Investigations • Innovation • Clinical Application
New Frontiers and Advances in
Oral Therapy for Type 2 Diabetes
Focus on DPP-4 Inhibition and
Incretin-Based Therapy (IBT)
Program Chairman
Charles Faiman, MD, FRCPC,MACE
Past Chairman
Consultant Staff
Department of Endocrinology, Diabetes and Metabolism
Cleveland Clinic Foundation
Welcome and Program Overview
CME-certified symposium jointly
sponsored by the University of
Massachusetts Medical School and
CMEducation Resources, LLC
Commercial Support: Sponsored by
an independent educational grant
from Bristol-Myers Squibb and
AstraZeneca Partnership
Faculty disclosures: Listed in
program syllabus
Program Faculty
Program Chairman
Charles Faiman, MD, FRCPC,MACE
Past Chairman
Consultant Staff
Department of Endocrinology, Diabetes
and Metabolism
Cleveland Clinic Foundation
Samir Malkani, MD
Director, Adult Diabetes Clinic,
University Campus
UMass Memorial Medical Center
Clinical Associate Professor of Medicine
University of Massachusetts Medical
School
UMASS Memorial Medical Center
Worcester, MA
Alexander Turchin, MD, MS
Assistant Professor
Harvard Medical School
Brigham and Women's Hospital
Boston, MA
Derek LeRoith, MD, PhD, FACP
Chief, Division of Endocrinology,
Diabetes and Bone Disease
Director, Metabolism Institute,
Mount Sinai School of Medicine
New York, NY
New Frontiers and Advances in
Oral Therapy for Type 2 Diabetes
Type 2 Diabetes 2010:
New Frontiers
Program Chairman
Charles Faiman, MD, FRCPC,MACE
Past Chairman
Consultant Staff
Department of Endocrinology, Diabetes and Metabolism
Cleveland Clinic Foundation
Number of People with Diabetes (20-79 years)
2010 and 2030
Country/Territory
2010 Millions
Country/Territory
2030 Millions
India
50.8
India
87.0
China
43.2
China
62.6
United States
26.8
United States
36.0
Russian Federation
9.6
Pakistan
13.8
Brazil
7.6
Brazil
12.7
Germany
7.5
Indonesia
12.0
Pakistan
7.1
Mexico
11.9
Japan
7.1
Bangladesh
10.4
Indonesia
7.0
Russian Federation
10.3
Mexico
6.8
Egypt
8.6
IDF Diabetes Atlas, 4th ed. International Diabetes Federation, 2009
At a Glance: World
At a Glance
2010
2030
Total world population (billions)
7.0
8.4
Adult population (20-79 yrs, billions)
4.3
5.6
Global prevalence (%)
6.6
7.8
Comparative prevalence (%)
6.4
7.7
Number of people with diabetes (millions)
285
438
Global prevalence (%)
7.9
8.4
Comparative prevalence (%)
7.8
8.4
Number of people with IGT (millions)
344
472
Diabetes (20-79 Years)
IGT (20-79 years)
Millions
Number of People with Diabetes
by Age Group, 2010 and 2030
Millions
Number of People with Impaired Glucose
Tolerance by Age Group, 2010 and 2030
North America and Caribbean Region
At a Glance
2010
2030
Total population (millions)
477
555
Adult population (20-79 yrs, millions)
320
390
Regional prevalence (%)
11.7
13.6
Comparative prevalence (%)
10.2
12.1
Number of people with diabetes (millions)
37.4
53.2
Regional prevalence (%)
11.4
12.6
Comparative prevalence (%)
10.4
11.6
Number of people with IGT (millions)
36.6
49.1
Diabetes (20-79 Years)
IGT (20-79 years)
North America and Caribbean Region
At a Glance
2010
2030
Type 1 diabetes (0-14 years)
Number of children with type 1 diabetes
(thousands)
96.7
Number of newly-diagnosed cases per year
(thousands)
14.7
Diabetes mortality (20-79 years)
Number of deaths, male (thousands)
141.0
Number of deaths, female (thousands)
172.2
Health expenditure for diabetes (USD)
Total health expenditure, R=2 (billions)
214.2
288.7
Highest Prevalence
Diabetes
►
Pacific Island - 43%
►
Arab Gulf States (U.A.E.) - 19%
►
U.S.A. / Canada
- Natives
- Blacks / Hispanics
Costs for DM Care: 2010
► United
► World
States
$198 billion
$376 billion
Definition of Diabetes
American
(mg/dL)
SI
(mmo/L)
Normal
65 - 99
3.6 – 5.5
DM
> 126
> 7.0
Random (with
symptoms)
DM
> 200
> 11.1
GTT (2 hr.)
