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Dr. First Name Last Name
ROAR DM Speaker
Financial Disclosure:
Grants/Research Support
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Disclosure of Potential Conflict of Interest
Dr. First Name Last Name
ROAR DM Speaker
Financial Disclosure:
Grants/Research Support
Speaker Bureau/Honoraria
Consulting Fees:
Other:
Accreditation Statement
This program meets the accreditation criteria of
The College of Family Physicians of Canada and has been
accredited for up to 7 Mainpro-C credits.
This program was planned by the Canadian Heart
Research Centre, a not-for-profit academic organization,
and a national Planning Committee to achieve scientific
integrity, objectivity, and balance.
Eli Lilly Canada and Boehringer-Ingelheim have provided funding for this program but
have not been involved in the needs assessment, objectives, agenda, content, or
evaluation.
Learning Objectives:
At the completion of this program, participants will be able to:
1.
Identify currently available treatments for type 2 diabetes, their
pharmacological target among multiple risk factors contributing to
hyperglycemia, and their treatment indications
2.
Design an effective treatment plan for type 2 diabetes, combining lifestyle
modification and available pharmacological options
3.
Describe the renal and cardiovascular complications of diabetes and the
factors linking them
4.
Explore the effects of kidney function on the selection of diabetes
medications in terms of efficacy and side effects to identify the appropriate
choice for each patient
5.
Employ guidelines, improve office systems for the comprehensive
treatment of type 2 diabetes, and adapt educational resources and patient
education materials to improve the care of patients with type 2 diabetes
Module 1
Diabetes in Canada:
A Challenge for the Busy Primary
Care Practitioner
The Prevalence of Diabetes
in Canada is Increasing
• The prevalence of diabetes in Canada is
expected to increase by ~6% per year
• By 2012, ~2.8 million Canadians will have
diagnosed diabetes
• This will represent a 25% increase in
prevalence from 2007
Public Health Agency of Canada. 2009. Available at: http://www.phac-aspc.gc.ca.
Family Physicians
Provide 92% of Diabetes Care
74% family
physician
care alone
92%
1% specialist alone
18% family physician
and specialist care
7% no diabetes care
(orphans)
Jaakkimainen L, ICES. 2003.
Glycemic Management in Two Canadian
Cohorts with T2DM
DICE1
(2002-2003)
N = 2473
DRIVE2
(2005-2006)
N = 3002
Oral agents only
73.0
76.0
Monotherapy
36.0
48.5
Dual therapy
30.0
36.5
3+ agents
8.0
15.0
(Using metformin)
61.0
72.0
12.0
15.0
Insulin monotherapy
6.0
5.0
Insulin with oral agents
6.0
10.0
15.0
9.0
Treatment, % of patients
Insulin
No antihyperglycemic agents
1Harris
S, et al. Diabetes Res Clin Prac. 2005;70(1):90-97.
M, et al. Can J Cardiol. 2010;26(6):297-302.
2Braga
What do you believe is/are the most
challenging guideline goal(s) to achieve in your
practice?
1.
2.
3.
4.
A1C at target
LDL-C < 2.0 mmol/L
BP < 130/80
All of the above
What strategies do you think improve clinical
diabetes care the most in family practice?
1. Use of flow sheets
2. Financial incentives
(i.e., billing)
3. Delegation of DM care
clinical follow-up
4. Use of ‘‘mini-clinics’’
5. Establishing a diabetes
registry from your
practice
0%
1
0%
0%
2
3
0%
0%
4
5
Module 2
Therapeutic Options:
How do incretins fit into
our practice?
With regard to GLP-1 Which of the following
statements is TRUE ?
1. GLP-1 increases insulin
secretion in a glucosedependent fashion
2. GLP-1 decreases glucagon
secretion in a glucosedependent fashion
3. GLP-1 increases insulin
secretion and decreases
glucagon secretion in a
glucose-dependent fashion
0%
1
0%
2
0%
3
Incretins Regulate Glucose Homeostasis
Through Effects on Islet Cell Function
Ingestion
of food
Glucose dependent
 Insulin
from beta cells
(GLP-1 and GIP)
Release of
incretin gut
hormones
Pancreas
Beta cells
Alpha cells
Insulin
increases
peripheral
glucose
uptake
Blood
glucose control
Active
GLP-1 and GIP
GI tract
 Glucagon
from alpha cells
(GLP-1)
Glucose dependent
Increased insulin and
decreased glucagon
reduce hepatic
glucose
output
Adapted from Brubaker PL, Drucker DJ. Endocrinology. 2004;145:2653–2659; Zander M, et al. Lancet. 2002;359:824–830; Ahrén B, Curr Diab Rep. 2003;3:365–372; Buse
JB, et al. In Williams Textbook of Endocrinology. 2003;(10th ed. Philadelphia, Saunders):1427–1483.
Incretin Effect in T2DM
Nauck MA, et al. Diabetologia.1986;29:46–52.
GLP-1 actions are glucose dependent in patients
with T2DM – Lower Hypoglycemia Risk
Nauck MA, et al. Diabetologia.1993;36:741–744.
Summary of Incretin Actions on Different
Target Tissues: GLP-1
Heart
Brain
Neuroprotection
Appetite
Gastric
Emptying
Cardioprotection
Stomach
Cardiac Output
_
Liver
GI Tract
(indirect
effect)
Insulin Secretion
β-Cell Neogenesis*
Glucose
Production
Adapted from Drucker DJ. Cell Metab. 2006;3:153-165.
Muscle
(indirect effect)
+
β-Cell Apoptosis*
Glucose
Uptake
Glucagon Secretion
* preclinical data
Strategies to Exploit the
Beneficial Actions of Incretins
GLP-1 mimetic/GLP-1R agonists
Stable peptide preparations with actions similar to the natural
incretin hormones
• Exenatide
• Liraglutide
Incretin enhancers (DPP-4 inhibitors)
Inhibit the normal degradation of incretin hormones and thereby
increase their plasma concentrations and biological actions
• Linagliptin
• Saxagliptin
• Sitagliptin
Which of the following statements about
incretins is/are CORRECT?
1.
2.
3.
4.
5.
Both DPP-4 inhibitors and GLP-1R
agonists raise GLP-1 levels into the
pharmacological range
The use of both DPP-4 inhibitors and
GLP-1R agonists is typically associated
with weight loss
The use of GLP-1R agonists is typically
associated with weight loss
The use of DPP-4 inhibitors is typically
associated with nausea
1 and 3
0%
1
0%
0%
2
3
0%
0%
4
5
Effects of GLP-1: Dose-response relationship
Vomiting
Increasing plasma
GLP-1 concentrations
Diarrhea
Nausea
Abdominal pain
 Appetite
 Food intake
= Weight loss
GLP-1 levels
achieved with
GLP-1-receptor
agonists
 Gastric emptying
Pharmacological effects
 Insulin secretion
 Glucagon secretion
= improved glycemic control
Physiological effects
GLP-1 levels
achieved with
DPP-4 inhibitors
GLP-1 effects
Holst JJ, et al. Trends Mol Med. 2008;14:161–168.
Which of the following statements with regard
to the DPP-4 inhibitors is/are CORRECT?
