
Thank you for joining us today!