DM
> 200
> 11.1
HbA1c
DM
Indicator
Glucose – Fasting
> 6.5%
Definition of Impaired Glucose Tolerance
Indicator
mg/dL
mmo/L
Fasting glucose
100 – 125
>5.6 – 6.9
Glucose tolerance test
140 – 199
7.8 – 11.0
HbA1c
5.7% – 6.4%
Types Of Diabetes
►
Type 1 (Juvenile-Onset)
►
Type 2 (Adult-Onset)
►
Other types including:
- Gestational diabetes
- MODY (maturity onset diabetes of the young)
- LADA (latent auto-immune diabetes of adults)
- Others
Cause of Type 1 DM
►Auto-immune
destruction of
insulin-producing β-cells in
the pancreas
Cause of Type 2 DM
►
Insulin resistance (genetics)
- aggravated by obesity
- aggravated by lack of exercise
►
“Exhaustion” of insulin-producing β-cells
Major Metabolic Defects
in Type 2 Diabetes
►
Peripheral insulin resistance in
muscle and fat
►
Decreased pancreatic
insulin secretion
►
Increased hepatic glucose output
Haffner SM, et al. Diabetes Care, 1999
Development and Progression
of Type 2 Diabetes*
NGT  Insulin  IGT/ IFG  Type 2 Diabetes
Resistance
Postprandial glucose
Glucose
Fasting glucose
-10
Relative
Activity
-5
0
5
Insulin level
10
15
20
25
30
Insulin resistance —
hepatic and peripheral
Beta-cell function
–10
*Conceptual representation.
–5
0
5
10
15
20
Years from Diabetes Diagnosis
25
30
NGT=normal glucose tolerance; IGT=impaired glucose tolerance; IFG=impaired fasting glucose.
Adapted from Ferrannini E. Presentation at 65th ADA in Washington, DC, 2006.; and Ramlo-Halsted et al. Prim Care.
1999;26:771–789.
Functional Defects in ß-Cells in the
Development of Diabetes
►
Progressive decrease in b-cell insulin
secretion in response to nutrients
● First manifested as a decrease in early or
acute insulin secretion (decreased first
phase insulin secretion)
►
Loss of normal minute-by-minute pulsatile
insulin secretion and daily ultradian rhythm
of secretion
►
Decreases in insulin processing with
increased proinsulin:insulin ratio
Type 2 Diabetes: Pathogenesis in a
Nutshell (cont.)
►
Type 2 diabetes has been considered a
PROGRESSIVE disease
● b-cell dysfunction first leads to impaired
glucose tolerance, which in some individuals
progresses to type 2 diabetes
● b-cell dysfunction starts long before blood
glucose rises and worsens after diabetes
develops
►
Hyperglycemia may cause additional defects
in insulin secretion and insulin action
(glucotoxicity)
Buchanan TA. Clin Ther. 2003;25(suppl B):B32-B46.
DeFronzo RA. Med Clin North Am. 2004;88:787-835.
Kahn SE. J Clin Endocrinol Metab. 2001;86:4047-4058.
UKPDS: Progressive Deterioration in
Glycemic Control Over Time
A1C
9
80
8
7
Conventional
Intensive
6
0
0
3
6
9
12
15
Time from randomization (y)
UKPDS Group. Lancet. 1998;352:837-853.
b-cell function (%)
Median A1C (%)
100
60
40
20
0
-12 -10 -8 -6 -4 -2 0
2
4 6
Years from diagnosis
Holman RR. Diabetes Res Clin Pract.
1998;40(suppl):S21-S25.
Mechanisms Responsible for Changes
in Insulin Levels
►
Normal b-cell adaptation to insulin
resistance
●
●
►
Increased secretion from each cell
Increased b-cell mass
Impaired b-cell adaptation in type 2
diabetes result of
●
●
Decreased secretion from each cell
Reduced b-cell mass
Potential Causes for Declining
Insulin Secretion
Glucotoxicity
Lipotoxicity
b-cell
Insulin
Secretion
Prentki M et al. Diabetes. 2002;51(suppl 3):s405-s413.
Apoptosis
Abnormalities of α-Cell
Function in Type 2 Diabetes
►
Elevated glucagon levels
►
Loss of insulin-induced suppression
►
Loss of glucose-induced suppression
►
Increased stimulatory effect of arginine
Dunning BE et al. Diabetologia. 2005;48:1700-1713.
Summary
►
Islets can adapt to insulin resistance
►
Failure of adaptation results in impaired glucose
tolerance and eventually, type 2 diabetes
►
Failure appears to be due to reduced insulin
secretion per islet and a reduction in the
number of islets
►
Increased glucagon contributes to hyperglycemia
in type 2 diabetes
Global Cardiometabolic Risk*
Gelfand EV et al, 2006; Vasudevan AR et al, 2005
* working definition
Differentiating Type 1 Vs. Type 2 DM
►
Presentation with ketoacidosis
►
Age at onset
►
Testing for C-peptide levels
►
Testing for antibodies
- GAD-65
- IA2
- Insulin
- Islet-cell
►
Trial of oral agents
Other Kinds of Diabetes
► LADA (latent autoimmune disease of adults)
► MODY (maturity-onset diabetes of the young)
► Gestational diabetes
► Stress-induced
► Post-transplant
Complications of Diabetes
►
Small Blood Vessel
- eye (retina) – blindness
- kidney failure – dialysis
►
Large Blood Vessel
- heart attacks
- strokes
- peripheral vascular : amputations
►
Neuropathy
►
Erectile dysfunction (both vascular and nerve damage)
Avoiding Complications - I
►
Diet / exercise
►
‘Girth’ control
►
Sugar control
►
Lipid (cholesterol) control
►
Blood pressure control
Avoiding Complications - II
►
Self-monitoring glucose
►
Visits to PCP – endocrinologist: goals
►
Eye exams
►
Podiatry exams
►
Periodic blood / urine lab testing
Standards of Care
American Diabetes Association
►
Glycemia: HbA1c <7.0%,
FPG 90-130 mg/dL, PP <180 mg/dL
►
Blood Pressure: <130/80 mm Hg
►
Lipids: LDL <100 mg/dL; TG <150 mg/dL
►
Yearly
●
►
Dilated eye exam; urinary protein;
foot exam; flu shot
Other
●
Aspirin usage; pneumococcal vaccine
FPG – fasting plasma glucose
PP - Postprandial
ADA. Diabetes Care. 2009;32(suppl 1);S13-S61.