1. They all lower A1c to a similar
degree
2. The use of all of them can be
associated with nausea
3. They all have similar routes of
excretion
4. They all have similar indications
in Canada
0%
1
0%
2
0%
3
0%
4
Dosing and
monitoring
Excretion
Metabolism
Pharmacological Features of the
DDP-4 Inhibitors
Alogliptin
25 mg QD
Linagliptin
5 mg QD
Saxagliptin
5 mg QD
Sitagliptin
100 mg QD
Vildagliptin
50 mg BID
Relevant organ
for metabolism1
None
None
Liver
None
Liver
Active
metabolites
No
No
Yes
No
No
Main route of
excretion
Kidney
Bile & gut
Kidney
Kidney
Kidney
Share of renal
excretion2
60 - 71%
5%
75%
87%
85%
Dose adjustment
and/or limitations
in RI3
Yes
No
Yes
Yes
Yes
Drug-related
monitoring
Kidney
function
No
Kidney
function
Kidney
function
Kidney and liver
function
1 If metabolized to a relevant degree
2 Including metabolites and unchanged drug; excretion after single-dose administration of C14-labelled drug
3 As recommended in countries where respective DPP-4 inhibitor is available
Respective US prescribing information or EUSmPc: Scheen, et al. DOM. 2010;2:648-658; Deacon, et al. DOM. 2011;13:7-18; Vincent, et al. Drug Metab
Dispos. 2007;35:533-538; He, et al. Drug Metab Dispos. 2009;37:536-544; Christopher, et al. Clin Ther. 2008;30:513-527.
Efficacy of DPP-4 Inhibitors
in Monotherapy Trials
Placebo-corrected, adjusted mean change from baseline HbA1c
Dosage
Baseline
HbA1c
Linagliptin1*
5 mg QD
8.1%
Linagliptin1
5 mg QD
8.0%
Saxagliptin2 Saxagliptin2
5 mg QD
5 mg QD
≥7% to ≤10%
8.0%
Sitagliptin3*
100 mg QD
8.0%
Sitagliptin3
100 mg QD
8.0%
Vildagliptin4 Vildagliptin4
50 mg BID
50 mg BID
8.6%
8.4%
-0.4%
-0.5%
-0.6%
-0.6%
-0.6%
-0.7%
-0.7%
-0.8%
n=
p-value†
147
272
69
103
193
229
90
79
<0.0001
<0.0001
=0.0059
<0.0001
<0.0001
<0.0001
<0.05
<0.05
* 18 weeks’ treatment duration, 24 weeks otherwise
† Between-group difference versus placebo
1– 3. US PI for linagliptin, saxagliptin, sitagliptin
4. EU SmPC for vildagliptin
Efficacy of DPP-4 Inhibitors
in Add-on to Metformin Trials
Placebo-corrected, adjusted mean change from baseline HbA1c
Dosage
Baseline
HbA1c (%)
Linagliptin2
5 mg QD
8.1
Linagliptin1*
5 mg QD
Saxagliptin3
5 mg QD
8.1
8.1
-0.8%
-0.8%
Sitagliptin4
100 mg QD
8.0
Vildagliptin5
50 mg BID
8.4
-0.6%
-0.7%
-1.1%
n=
p-value
513
209
186
453
143
<0.0001
< 0.0001
<0.0001
<0.0001
<0.05
* 12 weeks’ treatment duration, 24 weeks otherwise Sources:
1. Linagliptin data on file 2–4. US PI for linagliptin, saxagliptin, sitagliptin 5. EU SmPC for vildagliptin
Linagliptin Brings Patients to Target (Hba1c <7%) with
Significantly Less Hypoglycemia and Relative Weight
Loss Compared to Glimepiride
Adjusted2 means for body weight change
from baseline ± SE
Linagliptin
Kg - FAS (OC)
Incidence of hypoglycemia
Percentage of patients - Treated set1
Glimepiride
2.0
1.5
50
1.0
p<0.0001
0.5
40
Rate of patients achieving
0
HbA1c target of <7%
-0.5
Percentage of patients at
week 104 completers cohort3 -1.0
30
20
10
7.5
Linagliptin
Glimepiride
12
28
52
78
104
weeks
-1.5
-1.5
100
-2.0
0
+1.4
p<0.0001
-2.9
80
75.6
76.4
60
40
20
0
1 Treated set: linagliptin n=776, glimepiride n=775
Linagliptin
Glimepiride
2 Model includes baseline HbA1c, baseline weight, no. prior OADs, treatment, week repeated within patients and week by treatment interaction
3 Completers cohort: linagliptin n=233, glimepiride n=271
Gallwitz B, et al. ADA. 2011 Late Breaker 39-LB.
Linagliptin: Safety and Tolerability
Organ-specific adverse event (AE) rate for AE previously associated with the DPP-4 inhibitor class1
Linagliptin Placebo
n
2,523
1,049
Pancreatitis:
Pancreatitis was reported more
often in patients randomized to
linagliptin
(1 per 538 person years versus
zero in 433 person years for
comparator)*
Headache
2.9%
3.1%
Upper respiratory tract
infection
3.3%
4.9%
5.9%
1.7%
5.1%
1.0%
0.1%
0.1%
Serum creatinine increase 0.0%
0.1%
Nasopharyngitis
Cough
Hepatic enzyme increase
Urinary tract infection
2.2%
2.7%
Blood and lymphatic
system disorders
1.0%
1.2%
Hypersensitivity
0.1%
0.1%
1. Organ-specific adverse events taken from label of currently marketed DPP-4 inhibitor in the US; * Linagliptin US PI
Schernthaner G, et al. ADA. 2011 Abstract 2327-PO. Pooled data from 8 studies.
Which of the following statements with regard
to the GLP-1R Agonists is CORRECT?
1. They lower body weight to a
similar degree in all patients
2. The use of all of them may be
associated with allergic reactions
3. They reduce A1C to a similar
degree in all patients
4. The nausea is typically transient
0%
1
0%
2
0%
3
0%
4
Exenatide: A1C Lowering in Major Trials
NI: Non-Inferior
Buse JB, et al. Diabetes Care. 2004;27:2628-2635; DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100;
Kendall DM, et al. Diabetes Care. 2005;28:1083-1091; Zinman B, et al. Ann Intern Med 2007;146:477-485;
Moretto TJ, et al. Clin Ther. 2008; 30:1448-1460; Heine R, et al. Ann Intern Med 2005;143:559-569.
Exenatide Large Phase 3 Clinical Studies –
Combined (ITT): Adverse Events
Results of 30-week exenatide studies
Adverse event
Placebo BID
(n = 483)
Exenatide BID
5 mcg and 10 mcg
(n = 963)
Nausea
18%
44%
Vomiting
4%
13%
Diarrhea
6%
13%
Feeling jittery
4%
9%
Dizziness
6%
9%
Headache
6%
9%
Dyspepsia
3%
6%
If pancreatitis is suspected, exenatide should be discontinued.
FDA. Available at: http://www.fda.gov/cder/foi/label/2008/021773s012lbl.pdf. Accessed September 29, 2008.
FDA. Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/exenatide2008HCP.htm. Accessed September 29, 2008.
Liraglutide: A1C Lowering in Major Trials
Marre, et al. Diabetic Medicine. 2009; Nauck MA, et al. Diabetes Care. 2009;32:84-90; Pratley, et al. Lancet. 2010;
Garber A, et al. Lancet. 2009; Zinman B, et al. Diabetes Care. 2009;
Russell-Jones, et al. Diabetologia. 2009; Buse J, et al. Lancet. 2009.