AACE goals
HbA1c 6.5%
FPG 110 mg/dL
PP 140 mg/dL
NCEP
LDL ≤70 mg/dL
Oral Drugs for Rx DM2
►
Metformin (glucophage)
►
Sulfonylureas (glyburide, glipizide, glimepiride)
►
Thiazolidinediones (actos, avandia)
►
DPP-IV inhibitors (januvia, onglyza)
►
Glucosidase inhibitors (acarbose, miglitol)
►
Others: colesevelam ; bromocriptine
Injectables For RX DM2
►
Pramlintide (Symlin)
►
Exenatide (Byetta) / liraglutide (Victoza)
►
Insulins
Native
- Regular (short-acting)
- Isophane (NPH : intermediate)
- Mixtures
Analogues
- Glargine / Detemir (long-acting)
- Humalog, Novolog, Apidra (rapid)
- Mixtures
Conclusions
► No specific drugs or regimens seem to have a
necessarily adverse effect on cardiovascular event rates
despite expressed concerns about certain drugs
► A1C goal should be individualized
• <6.5% if healthy, and short duration diabetes and long life expectancy
• <7% average patient
• <7.5-8% medically complex, clinical cardiovascular disease, failed
to achieve lower target with lifestyle, metformin and adequate doses
of insulin
► The future: continuing surveillance of newer classes of
drugs for adverse – or beneficial – cardiovascular effects
Future Rx DM2
►
Longer acting GLP-1 analogues
►
More DPP-IV inhibitors
►
More TZD’s
►
Newer drug classes : e.g., SGLT2-inhibitors
NOTE : FDA requires longer duration studies in DM2 to
better understand risk / benefit before approval
Prevention of DM
►
TYPE 1
- Immune modulation
►
TYPE 2
- Diet/exercise
- Drugs: Metformin
TZD’s
Glucosidase inhibitors
Others?
Today’s Program
►
Evolving science & medicine of incretinbased therapy
►
Options, strategies and combinations
►
Practice – focused overview
►
T2DM Rx in 2010 – where are we?
Stamp Out Diabetes!
Investigations • Innovation • Clinical Application
The Current Armamentarium of Oral Agents
for Type 2 Diabetes Mellitus—Sequencing
Oral Therapy
When and Where Do We Start? When Do We
Add? How Do The Guidelines Guide Us?
Samir Malkani, MD
Director, Adult Diabetes Clinic, University Campus
UMass Memorial Medical Center
Clinical Associate Professor of Medicine
University of Massachusetts Medical School
UMASS Memorial Medical Center
Worcester, MA
Number and Percentage of U.S. Population
with Diagnosed Diabetes, 1958-2008
7
20
Percent with Diabetes
16
Percent with Diabetes
Number with Diabetes
5
14
12
4
10
3
8
6
2
4
1
2
0
0
1958
61
64
67
70
73
76
79
82
85
88
91
94
97
00
03
Year
CDC’s Division of Diabetes Translation. National Diabetes Surveillance System
available at http://www.cdc.gov/diabetes/statistics
06
Number with Diabetes (Millions)
18
6
U.S. Population with Diagnosed Diabetes,
1995-2008
1995
U.S. Population with Diagnosed Diabetes,
1995-2008
2001
U.S. Population with Diagnosed Diabetes,
1995-2008
2008
U.S. Population with Diagnosed Diabetes,
1995-2008
Too thin
Too fat
Relative b-cell
function (%)
Natural History of Type 2 Diabetes
Insulin resistance
300
200
100
0
Insulin output
Beta-cell failure
At risk for
diabetes
–10 –5
0
5
10
15
20
25
30
Glucose (mg/dL)
Years of diabetes
Post-meal glucose
300
Fasting glucose
200
100
50
Diabetes
The Importance of ß-Cell Failure in the Development
and Progression of Type 2 Diabetes
Steven E Kahn
FIG. 7. Model for the relationship between b cell dysfunction and deterioration of
glucose tolerance. As b cell function declines, glucose tolerance deteriorates so that the
criteria for impaired fasting glucose and/or impaired glucose tolerance are reached.
Subsequently, with a further loss of b cell function, diabetes develops
based on either or both the fasting and 2-h glucose levels
The Journal of Clinical Endocrinology & Metabolism, September 2001, 86(9):4047–4058
HbA1c Trend with Time - UKPDS
9
HbA1c (%)
Conventional
8
Intensive
7
6.2% upper limit of normal range
6
0
0
3
6
9
12
Years from randomisation
15
Targets for Glycemia Control
Recommendations for glycemia control from the American Diabetes Association and the
American Association of Clinical Endocrinologists. *The glycated hemoglobin (HbA1c) goal for
patients in general is less than 7.0%, while the HbA1c goal for selected patients is as close to
normal (<6.0%) as possible without significant hypoglycemia. Sources: American Diabetes
Association. Diabetes Care. 2010;33(suppl 1):S11-S61; ACE/AACE Diabetes Road Map Task
Force. Endocr Pract. 2007;13:260-268.