Weight Loss with GLP1s is Variable
0–Q1: mean weight change for the 25% of subjects who had the largest weight loss
Q1–Q2: mean weight change for the 25–50% weight loss quartile
Q2–Q3: mean weight change for the 50–75% weight loss quartile
Q3–Q4: mean weight change for the 75–100% weight loss quartile, that is, the 25% who had the smallest weight loss
Nauck, et al. Diabetes Care. 2009;32;84–90 (LEAD-2).
CV Meta-analyses of Individual Incretin Agents
No increased risk of CV events was observed in patients
randomly treated with DPP-4 inhibitors or GLP-1R agonists
FDA Upper
Bound 95%
Criterion for
Approvability
Exenatide1
0.38
1.31
0.7
Linagliptin2
0.15 0.34
Total patients
in analysis
CV composite
endpoint
3,945
MedDRA terms for stroke,
MI, cardiac mortality, ACS,
revascularization
Post hoc/
No formal
adjudication
5,239
CV death, MI, stroke,
hospitalization due to
angina pectoris
Prespecified/
Independent
adjudication
MedDRA terms
for MACE
Post hoc/
No formal
adjudication
0.74
6,638
Liraglutide3
0.32
1.24
0.63
Saxagliptin4
4,607
0.23 0.43
0.80
Sitagliptin5
10,246
0.41 0.68
0.125
0.25
0.5
Incretin agent better
MI, stroke, CV death
1.12
1
2
4
MedDRA terms
for MACE
Comments
Post hoc/
Independent
adjudication
Post hoc/
No formal
adjudication
8
Comparator better
Risk ratio for major CV events1-5
Ratner R, et al. Cardiovascular Diabetology. 2011;10:22.
Johansen O-E, et al. ADA. 2011 Late breaker 30-LB.
www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4422b2-01-FDA.pdf. Accessed Sept. 23, 2011.
Frederich R, et al. Postgrad Med. 2010;122(3):16–27.
Williams-Herman D, et al. BMC Endocr Disord. 2010;10:7.
Incretin-based Therapies: Pancreatitis
Patients with type 2 diabetes have a 2.8-fold higher risk than the general
population (4.2 vs. 1.5 cases per 1000 pt-yrs)
Exenatide:
Isolated cases in clinical development program (8 cases = 1.8 per 1,000 pt-yrs)
Incidence consistent with expected rate in type 2 diabetes and similar to placebo (2.6 per 1,000 pt-yrs)
971 post-marketing cases reported to FDA AERS 2004-2009
Linagliptin:
Isolated cases reported during clinical development (8 cases = 1.9 per 1,000 pt-yrs)
Incidence consistent with expected rate in type 2 diabetes patients
Liraglutide:
Isolated cases reported in clinical development program (7 cases = 2.2 cases per 1,000 pt-yrs)
Incidence consistent with expected rate in type 2 diabetes patients
Saxagliptin:
Isolated cases reported during clinical development (6 cases = 0.2%)
Consistent with expected rate in type 2 diabetes and similar to comparators (2 cases = 0.6%)
Sitagliptin:
Isolated cases reported in controlled clinical trials (4 cases = 0.8 per 1,000 pt-yrs)
Consistent with expected rate in type 2 diabetes and similar to comparators (1 per 1,000 pt-yrs) 131 post-marketing
cases reported to FDA AERS 2004-2009
Noel R, et al. Diabetes Care. 2009;32(5):834-838; Victoza, Product Monograph. Novo Nordisk Canada Inc., 2010;
Anderson S, et al. Ann Pharmacother. 2010;44; Engel S, et al. Int J Clin Pract.2010; FDA. September 25, 2009. www.fda.gov/Drugs/DrugSafety/
PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm183764.htm.
Saxagliptin FDA Briefing Document March 2009; Elashoff M, et al. Gastroenterology. 2011;doi:10.1053/j.gastro.2011.02.018; Linagliptin Procuct Monograph Canada 2011 .
Which of the Following Differences Between DPP-4
inhibitors and GLP-1R agonists is CORRECT?
1. They both decrease
gastric emptying
2. They both increase satiety
3. They both reduce glucagon
secretion
4. They both can be given orally or
subcutaneously
0%
1
0%
2
0%
3
0%
4
GLP-1R Agonists vs. DPP- 4 Inhibitors
GLP-1R Agonists
DPP-4 Inhibitors
Injection
Orally available
GLP-1 concentrations
Pharmacological
Physiological
Mechanisms of action
GLP-1
GLP-1 + GIP
Activation of portal glucose
sensor
No
Yes
Insulin secretion
+++
+
Glucagon secretion
++
++
Inhibited
+/-
Yes
No
In preclinical studies
Yes
Yes
Nausea and vomiting
Yes
No
Potential immunogenicity
Yes
No
Administration
Gastric emptying
Weight loss
Expansion of beta-cell mass
Patient Targets for Incretin-Based Therapy

GLP-1 agonists
DPP- 4 inhibitors
• Obese type 2 diabetes
patients
• Dysfunctional needle phobia
• Patients failing to maintain
goals with oral agents
• Add-on to other agents,
including insulin*
• Advantages
– weight loss
– easy dosing
– new mechanism with
possible beta cell sparing
• Add-on to other oral agents,
including insulin*
• Advantages
– oral availability
– excellent tolerance
– weight neutral
– new mechanism with possible
beta cell sparing
* The combination of an incretin agent with insulin is not approved in Canada
Approved Canadian Indications for
Incretin-Based Therapies
Monotherapy
(Met intol. or
contraind.)
Add-on to
metformin
(dual Tx)
Add-on to
sulfonylureas
(dual Tx)
Add-on to
metformin and
sulfonylureas
(triple Tx)






DPP-4
inhibitors
Linagliptina
Saxagliptinb
Sitagliptinc



GLP-1 receptor
agonists
Exenatided

Liraglutidee




a: Based on Canadian linagliptin product monograph of July 26,2011.
b: Based on Canadian saxagliptin product monograph of Sept 14,2009.
c: Based on Canadian sitagliptin product monograph of Oct 25,2010.
d: Based on Canadian exenatide product monograph of Jan 11,2011.
e: Based on Canadian liraglutide product monograph of May 21,2010.
Antihyperglycemic Medications and Renal Function
CKD Stages (GFR)
1
(> 90)
2 Mild (60-89)
3 Moderate (30-59)
4
GLP-1R Agonists
DPP-4 Inhibitors
Acarbose
Severe (15-29)
25
Linagliptin
15
5 mg OD
Saxagliptin
50
5 mg OD
Sitagliptin
5 ESKD* (<15)
30
15
2.5 mg OD
50
100 mg OD
50 mg OD
Exenatide
50
Liraglutide
50
30
25 mg OD
30
Repaglinide
Sulfonylurea
Metformin
60
30
Gliclazide/Glimepiride
Glyburide
50
Thiazolidinediones
30
30
Insulin
100
CKD = Chronic Kidney Disease
GFR = Glomerular Filtration Rate
* ESKD – End Stage Kidney Disease
Based on Canadian product monographs as of September 10, 2012
75
GFR (ml/min)
50
25
0
Adapted from product monographs, CDA Guidelines, 2008 and
Yale JF, J Am Soc Nephrol. 2005;16:S7-S10.
Summary
• The incretin agents, are efficacious in monotherapy and in
combination with other antihyperglycemic agents with the lack of
hypoglycemia and beneficial/neutral effects on body weight
providing potential advantages relative to other classes of
antihyperglycemic agents
• The incretin agents may have other important pancreatic and
non-pancreatic benefits (e.g., beta cell preservation, CV risk
reduction), but these must be proven in long-term studies
• Chronic kidney disease is common in diabetes and is one of a
number of factors that must be considered in the selection of an
appropriate antihyperglycemic agent
Module 3
How the Kidney Affects Diabetes
Control and its Complications
Contributing factors to hypoglycemia in CKD
patients include:
1. Loss of renal cortical
gluconeogenesis
2. Malnutrition
3. Decreased insulin clearance
4. Failure to adjust dose
of antihyperglycemic medication
5. All of the above
0%
1
0%
0%
2
3
0%
0%
4
5
Incident Rate Ratios
Risk For Hypoglycemia in Veterans Classified by
Presence or Absence of Chronic Kidney Disease (CKD)
And Diabetes
8.43
9
8
7.21
7
6
4.09
5
4
3
2
3.56
1.62
3.28
1
1.58
1
1.66
0
Glucose < 2.8 mmol/L
1
1.53
Glucose < 3.3 and >2.8 mmol/L
1
+CKD, +Diabetes
-CKD, +Diabetes
Glucose < 3.9 and >3.3 mmol/L
+CKD, -Diabetes
-CKD, -Diabetes
All p-values <0.0001, (95% CI)
Moen MF, et al. CJASN. 2009;4:1121-1127.
Etiology Of Hypoglycemic Events in ESRD*
Patients Hospitalized Due to Hypoglycemia
7% 2%
2% 2%
46%
Hypoglycemic Agents
Sepsis
Severe Malnutrition
Liver Failure
Alcohol
Malignancy
39%
Hypoglycemia often caused by drugs in CKD patients
ESRD: End Stage Renal Disease
Yosef S, et al. Renal Failure. 2000;22(2):219-223.
Possible Mechanisms of Hypoglycemia in CKD
• Most advanced CKD patients with hypoglycemia have
some degree of cachexia/malnutrition/anorexia
• Chronic malnutrition decreases hepatic glycogen content
and may also contribute to hypoglycemia in CKD
• Decreased gluconeogenesis:
• Substrate limitation hepatic and renal
• Reduced renal cortical mass
• Decreased renal clearance of insulin and AHA in diabetes
• Use of either a contraindicated drug (most often an antidiabetic agent) or one requiring dose adjustment increased
6-year mortality by 40% in the elderly
Nephrol Dial Transplant (2011) 26 (9): 2852-2859
Nephrol Dial Transplant (2011) 26: 1888–1894
According to their product monographs, which
of the following antihyperglycemic agents are
contraindicated or require dose adjustment
when eGFR is <50?
1.
2.
3.
4.
5.
Metformin
Saxagliptin
Exenatide
Glyburide
All of the above
0%
1
0%
0%
2
3
0%
0%
4
5
Antihyperglycemic Medications and Renal Function
CKD Stages (GFR)
1
(> 90)
2 Mild (60-89)
3 Moderate (30-59)
4
GLP-1R Agonists
DPP-4 Inhibitors
Acarbose
Severe (15-29)
25
Linagliptin
15
5 mg OD
Saxagliptin
50
5 mg OD
Sitagliptin
5 ESKD* (<15)
30
15
2.5 mg OD
50
100 mg OD
50 mg OD
Exenatide
50
Liraglutide
50
30
25 mg OD
30
HEMO
Repaglinide
Sulfonylurea
Metformin
60
30
Gliclazide/Glimepiride
Glyburide
50
Thiazolidinediones
30
30
Insulin
100
CKD = Chronic Kidney Disease
GFR = Glomerular Filtration Rate
* ESKD – End Stage Kidney Disease
Based on Canadian product monographs as of September 10, 2012
75
GFR (ml/min)
50
25
0
Adapted from product monographs, CDA Guidelines, 2008 and
Yale JF, J Am Soc Nephrol. 2005;16:S7-S10.
Intensive glucose control has been shown to
delay the progression of CKD in the setting of
diabetes
1. True
2. False
0%
1
0%
2
Cumulative Incidence of an Impaired Glomerular
Filtration Rate According to Treatment Group
The DCCT/EDIC Research Group. N Engl J Med. 2011;DOI:10.1056/NEJMoa1111732.
CHEP 2012: Treatment of Hypertension in
association with Diabetic Nephropathy
THRESHOLD equal to or over 130/80 mmHg and TARGET below 130/80 mmHg
DIABETES
ACE Inhibitor
or ARB
With Nephropathy
IF ACEI and ARB are
contraindicated or not tolerated,
SUBSTITUTE
• Long-acting CCB or
• Thiazide diuretic
Addition of one or more of
long-acting CCB or thiazide diuretic
3 - 4 drugs combination
may be needed
If creatinine over 150 µmol/L or creatinine clearance below 30 ml/min ( 0.5 ml/sec), a loop diuretic should be substituted
for a thiazide diuretic if control of volume is desired
Monitor serum potassium and creatinine carefully in patients with CKD
prescribed an ACEI or ARB
Chronic Kidney Disease in Diabetes
The DCCT/EDIC Research Group. N Engl J Med. 2011;DOI:10.1056/NEJMoa1111732.
Module 4
Optimal Glucose Management:
How to choose the right agent for
the right patient
2008 CDA Guidelines
CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2008;32(suppl 1):S1-S201.
Antihyperglycemic Agents
Insulin Resistance Insulin Deficiency
 Metformin
 TZD
Other
 Acarbose
 Insulin
Secretagogue
 DPP-4 Inhibitor
 GLP-1 RA
Cheng AYY, Fantus IG. CMAJ 2005; 172:213-26.
Palalau AI, et al. Postgrad Med 2009; 121(6):70-100.
What is your level of comfort in discussing the
pros and cons of the various classes?
1.
2.
3.
4.
5.
Uncomfortable
Somewhat uncomfortable
Neutral
Comfortable
Very comfortable
0%
1
0%
0%
2
3
0%
0%
4
5
Pros and Cons
Insulin Resistance Insulin Deficiency
 Metformin
 TZD
Other
 Acarbose
 Insulin
Secretagogue
 DPP-4 Inhibitor
GLP-1 RA
Cheng AYY, Fantus IG. CMAJ 2005; 172:213-26.
Palalau AI, et al. Postgrad Med 2009; 121(6):70-100.
When selecting the next agent after metformin,
which of the following statements best
describe you?
1. I use the same second-line agent
for all patients unless there is a
contraindication
2. I like having multiple options and
consider all of them before
selecting the best one for the
patient
3. I use one of 2 classes only
0%
1
0%
2
0%
3
What is your level of comfort in individualizing
therapy?
1.
2.
3.
4.
5.
Uncomfortable
Somewhat uncomfortable
Neutral
Comfortable
Very comfortable
0%
1
0%
0%
2
3
0%
0%
4
5
Questions to Consider When Individualizing …
What is the degree of hyperglycemia?
Is the patient at risk for hypoglycemia?
Does the patient have a drug plan?
Other Considerations:
Contraindications, weight, glycemic durability,
side effects, comfort, preference
Glucose Lowering
A1c
FAST
↓↓↓
Insulin
↓↓
↓
MOD
DPP-4
Secretagogue
GLP-1 RA
SLOW
TZDs
Acarbose
2008 CDA Guidelines
Questions to Consider When Individualizing …
What is the degree of hyperglycemia?