Dietary Therapy
►
Best implemented by a registered dietitian
experienced in behavioral modification
►
Individualized diet based on weight, lipids, lifestyle
●
Total carbohydrates 45-65% of daily energy intake
• Avoid sugars, increase complex carbohydrates,
50 gram of fiber daily
●
►
Fat <30% calories (<7% saturated)
Dietary therapy alone can reduce A1C by 0.25-3%
or more
Diabetes Care, 2010. 33 (Supp 1) S11-S48
Physical Activity
►
Perform at least 150 minutes of
moderate-intensity* aerobic physical
activity per week
►
In the absence of contraindications,
perform resistance training three times a
week
* 50-70% of max heart rate
Diabetes Care, 2010. 33 (Supp 1) S11-S48
Patient Education in Diabetes Mellitus:
10 Content Areas
Integrating
Psychosocial
Adjustment
To Daily Living
Promoting Care
prior to and during
Pregnancy
Goal setting for
Health &
Daily Living
Nutritional
Management
Diabetes SelfManagement
Education
Preventing,
Detecting & Treating
Chronic Complications
Preventing,
Detecting & Treating
Acute Complications
Funnell et. al. Diabetes Care 2010:33 (Suppl1) S89-96
Diabetes
Disease
Process
Monitoring
Blood Glucose
Physical
Activity
Utilizing
Medication
Type 2 Diabetes Medication Choices
Experience and Potency
Route
Year
Efficacy as monotherapy: %
 in HgbA1c
Insulin
s.c.
1921
2.5
Sulfonylureas
Oral
1946
1.5
Glinides
Oral
1997
1.0-1.5
Metformin
Oral
1995
1.5
-glucosidase inhibitors
Oral
1995
0.5-0.8
TZDs
Oral
1999
0.8-1.0
GLP analogue
s.c.
2005
0.6
DPP-IV Inhibitors
Oral
2006
0.5-0.8
Amylin analogue
s.c.
2005
0.6
Colesevelam
Oral
2008
0.5
Bromocriptine mesylate
Oral
2009
0.2-0.4
Medication
Type 2 Diabetes Medication Choices
Experience and Potency
Medication
Route
Year
Efficacy as monotherapy:
%  in HgbA1c
Insulin
s.c.
1921
2.5
Sulfonylureas
Oral
1946
1.5
Glinides
Oral
1997
1.0-1.5
Metformin
Oral
1995
1.5
-glucosidase inhibitors
Oral
1995
0.5-0.8
TZDs
Oral
1999
0.8-1.0
GLP analogue
s.c.
2005
0.6
DPP-IV Inhibitors
Oral
2006
0.5-0.8
Amylin analogue
s.c.
2005
0.6
Colesevelam
Oral
2008
0.5
Bromocriptine mesylate
Oral
2009
0.2-0.4
Mechanisms of Action of Pharmacologic
Agents for Diabetes
Improving Outcomes in Patients With Type 2 Diabetes Mellitus: Practical Solutions for Clinical Challenges
James R. Gavin, III, MD, PhD; Mark W. Stolar, MD; Jeffrey S. Freeman, DO; Craig W. Spellman, DO, PhD
JAOA • Vol 110 • No 5suppl6 • May 2010 • 2-14
Oral Medications for Type 2 Diabetes
Drug
Initial Dose
Maximum Dose
Usual Dose
500 mg bid
2550 mg/d
500-1000 mg bid
500 mg/d
2000 mg/d
1500-2000 mg/d
1-2 mg/d
8 mg/d
4 mg/d
Glipizide
2.5-5 mg/d
40 mg/d
10-20 mg/d
Glipizide SR
2.5-5 mg/d
20 mg/d
5-20 mg/d
Glyburide
2.5-5 mg/d
20 mg/d
5-10 mg/d
Glyburide Micronized
0.75-3 mg/d
12 mg/d
3-12 mg/d
Pioglitazone
15-30 mg/d
45 mg/d
15-45 mg/d
Rosiglitazone
4 mg/d
8 mg/d
4-8 mg/d
Acarbose
25 mg tid
100 mg tid
25-100 mg tid
Miglitol
25 mg tid
100 mg tid
25-100 mg tid
Repaglinide
0.5 mg before meals
4 mg before meals
0.5-4 mg before meals
Nateglinide
60-120 mg tid before meals
120 mg tid before meals
60-120 mg tid before meals
Sitagliptin
100 mg/d
100 mg/d
100 mg/d
Saxagliptin
2.5 mg/d
5 mg/d
5 mg/d
375 mg/day
375 mg/day
375 mg/day
Biguanide
Metformin
Metformin XR
Sulfonylurea
Glimepiride
Thiazolidinedione
-Glucosidase inhibitor
Metiglinide
DPP4 Inhibitor
Bile Acid Sequestrants
Colesevelam
Adapted from: Annals of Internal Medicine, March 2010 “In the Clinic”
Type 2 Diabetes Medication Choices
and Potency
►
Higher baseline A1C levels predict
greater drop in A1C
►
Shorter duration of diabetes predicts
greater drop in A1C with any oral agent
►
All oral agents require presence of some
endogenous b cell function, as they work
by either increasing insulin sensitivity or
augmenting b cell insulin release
Sherifali et.al. Diabetes Care. 2010; 33: 1859-1864
Percentage of Individuals with A1C>7%
NHANES surveys
Hoerger TJ et. al. Diabetes Care. 2008; 31:81-86
Metformin - Drug Profile
No hypoglycemia
Weight loss
Advantages
Cardiovascular benefit
Reduces LDL-C (approx 10 mg/dL),
reduces TG
Diarrhea is common
Disadvantages
Contraindicated in renal impairment,
liver failure, advanced cardiac failure
Risk of lactic acidosis not increased
in meta-analyses and systematic
reviews
Concomitant use with other drugs
Can be used as monotherapy and
with all classes including insulin
Sulfonylureas - Drug Profile