Is the patient at risk for hypoglycemia?
Does the patient have a drug plan?
Other Considerations:
Contraindications, weight, glycemic durability,
side effects, comfort, preference
Risk of Causing Hypoglycemia
High
 Insulin
 Secretagogue
Low





Acarbose
DPP-4 Inhibitor
GLP-1 RA
Metformin
TZDs
CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2008;32(suppl 1):S1-S201.
Who is at Risk for Hypoglycemia?
Risk factors for hypoglycemia
 Variable eating
 Variable activity
 Poor recognition of hypoglycemia
(elderly, dementia)
 Chronic kidney disease
High-risk consequences of hypoglycemia
 Bus driver, pilot, truck driver, etc.
 Living alone
Questions to Consider When Individualizing …
What is the degree of hyperglycemia?
Is the patient at risk for hypoglycemia?
Does the patient have a drug plan?
Other Considerations:
Contraindications, weight, glycemic durability,
side effects, comfort, preference
Other Considerations
 Absence of contraindications
 Glycemic durability
 Weight effects
 Side effects
 Comfort of prescriber
 Patient preference
Secretagogue
Insulin
Acarbose
TZD
DPP-4
Inhibitors
GLP-1 RA
+
+
Neutral
+
Neutral
Loss
FLUID RETENTION /
CHF
None
Rare
None
+
None
None
FRACTURES
None
None
None
+
None
None
GI INTOLERANCE
None
None
+
None
None
+
GLYCEMIC
DURABILITY
Poor
??
??
??
??
2-year
New
WEIGHT GAIN
LONG-TERM
EXPERIENCE
PRESCRIBER
COMFORT
PATIENT
PREFERENCE
© Alice Y.Y. Cheng 2010
Summary
• Pros and cons of each class
̵
Hypoglycemia, weight, side effects,
degree of control, etc.
• What is the degree of hyperglycemia?
• Is the patient at risk for hypoglycemia?
• Does the patient have a drug plan?
• Other: contraindications, glycemic
durability, weight, side effects, comfort,
preference
Module 5
Interactive Case: Leon
Leon
• 70-year-old hypertensive for 15 years
with type 2 diabetes for 10 years
• Presents to emergency with
acute hypoglycemia
• His blood sugar is 2.8
What we know…..
eGFR
Blood Pressure
Waist Circumference
ACR
Uric Acid
LDL
40 ml/min
144/92 mmHg
104 cm
24 mg/mmol
420 µmol/L
2.4 mmol/L
Leon’s Medications
Metformin
1,000 mg BID
Glyburide
5 mg BID
Ramipril
10 mg OD
Atorvastatin
10 mg OD
Leon’s ACR of 24 requires therapy targeted to
reduce this value in order to reduce future CV
events
1. True
2. False
0%
1
0%
2
Cardiovascular risk is greatest when both
diabetes and nephropathy are present
x 2.1
Incidence per 100 patient-years
30
x 1.7
x 2.5
25
20
15
x 2.2
10
5
0
AMI
CVA/TIA
PVD
Death
Foley RN, et al. J Am Soc Nephrol. 2005;16:489–495.
Age-standardized event rate (per 100 person-yr)
Relationship Between eGFR
and Clinical Outcomes
Death from any cause
Cardiovascular events
Any hospitalization
Total events = 51,424
Total events = 139,011
Total events = 554,651
eGFR (mL/min/1.73 m2)
Go AS, et al. N Engl J Med. 2004;351:1296-305.
Risk Classification of CKD
Proteinuria
Alternate System
eGFR, mL/min/1.73 m2
≥ 90
60-89.9
45 – 59.9
30 – 44.9
15 – 29.9
Normal
Mild
Heavy
ACR < 30 mg/g or urine
dipstick negative
ACR 30-300 mg/g or
urine dipstick trace or 1+
ACR > 300 mg/g or
urine dipstick ≥ 2+
Risk Category
Risk Category
Risk Category
0
(No CKD)
1
3
Risk Category
Risk Category
1
2
Risk Category
Risk Category
Risk Category
2
3
4
Risk Category
Risk Category
3
4
Tonelli M, et al. Ann Intern Med. 2011;154:12.
Approximately 40% of type 2 diabetes patients
have renal complications†
2.3
9.5
17.7
50.8
Data missing
No CKD
CKD stage 1
CKD stage 2
CKD stage 3
CKD stage 4/5
11.1
8.6
CKD prevalence was greater among people with diabetes than among
those without diabetes (40.2% versus 15.4%)
* No signs of kidney damage
** Albuminuria – kidney damage
†Based on data from 1,462 patients aged ≥20 years with T2DM who participated in the Fourth National Health and Nutrition Examination Survey (NHANES IV) from 1999 to 2004.
ACCOMPLISH: Diabetes Subset
ACEI + CCB better than ACEI + HCTZ
Non-Diabetes
All Diabetes
0.24
0.24
0.12
0.06
B+H
2,293
0.18
0.12
0.06
0 0
6 12 18 24 30 36 42
2,172
2,087 2,012 1,937 1,839
1,102 534
B+H
3,468
B + A (events = 195)
B + H (events = 244)
HR = 0.77 (0.64–0.93; p = 0.007)
Proportion of patients
0.18
0.24
B + A (events = 307)
B + H (events = 383)
HR = 0.79 (0.68–0.92; p = 0.003)
Proportion of patients
Proportion of patients
B + A (events = 245)
B + H (events = 296)
HR = 0.82 (0.69–0.97; p = 0.020)
00
High-Risk Diabetes
0.18
0.12
0.06
6 12 18
3,310
24 30 36 42
3,186 3,069 2,954 2,815
1,647 856
00
B+H
1,410
6 12 18
1,333
24 30 36 42
1,263 1,197 1,145 1,058
628
310
Weber MA, et al. J Am Coll Cardiol. 2010;56:77.
SHARP:
Major Atherosclerotic Events
The Lancet, 377 (9784); 2181 - 2192, 25 June 2011
Leon’s proteinuria is……….
1. A predictor for stroke and CHD
events
2. A target for therapy to reduce CV
events
3. A strong predictor of future
progression of his CKD
4. All of the above
5. 1 and 3
6. 1 and 2
0%
0%
1
2
0%
0%
0%
0%
3
4
5
6
Proteinuria as a Predictor of Stroke and CHD
Events in Type 2 Diabetes
40
0.9
A
0.8
B
0.7
C
0.6
Incidence (%)
CV Mortality
1.0
p<0.001
30
20
10
0.5
p<0.001
0
0
0
20
40
60
Stroke
80
CHD events
Months
A: U-Prot < 150 mg/l
B: U-Prot 150-500 mg/l
C: U-Prot > 500 mg/l
Mietinen H, et al. Stroke. 1996;27:2033-2039.
Identify Patients in Your Practice At High Risk For Chronic Kidney Disease
• Patients with hypertension
• Patients with diabetes mellitus
• Patients with atherosclerotic coronary, cerebral, or peripheral vascular disease
eGFR <30
•
•
•
•
eGFR 30-60
Consider reversible factors:
• Medication
• Volume Depletion
CKD is diagnosed in this group only
if other renal abnormalities are present
(i.e. proteinuria, hematuria, anatomical)
Repeat tests in 2 - 4 weeks
Nephrology referral
recommended
eGFR >60
Individualized follow-up
and treatment
• Intercurrent illness
• Obstruction
eGFR <30
Patients with heart failure
Patients with unexplained anemia
Patients with a family history of end-stage renal disease
First Nations peoples
eGFR 30-60
• Follow eGFR at 3 months, then serially
• Assess for persistent significant proteinuria
• Implement risk reduction
eGFR < 30
or progressive decline in eGFR
or persistent significant proteinuria
or inability to attain treatment targets
Stable eGFR 30-60 and
no significant proteinuria
Canadian Society of Nephrology - Société Canadienne de Néphrologie - www.csnscn.ca
What we should aim for…….
eGFR
Blood Pressure
Waist
Circumference
ACR
Uric Acid
LDL
40 ml/min
<130/80
144/92 mmHg
104 cm
<94
24 mg/mmol
<360
420 µmol/L
<2.0
2.4 mmol/L
Module 6
Interactive Case: Catherine
About Catherine
European Origin
• 64 years old
Family history:
• Mother: diabetes, amputation age 70 years
• Father: MI age 69 years
Social history:
• Married with 2 children and 4 grandchildren
• Non-smoker
• 30-minute walk 3 times/wk
Catherine’s Medical History
• Type 2 diabetes for 5 years and hypertension for
3 years
• SU added to metformin 3 months ago
• Mild hypoglycemia 6 times in last 2 months,
related to delayed or smaller meal or exercise
• One severe episode required help from
her husband
• SMBG: fasting 6.5 -7.8; ac supper 6.4 to 8.9
Catherine’s Medications
Metformin 1,000 mg BID
Gliclazide MR 30 mg OD
Ramipril 10 mg OD
Catherine’s Exam and Labs
Exam
Laboratory
Weight: 75 kg
Height: 1.6 m
BMI: 29 kg/m2
Waist Circumference: 95 cm
Heart Rate: 76 bpm
BP: 142/84 mmHg
No carotid bruit
Pedal pulse palpable
Optic fundi normal
Creatinine: 109 µm/l
eGFR: 54
Urine: ACR 20.4 (N < 2.8)
FPG: 7.6
A1C: 7.6%
Cholesterol: 6.4
HDL-C: 1.1
LDL-C: 4.4
TG: 1.9, TC: HDL-C: 5.8
ECG: normal
How would you determine Catherine’s risk for
CVD?
1. Eyeball based on
risk factors
2. Put her in high risk category
because all patients with DM are
high risk
3. Use a risk-assessment tool (e.g.,
Framingham)
4. Use CDA Guideline criteria for
who is at high risk
0%
1
0%
2
0%
3
0%
4
Diabetes and High Risk
for Cardiovascular Events
The following individuals with diabetes should be
considered at high risk for cardiovascular events:
• Men aged ≥ 45 years, women aged ≥ 50 years
[Grade B, Level 2]
• Men < 45 years and women < 50 years with ≥ 1 of the following
[Grade D, Consensus]:
̵
̵
̵
̵
macrovascular disease (e.g., MI, peripheral arterial disease, or
cerebrovascular disease)
microvascular disease (nephropathy and retinopathy)
multiple additional risk factors
extreme level of single risk (e.g., LDL-C > 5.0 mmol/L, SBP >
180 mmHg) duration of diabetes > 15 years with age > 30 years
CDA Guidelines 2008.
Vascular Protection in the
Patient with Diabetes
For patients at high risk of a CV event
1. ACE inhibitor or ARB therapy (independent of BP)
2. Lipid-lowering therapy (primarily statins)
3. Antiplatelet therapy (as recommended)
For all patients with diabetes:
1. Lifestyle modification
•
•
•
•
achievement and maintenance of healthy body weight
healthy diet
regular physical activity
smoking cessation
2. Optimize blood pressure control
3. Optimize glycemic control
CDA Guidelines 2008.
What is your target A1C for Catherine?
1.
2.
3.
4.
≤ 6.5%
≤ 7.0%
≤ 7.5%
≤ 8.0%
0%
1
0%
2
0%
3
0%
4
2008 CDA Guidelines1:
Recommended Glycemic Targets
A1C (%)*
Type 1 and type 2
diabetes
≤ 7.0
FPG or
preprandial PG
(mmol/L)
4.0 – 7.0
2-hour
postprandial PG
(mmol/L)
5.0 – 10.0
(5.0 – 8.0 if A1C targets
not being met)
* Treatment goals and strategies must be tailored to the individual with diabetes, with consideration given to individual
risk factors. Attain A1C target within 6 to 12 months.
Evidence shows that approximately half of Canadian patients do not achieve
their A1C targets (DICE2 and DRIVE3 studies)
1.CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008; 32(suppl 1):S1-S201.
2.Harris SB, et al. Diabetes Res Clin Pract 2005; 70(1):90-7.
3.Braga M, et al. Presented at the American Diabetes Association 68th Scientific Sessions 2008, San Francisco.
Determining Glycemic Targets
Ismail-Beigi F, et al. Ann Inttern Med. 2011;154:554-559.
Catherine is having episodes of hypoglycemia.
These episodes can be associated with which of
the following?
1. Higher mortality rate
2. Higher rate of microvascular
complications
3. Higher rate of cardiovascular
complications
4. All of the above
5. 1 and 3
0%
1
0%
0%
2
3
0%
0%
4
5
Severe Hypoglycemia Significantly Increases the Risk for
Adverse Outcomes in Patients With T2DM
Hazard ratios represent the risk of an adverse cardiovascular outcome or
death among patients reporting severe hypoglycemia (<2.8 mmol/L)* as
compared with those not reporting severe hypoglycemia
Clinical Outcome and
Interval After Hypoglycemia
Hazard Ratio
(95% CI)†
Microvascular events
Macrovascular events
Death from any cause
2.07 (1.32-3.26)‡
3.45 (2.34-5.08)‡
3.30 (2.31-4.72)‡
Death from non-CV cause
2.86 (1.67-4.90)‡
Death from CV cause
3.78 (2.34-6.11)‡
*Severe
hypoglycemia blood glucose <2.8 mmol per liter with transient dysfunction of the CNS, without other apparent cause, during which the patient was unable to administer treatment
(requiring help from another person).
†Adjusted
for multiple covariates: sex, duration of diabetes, treatment assignment, presence or absence of a history of macrovascular disease, presence or absence of a history of
microvascular disease, and smoking status at baseline. Time-dependent covariates during follow-up included age; level of glycated hemoglobin; body-mass index; creatinine level; ratio
of urinary albumin to creatinine; systolic blood pressure; use or non-use of sulfonylurea, metformin, thiazolidinedione, insulin, or any other diabetes drug; and use or non-use of
antihypertensive agents.
‡p<0.001
CI=confidence interval.
Zoungas S.N, Engl J Med. 2010;363(15):1410-1418.
ACCORD: Mortality by Study Group
and Hypoglycemia Occurrence
HR for mortality higher in
those with hypoglycemia, regardless
of treatment group
STD
(n = 175
w/events)
INT
(n = 528
w/events)
HR
INT vs. STD
(95% CI)
No severe hypoglycemia
1.0%/year
180 deaths
17,516 PYs
1.3%/year
220 deaths
17,031 PYs
1.25
(1.03-1.52)
At least one severe
hypoglycemia event
4.9%/year
17 deaths
345 PYs
2.8%/year
34 deaths
1,208 PYs
0.55
(0.31-0.99)
HR (hypoglycemia vs. no
hypoglycemia) (95% CI)
2.87
(1.73-4.76)
1.28
(0.88-1.85)
In those with
hypoglycemia, mortality rate
lower in INT than
STD group
PY = person-year.