Potent glucose lowering effect
Advantages
Favorable adverse effect profile
Hypoglycemia, more with
Glyburide
Disadvantages
Glyburide contraindicated in renal
impairment
?Glyburide impairs ischemic
preconditioning in heart (UKPDS
did not reveal increased cardiac
risk)
Concomitant use with other drugs
Can be used as monotherapy and
with all classes including insulin
Repaglinide and Nateglinide: Drug Profiles
Advantages
Disadvantages
Less hypoglycemia than
sulfonylureas
Favorable adverse effect
profile
Less potent than
sulfonylureas; target mainly
post-prandial glucose
Nateglinide less potent than
Repaglinide
Concomitant use with other
drugs
Can be used with all classes
including insulin
TZDs - Drug Profile
No hypoglycemia
Advantages
May be useful in nonalcoholic fatty
liver disease
Increased fracture risk
Weight gain
Disadvantages
Concomitant use with other drugs
Edema and exacerbation of CHF
Rosiglitazone increases LDL-C
(10mg/dL), TG (15-50mg/dL) and
possible increase in MI
Can be used with other classes
including insulin. Increased fluid
retention and weight gain with
insulin
Alpha Glucosidase Inhibitor (AGI) Drug Profile
Advantages
Disadvantages
No hypoglycemia
Weight neutral
Targets only postprandial
glucose
GI side effects
Concomitant use with other
drugs
Can be used as
monotherapy and with all
classes including insulin
DPP4 Inhibitors – Drug Profile
Weight neutral
Advantages
Favorable adverse effect profile
No hypoglycemia
Limited track record
Disadvantages
Nasopharyngitis, upper
respiratory infections
Rare pancreatitis
Concomitant use with other
drugs
Can be used as monotherapy
and with SU, TZD, metformin
(some have been studied with
insulin)
Colesevelam - Drug Profile
No hypoglycemia
Advantages
Reduces LDL-C (approx 10 mg/dL),
Constipation is common
Disadvantages
Increase in triglycerides
Malabsorption of fat soluble vitamins
Concomitant use with other drugs
Can be used as combination therapy
with metormin
ADA/EASD Guidelines
ADA/EASD:
Considerations for the Guidelines
1. Use of information from clinical trials that address the
efficacy and safety of different modalities of treatment

Paucity of high quality evidence was an impediment
2. Clinical judgment of the panel participants
3. Extrapolation of UKPDS data that glucose lowering of drugs
(metformin, sulfonylureas, insulin) predicted decrease in
complications.
4. Nonglycemic effects of medication, such as effect on CV risk,
lipids, hypertension or insulin resistance
5. Safety, side effects, ease of use and expense
ADA Algorithm for Management of Diabetes
Diabetes Care. 2009, 32:193-203
Tier 1: Well-validated core therapies
At diagnosis:
Lifestyle
+
Metformin
Step 1
Tier 2: less well-validated
therapies
*Useful when
hypoglycemia is to be
avoided
Amylin agonists, Glinides
DPP-4 inhibitors may be
appropriate in selected
patients
Lifestyle+Metformin
+
Basal Insulin
Lifestyle+Metformin
+
Intensive insulin
Lifestyle+Metformin
+
Sulfonylurea
Step 3
Step 2
Lifestyle+Metformin
+
Pioglitazone
(No hypoglycemia, edema,
CHF, bone loss)
Lifestyle+Metformin
+
GLP1
(No hypoglycemia, wt loss,
Nausea/vomiting)
Lifestyle+Metformin
+
Pioglitazone
+
Sulfonylurea
Lifestyle+Metformin
+
Basal Insulin
Review
Annals of Internal Medicine
Systematic Review: Comparative Effectiveness and
Safety of Oral Medications for Type 2 Diabetes
Mellitus
Shari Bolen, MD, MPH; Leonard Feldman, MD; Jason Vassy, MD, MPH; Lisa Wilson, BS, ScM; Hsin-Chieh Yeh, PhD;
Spyridon Marinopoulos, MD, MBA; Crystal Wiley, MD, MPH; Elizabeth Selvin, PhD; Renee Wilson, MS; Eric B. Bass,
MD, MPH; and Frederick L. Brancati, MD, MHS
Background: As newer oral diabetes agents continue to emerge on the market, comparative
evidence is urgently required to guide appropriate therapy.
Purpose: To summarize the English-language literature on the benefits and harms of oral
agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and glucosidase inhibitors) in the treatment of adults with type 2 diabetes mellitus.
Conclusions: Compared with newer, more expensive agents (thiazolidinediones,
glucosidase inhibitors, and meglitinides), older agents (second-generation
sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids,
and other intermediate end points. Large, long-term comparative studies are needed
to determine the comparative effects of oral diabetes agents on hard clinical end
points.