Adapted from: Bonds DE, et al. BMJ. 2010;340:b4909.
Risk Factors for Hypoglycemia
• Older age
• Long duration of diabetes treatment
• Chronic Kidney Disease
• Prior episode of severe hypoglycemia
• Other glucose-lowering medications
• Glycemic control – inverse? or correlated?
• Hypoglycemia unawareness, especially during sleep
• Delayed, smaller, or missed meal
• Alcohol
• Recent moderate or intensive exercise
1. CDA. Can J Diabetes. 2008;32:S29–S31; 2. Workgroup on Hypoglycemia, American Diabetes Association, Diabetes Care. 2005;28(5):1245-1249; 3. Frier BM, Diabetes Metab Res Rev. 2008;24(2):87-92; 4. Cryer PE, Diabetes. 2008;57(12):3169-3176.
Pathophysiologic Cardiovascular
Consequences of Hypoglycemia
CRP
VEGF
IL-6
Inflammation
Neutrophil
activation
Blood coagulation
abnormalities
Hypoglycemia
Endothelial
dysfunction
Platelet
activation
Factor VII
Sympathoadrenal response
Rhythm abnormalities
Heart rate variability
Vasodilation
Hemodynamic changes
 Adrenaline
 Oxygen consumption
 Contractility  Heart workload
CRP=C-reactive protein; IL-6=interleukin 6; VEGF=vascular endothelial growth factor. Desouza CV, et al. Diabetes Care. 2010;33(6):1389-1394.
Catherine’s A1C is 7.6% with metformin 1,000 mg bid and
gliclazide MR 30 mg od. She is reporting episodes of
hypoglycemia. Her eGFR is 54. How would you manage
her antihyperglycemic agents?
1.
2.
3.
4.
5.
6.
7.
Reduce dose of metformin and increase dose
of gliclazide
Reduce dose of metformin, stop gliclazide,
and add another agent
Continue metformin and increase dose of
gliclazide
Continue metformin, stop gliclazide, and add
another agent
Continue metformin and gliclazide and add
another agent
Add basal insulin and consider stopping
gliclazide
Other
0%
0%
0%
0%
0%
0%
0%
1
2
3
4
5
6
7
You Decide on Option 4: Continue Metformin, Stop
Gliclazide, and Add Another Agent.
This New Agent Would Be?
1.
2.
3.
4.
5.
An alpha-glucosidase inhibitor
A DPP-4 inhibitor
A GLP-1R agonist
A meglitinide
A thiazolidinedione
0%
1
0%
0%
2
3
0%
0%
4
5
Second-Line Agents in CDA 2008 Guidelines
Add an agent best suited to the individual based on its advantages/disadvantages
Class
A1C
Alpha-glucosidase inhibitor
Incretin agent:
DPP-4 inhibitor
GLP-1R agonist*
to
to
Insulin
Hypoglycemia
Other advantages
Other disadvantages
Rare
Improved postprandial control Weight neutral
GI side effects
Rare
Improved postprandial control Weight neutral
Improved postprandial control
Weight loss
New agent (unknown long-term safety)
Injectable, nausea and vomiting,
new agent
Rare
Yes
No dose ceiling
Many types, flexible regimens
Weight gain
to
Insulin secretagogue:
Meglitinide
Sulfonylurea
Yes**
Yes
Improved postprandial control
Newer sulfonylureas
(gliclazide, glimeripide) are associated with less
hypoglycemia than glyburide
Rare
Durable monotherapy
None
Weight loss
TZD
Weight-loss agent
Requires TID to QID dosing
Weight gain
Requires 6-12 weeks for
maximal effect
Weight gain
Edema, rare CHF, rare
fractures in female
Rosi: may CV risk Pio: may bladder
Ca risk
GI side effects (orlistat)
↓ = <1.0% decrease in A1C; ↓↓ = 1.0 – 2.0% decrease in A1C; ↓↓↓ = >2.0% decrease in A1C
*GLP-1R agonists were not available when 2008 CDA Guidelines were published. **Less hypoglycemia in the context of missed meals.
Adapted from 2008 CDA Clinical Practice Guidelines, Canadian Journal of Diabetes. 2008;32(Suppl 1):S1-S201.
What is the Ideal First Add-on to Metformin? Network
Meta-analysis Comparing Non-Insulin Antihyperglycemic
Drugs With PBO as Add-on to Metformin
Change in
A1C (%)
A1C Goal
Achieved
Change in
Body Weight (kg)
Overall
Hypoglycemia
Mean Diff.
RR
Mean Diff.
RR
0
1
0
1
Sulfonylureas
-0.79
2.49
2.06
4.57
Meglitinides
-0.65
2.25
1.77
7.50
TZDs
-0.85
2.71
2.08
0.56
AGIs
-0.64
ND
-1.80
0.42
DPP-4 inhibitors
-0.78
2.51
-0.14
0.63
GLP-1R agonists
-0.97
3.20
-1.74
0.89
PBO (Ref)
Phung OJ, et al. JAMA. 2010;303:1410-1418. Published online April 14, 2010.
Efficacy of Add-on Therapy to Metformin + SU:
Clinical Trials of Incretin Agents Indicated as Add-on to
Metformin + SU
Nauck M, et al. Diabetes Care. 2009;32:84-90.
Kendall D, et al. Diabetes Care. 2005;28:1083-1091.
Hermansen K, et al. Diabetes, Obesity & Metabolism. 2007;9:733-745.
Owens DR, et al. Diabetic Medicine 2011.
Catherine has an LDL-C of 4.4 mmol/L.
How would you manage this?
1.
2.
3.
4.
5.
6.
7.
8.
Start atorvastatin 10 mg or 20 mg and
titrate as necessary
Start atorvastatin 40 mg and titrate as
necessary
Start atorvastatin 80 mg
Start rosuvastatin 10 mg and titrate
as necessary
Start rosuvastatin 20 mg and titrate
as necessary
Start rosuvastatin 40 mg
Start a statin with ezetimibe
Other
0%
0%
0%
0%
0%
0%
0%
0%
1
2
3
4
5
6
7
8
Canadian Cardiovascular Society Guidelines
on Dyslipidemia 2009
Risk categories and treatment recommendations
Genest J et al. Can. J Cardiol 2009; 25: 567-579
Would you treat Catherine with low-dose ASA?
1. Yes
2. No
0%
1
0%
2
Aspirin for Primary Prevention of CV Events in
People with Diabetes: Meta-analysis of 6 Randomized
Trials (N=10,117)
Major CV events:
OR = 0.90 (0.81-1.00)
Myocardial infarction:
OR = 0.86 (0.61-1.21)
Stroke:
OR = 0.83 (0.60-1.14)
CV Death:
OR = 0.94 (0.72-1.23)
All cause Mortality:
OR = 0.93 (0.82-1.05)
De Berardis G, et al. BMJ. 2009;339:b4531.