Ann Intern Med. 2007;147:386-399.
www.annals.org
Review
Annals of Internal Medicine
Systematic Review: Comparative Effectiveness and
Safety of Oral Medications for Type 2 Diabetes
Mellitus
Shari Bolen, MD, MPH; Leonard Feldman, MD; Jason Vassy, MD, MPH; Lisa Wilson, BS, ScM; Hsin-Chieh Yeh, PhD;
Spyridon Marinopoulos, MD, MBA; Crystal Wiley, MD, MPH; Elizabeth Selvin, PhD; Renee Wilson, MS; Eric B. Bass,
MD, MPH; and Frederick L. Brancati, MD, MHS
Background: As newer oral diabetes agents continue to emerge on the market, comparative
evidence is urgently required to guide appropriate therapy.
Purpose: To summarize the English-language literature on the benefits and harms of oral
agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and glucosidase inhibitors) in the treatment of adults with type 2 diabetes mellitus.
Conclusions: Compared with newer, more expensive agents (thiazolidinediones,
glucosidase inhibitors, and meglitinides), older agents (second-generation
sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids,
and other intermediate end points. Large, long-term comparative studies are needed
to determine the comparative effects of oral diabetes agents on hard clinical end
points.
Ann Intern Med. 2007;147:386-399.
www.annals.org
Type 2 Diabetes: Assessing the
Relative Risks and
Benefits of Glucose-lowering
Medications
Richard M. Bergenstal, MD, Clifford
J. Bailey, PhD David M. Kendall, MD
International Diabetes Center,
Minneapolis, Minn; Diabetes Research,
Life and Health Sciences, Aston
University, Birmingham, UK.
The American Journal of Medicine
(2010) 123, 374.
Figure 4
Events per 1000 patient-years for representative endpoints. Black bars indicate excess risk of events in diabetes patients relative to
nondiabetic subjects;19,75,85,86 gray bars indicate excess risk of events in patients treated with specific glucose- lowering medications relative to
diabetic patients on other agents;2,25,41,54,60,61,74 and white bars indicate the decreased risk of events in patients undergoing intensive glucose
control policies. Foley RN et al. J Am Soc Nephrol. 2005;16(2):489-495; b = 19Haffner SM et al. N Engl J Med.1998;339(4)229-234; c = 75Noel RA et al.
Diabetes Care. 2009;32(5):834-838;d = 86Trautner C et al. Diabetes Care. 1997;20(7):1147-1153; e = 60,61HamptonT. JAMA. 2007;297(15):1645 and
Meier C et al. Arch Intern Med. 2008;168(8):820-825; f = 41Lago RM et al. Lancet. 2007;370(9593):1129-1136; g = 25Patel A et al. N Engl J Med.
2008;358(24):2560-2572; h = 2Nissen SE, Wolski K. N Engl J Med. 2007;356(24)2457-2471; i = 54Glucophage [package insert]. Princeton, NJ: BristolMyers Squibb Company; 2006; j = 74Dore DD et al.
Type 2 Diabetes: Assessing the Relative Risks
and Benefits of Glucose-lowering Medications
Richard M. Bergenstal, MD, Clifford J. Bailey, PhD David M. Kendall, MD
International Diabetes Center, Minneapolis, Minn; Diabetes Research, Life and Health Sciences,
Aston University, Birmingham, UK.
►
Glucose-lowering medications have a favorable risk-benefit
profile
►
The most common adverse event is hypoglycemia, particularly
among patients receiving sulfonylureas or insulin.
►
Metformin-associated lactic acidosis, exenatide-associated
pancreatitis, and sitagliptin-associated hypersensitivity reactions
appear to be rare.
►
Increased risks of congestive heart failure and bone
fractures in thiazolidinedione-treated patients, and reports
of increased cardiovascular events in rosiglitazone-treated
patients remain an issue.
Glycemic Durability of Rosiglitazone,
Metformin, or Glyburide Monotherapy
Steven E. Kahn, M.B., Ch.B., Steven M. Haffner, M.D., Mark A. Heise, Ph.D., William H. Herman, M.D., M.P.H., Rury R.
Holman, F.R.C.P., Nigel P. Jones, M.A., Barbara G. Kravitz, M.S., John M. Lachin, Sc.D., M. Colleen O’Neill, B.Sc.,
Bernard Zinman, M.D., F.R.C.P.C., and Giancarlo Viberti, M.D., F.R.C.P., for the ADOPT Study Group *
Cumulative Incidence of Monotherapy Failure
40
30
Hazard ratio (95% CI)
Rosiglitazone vs. metformin, 0.68 (0.55–0.85);
P<0.001
Rosiglitazone vs. glyburide, 0.37 (0.30–0.45);
P<0.001
Glyburide
20
Metformin
Rosiglitazone
10
1
2
3
4
Years
5
Rosiglitazone
1393
1207
1078
957
844
324
Metformin
1397
1205
1076
950
818
311
Glyburide
1337
1114
958
781
617
218
Figure 2. Kaplan–Meier Estimates of the Cumulative Incidence of Monotherapy Failure at 5 Years.
Treatment was considered to have failed if a patient had a confirmed or adjudicated level of fasting plasma
glucose of more than 180 mg per deciliter. Risk reduction is listed for comparisons of pairwise groups from a
baseline covariateadjusted Cox proportionalhazards model. Gray’s estimates of cumulative incidence adjusted
for all deaths were smaller than Kaplan–Meier estimates of treatment failure: 10% in the rosiglitazone group,
15% in the metformin group, and 25% in the glyburide group. I bars indicate 95% CIs.
N Engl J Med 2006;355:242743
AACE/ACE:
Considerations for the Guidelines
1. Minimizing risk and severity of hypoglycemia
2. Minimizing weight gain
3. Inclusion of all major classes of FDA-approved glycemic
medications
4. Selection of therapy stratified by hemoglobin A1C (A1C)
and based on documented A1C lowering potential
5. Consideration of both fasting and postprandial glucose
levels as end points
6. Consideration of total cost of therapy to individual and
society
- includes cost of medication, glucose monitoring,
hypoglycemic events, drug adverse events, and treatment
of complications
LIFESTYLE MODIFICATION
A1C 7.6-9.0%
A1C 6.5-7.5%
Monotherapy
MET
GLP1
DPP4
A1C >9%
Dual Therapy
TZD
GLP1 or
DPP4 or
TZD
AGI
MET
+
Drug naïve,
No symptoms
Triple Therapy
GLP1
or
DPP4
SU or
Glinides
Dual Therapy
GLP-1 or DPP4
MET
MET
TZD
+
Glinide or SU
TZD
+
MET
+
GLP1
or
DPP4
Colesevelam
AGI
MET
Triple Therapy
MET +
GLP1 or
DPP4
TZD
+
+
GLP1
or
DPP4
TZD
GLP1
or
DPP4
Triple Therapy
GLP-1 or DPP4
+
+SU
+TZD
+TZD
+SU
Symptoms or
under treatment
TZD
Glinides
or SU
Adapted from AACE
December 2009 update
with permission
Insulin + other agents
AACE/ACE Diabetes Algorithm
ADA/ EASD Criteria
►
►
►
►
Evidence based
Recognize that beta cell
failure is progressive, and
eventually insulin will be
required, so recommends
this transition early
Greater emphasis on
direct medication costs
and efficacy
Emphasis on one or two
drug regimens, minimizes
use of multiple drugs
AACE/ ACE Criteria
►
►
►
Attempts to provide a
place and
recommendation for all
FDA approved drugs
Greater emphasis on
hypoglycemia avoidance
Recognizes that people
may want choices, so
allows a wide variety of
choices and combinations
for individual situations
National Trends in Use of Different Therapeutic
Drug Classes to Treat Diabetes, 1994-2007
Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094.
Leading Diabetes Medications
by Treatment Class
Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094.
Complex Physiology
Glucose (mg/dL)
AGI: alpha glucosidase inhibitor
SFU: sulfonylurea
Lifestyle
Complex Management
Metformin, TZDs, AGIs, DPP4
Insulin
SFU, glitinides, exenatide
Post-meal glucose
300
Fasting glucose
200
100
50
Relative b-cell
function (%)
Insulin resistance
300
200
100
0
Beta-cell failure
Insulin output
At risk for
diabetes
–10 –5
0
5
10
15
20
Years of diabetes
25
30
Factors to Consider when Choosing
Pharmacological Agent(s) for Diabetes
►
Current A1C
►
Duration of diabetes
►
Body weight (BMI, abdominal obesity)
►
Age of patient
►
Co-morbidities
►
Cost of medication
►
Convenience
Considerations when Choosing a
Drug Within a Class
►
Adverse effects are not “class-specific”
●
●
►
Phenformin vs. Metformin
Troglitazone vs. Rosiglitazone vs.
Pioglitazone
Drugs within a class may not be equally
effective
LIFESTYLE MODIFICATION
Monotherapy
MET
DPP4
GLP1
TZD
AGI
GLP-1 or DPP4
MET
+
TZD
Glinide or SU
Dual Therapy
TZD
+
MET
+
GLP-1 or DPP4
Colesevelam
AGI
GLP1
or
DPP4
Triple Therapy
MET
+
+SU
TZD
GLP1
or
DPP4
+TZD
Insulin + other agents
symptomatic or
severe hyperglycemia
Investigations • Innovation • Clinical Application
The Role of Incretin Mimetics in
Treating Type 2 Diabetes
Program Chairman
Charles Faiman, MD, FRCPC,MACE
Past Chairman
Consultant Staff
Department of Endocrinology, Diabetes and Metabolism
Cleveland Clinic Foundation
Case Presentation
►
50-year-old patient with type 2 diabetes
on glyburide 5 mg/d and metformin 1000
bid presents with a random blood sugar of
240 mg/dL and HbA1c 8.0%
● Weight 250 lb Ht 5’9” BMI 36.9
What would be the best therapeutic
option to treat this patient’s diabetes?
1. Add pioglitazone 30 mg/d
2. Add insulin glargine 10 units qhs
3. Start nateglinide 120 mg tid
4. Start sitagliptin 100 mg/d
5. Start exenatide 5 mcg bid
What would be the best therapeutic
option to treat this patient’s diabetes?
1. Add pioglitazone 30 mg/d
2. Add insulin glargine 10 units qhs
3. Start nateglinide 120 mg tid
4. Start sitagliptin 100 mg/d
5. Start exenatide 5 mcg bid
David M. Nathan, MD
The New England Journal of Medicine
Perspectives February 1, 2007
“A host of medications that are already available
are effective as monotherapy or in combination
with metformin or one of the TZDs (the approved
uses of sitagliptin). The fact that these
medications achieve better glycemic control than
sitagliptin suggests the need for caution in
approving a new medication that has received
limited testing.”