Antiplatelet Recommendations For Primary
Prevention in Diabetes
• CDA 2008: The decision to prescribe antiplatelet therapy
for primary prevention of CV events should be based on
individual clinical judgement [Grade D, Consensus]
• CCS 2011: For patients with diabetes aged >40 years and
at low risk for major bleeding, low-dose ASA (75-162 mg
daily) may be considered for primary prevention in
patients with other CV risk factors for which its benefits
are established [Class IIb, Level B]
CDA Guidelines 2008.
CCS Guidelines 2011. Can J Cardiol. 27:S1-S59.
Catherine has a BP of 142/84 while treated with
ramipril 10 mg od. How would you manage her
BP?
1.
2.
3.
4.
5.
6.
7.
8.
Add a thiazide-like diuretic
Change to an FDC of an ACEidiuretic
Add a CCB
Change to an ARB plus a thiazide-like
diuretic
Change to an FDC of an ARB-CCB
Add an ARB
Add a DRI
Other
0%
0%
0%
0%
0%
0%
0%
0%
1
2
3
4
5
6
7
8
CHEP 2012: Treatment of Hypertension in
Association with Diabetes Mellitus Summary
Threshold equal to or over 130/80 mmHg and TARGET below 130/80 mmHg
with
Nephropathy
ACE inhibitor
or ARB
Diabetes
without
Nephropathy
A combination of 2 first-line drugs may
be considered as initial therapy if the
blood pressure is >20 mmHg systolic
or >10 mmHg diastolic above target.
Combining an ACEi and a DHP-CCB
is recommended.
1. ACE inhibitor
or ARB
or
2. DHP-CCB or
thiazide diuretic
> 2-drug combinations
Monitor serum potassium and creatinine carefully in patients with CKD prescribed an ACEI or ARB
Combinations of an ACEI with an ARB are specifically not recommended in the absence of proteinuria
More than 3 drugs may be needed to reach target values for diabetic patients
If creatinine over 150 µmol/L or creatinine clearance below 30 ml/min ( 0.5 ml/sec), a loop diuretic should be substituted for
a thiazide diuretic if control of volume is desired
ACCOMPLISH: Kaplan-Meier for Time to First
Primary Composite Endpoint
Cumulative event rate
CV Death, MI, Stroke, Hospitalized Angina, Cardiac Arrest,
Coronary Revascularization
ACEI / HCTZ
ACEI / CCB
N= 11,506 ; high-risk HTN
BP  0.9/1.1 ACE/CCB vs. ACE/HCTZ
20% Risk Reduction
HR: 0.80 (0.72-0.90)
P < 0.0001
60% had diabetes (n=6,946)
BP  1.2/1.1 ACE/CCB (131.5/72.6) vs.
ACE/HCTZ (132.7/73.7
HR: 0.79 (0.68-0.92); p=0.003
1st CV morbidity/mortality (days)
Jamerson K, et al. N Engl J Med. 2008; 359: 2417-2428.
Weber M, et al. JACC. 2010;56:77-85.
2012 CHEP Recommendations
Regarding Drug Combinations
When combining drugs, use first-line therapies.
• Two drug combinations of beta blockers, ACE inhibitors and
angiotensin receptor blockers have not been proven to have additive
hypotensive effects. Therefore these potential two drug combinations
should not be used unless there is a compelling (non blood pressure
lowering) indication
• Combinations of an ACEI with an ARB do not reduce cardiovascular
events more than the ACEI alone and have more adverse effects
therefore are not generally recommended
• Caution should be exercised in combining a non dihydropyridine CCB
and a beta blocker to reduce the risk of bradycardia or heart block.
• Monitor serum creatinine and potassium when combining K sparing
diuretics, ACE inhibitors and/or angiotensin receptor blockers.
• If a diuretic is not used as first or second line therapy, triple dose
therapy should include a diuretic, when not contraindicated.
2012 CHEP Recommendations
Regarding Drug Combinations
Diabetes and Hypertension:
•
Combination therapy using two first-line agents may also be considered as
initial treatment of hypertension if the SBP is 20 mmHg above the target or if
DBP is 10 mmHg above the target. However caution should be exercised in
patients in whom a substantial fall in blood pressure is more likely or poorly
tolerated (e.g. elderly patients, patients with autonomic neuropathy).
•
For persons with cardiovascular or kidney disease, including
microalbuminuria or with cardiovascular risk factors in addition to diabetes
and hypertension, an ACE inhibitor or an ARB is recommended as initial
therapy
•
For persons with diabetes and hypertension not included in the above
recommendation, appropriate choices include (in alphabetical order): ACE
inhibitors (Grade A), angiotensin receptor blockers (Grade B), dihydropyridine
CCBs (Grade A) and thiazide/thiazide-like diuretics (Grade A).
•
If target blood pressures are not achieved with standard-dose monotherapy,
additional antihypertensive therapy should be used. For persons in whom
combination therapy with an ACE inhibitor is being considered, a
dihydropyridine CCB is preferable to hydrochlorothiazide
Take-Home Points
• Assess CV risk using CDA Guideline criteria for “high risk”
• Glycemic control significantly reduces the risk of diabetes
complications, particularly microvascular complications
• Given the “legacy” benefits of early glycemic control,
intervention to achieve and maintain glycemic targets is
critical for the long-term prevention of diabetes complications
• A history of severe hypoglycemia is a predictor of poor
outcomes
• Glycemic targets must be achieved safely while striving to
minimize hypoglycemia
• In order to minimize CV risk, treat all CV risk factors
according to guidelines for multifactorial vascular protection
Take-Home Points
Patient education, which is essential for successful patient
self-management, should be provided by a multidisciplinary
diabetes care team
“Clinical inertia” can be minimized by expanding roles of
other healthcare providers
Take-Home Points
The incretin agents are efficacious in monotherapy and in
combination with other antihyperglycemic agents" Add a
second bullet " Compared to other classes of
antihyperglycemic agents the incretin agents offer the
potential advantage of beneficial/neutral effects on body
weight and a lack of hypoglycemia.
The incretin agents vary in route of administration, effect on
body weight, contraindications, and pharmacology, including
dosing adjustments for patients with renal impairment
Take-Home Points
When deciding which second agent to add, evaluate the pros
and cons of each (including contraindications, glycemic
durability, effect on body weight, side effects, patient and
physician comfort), as well as:
• What is the degree of hyperglycemia?
• Is the patient at risk for hypoglycemia?
• Does the patient have a drug plan?
Chronic kidney disease is common in diabetes and must
also be considered in the selection of an appropriate
antihyperglycemic agent
Take-Home Points
Identification of CKD in diabetes requires screening for
proteinuria, as well as an assessment of renal function
(eGFR)
All individuals with CKD should be considered at high risk for
cardiovascular events and should receive treatments to
reduce these risks
The progression of renal damage in diabetes can be slowed
through good glycemic control, good blood pressure control,
and the use of medications that disrupt the reninangiotensin-aldosterone system
Benefits of Mainpro-C
You should have received your full Mainpro-C
package from the CHRC, but in the meantime take a
few moments to…
1. Identify at least one thing you would like to
change or verify about your practice
2. Identify one question for which you still require
an answer or clarification
NOTE: If you choose not to complete the reflective exercise, you may claim Mainpro-M1 credits for your
participation in this program (but may not claim Mainpro-C credits).
Questions…
Contact the CHRC:
Phone:
Toll-Free:
Email:
416-977-8010
1-800-725-6585
[email protected]