A Consensus Statement From the American
Diabetes Association and the European
Association for the Study of Diabetes
Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Management of Hyperglycemia in T2DM
Diagnosis
Lifestyle intervention + Metformin
A1C≥7%
No
Add basal insulin*
- most effective
No
A1C≥7%
Yes*
Intensify insulin*
No
Yes*
Add sulfonylurea
- least effective
No
A1C≥7%
Add glitazone*
A1C≥7%
Yes*
No
A1C≥7%
Add basal insulin*
No
Yes*
Add glitazone
- no hypoglycemia
Add sulfonylurea*
A1C≥7%
Add basal or intensify insulin*
Intensive insulin + metformin ± glitazone
Adapted from Nathan DM et al. Diabetes Care. 2006;29:1963-1972.
Yes*
Yes*
Algorithm Overview
►
The algorithm takes into account the characteristics
of the individual interventions, their synergies, and
expense
►
The goal is to achieve and maintain glycemic levels
as close to the nondiabetic range as possible and to
change interventions at as rapid a pace as titration
of medications allows
►
Pramlintide, exenatide, α-glucosidase inhibitors, and
the glinides are not included in this algorithm, owing
to their generally lower overall glucose-lowering
effectiveness, limited clinical data, and/or relative
expense.
●
These may, however, be appropriate choices in selected patients
ADOPT: A Diabetes Outcome Progression
Trial—Safety Profile
Incidence of Selected Adverse Events
SU
(N=1441)
n (%)
RSG
(N=1456)
n (%)
MET
(N=1454)
n (%)
Gastrointestinal
335 (23.0)
557 (38.3)*
316 (21.9)
Edema
205 (14.1)
104 (7.2)*
123 (8.5)*
Hypoglycemia
142 (9.8)
168 (11.6)
557 (38.7)*
MI, fatal
2 (0.1)
2 (0.1)
3 (0.2)
MI, non-fatal
25 (1.7)
21 (1.4)
15 (1.0)
CHF
22 (1.5)
19 (1.3)
9 (0.6)†
Stroke
16 (1.1)
19 (1.3)
17 (1.2)
Selected Events
Change in weight observed in study: RSG +0.7 kg/year; MET -0.3 kg/year; SU 0.2 kg/year
* P≤0.01 vs RSG
† P≤0.05 vs RSG
Data from Kahn SE et al. N Engl J Med. 2006;355:2427-2443.
ADOPT—Implications
►
Current oral agent therapy is associated with
significant adverse events
►
Weight gain, edema, lactic acidosis, GI side
effects, and hypoglycemia are significant
problems
►
GLP-1 agonists cause significant weight loss
►
DPP-4 inhibitors have no associated weight gain
or complications
Relationship Between Weight Gain in
Adulthood and Risk of T2DM
6
Men
Relative Risk
5
Women
4
3
2
1
0
-10
-5
0
5
Weight Change (kg)
Data from Willett WC et al. N Engl J Med. 1999;341:427.
10
15
20
Weight Gain and Glycemic Control
►
Weight gain seems to be inseparable from
glycemic control with many antidiabetic
treatments, including sulfonylureas,
insulin, and thiazolidinediones, which have
an estimated 2 kg weight gain for every
1% decrease in HbA1C
Buse J et al. Clin Ther. 2007;29:139-153.
Clinical Role of GLP-1—Mimetics
►
Overweight patients with type 2 diabetes
requiring initial treatment
►
Overweight patients with type 2 diabetes
on metformin, sulfonylurea, or
combination
►
Addition to thiazolidinediones to avoid
weight gain
Reduced Incretin Effect in Patients
With T2DM
T2DM patients
80
80
60
60
40
*
20
* ** * *
*
0
Insulin (mU/L)
Insulin (mU/L)
Control subjects
Intravenous glucose
Oral glucose
40
**
20
*
0
0
30 60 90 120 150 180
Time (min)
*P≤0.05
Data from Nauck M et al. Diabetologia. 1986;29:46-52.
0
30 60 90 120 150 180
Time (min)
Summary of GLP-1—
Effects in Humans
Central nervous system
Promotes satiety and
reduction of appetite
Liver
 Glucagon reduces
hepatic glucose output
β cell
Enhances secretion of
glucose-dependent insulin
Potential increase in βcell mass
α cell
 Glucagon secretion
post-meal
Stomach
Regulates gastric
emptying
Flint A et al. J Clin Invest. 1998;101:515-520. Larsson H et al. Acta Physiol Scand. 1997;160:413422. Nauck MA et al. Diabetologia. 1996;39:1546-1553. Drucker DJ. Diabetes. 1998;47:159-169.
pmol/L
pmol/L
*
*
*
*
*
0
250
200
150
100
50
0
*
*
*
*
*
*
*
*
40
30
20
10
0
20
20
15
15
10
5
0
–30
*
*
*
10
*
5
Infusion
0
60
120
Minutes
Adapted from Nauck MA et al. Diabetologia. 1993;36:741-744.
0
180
240
Placebo
GLP-1
*P<0.05
Patients with T2DM
(N=10)
When glucose levels
approach normal values,
insulin levels decrease.
pmol/L
Glucagon
*
*
250
200
150
100
50
mU/L
Insulin
15.0
12.5
10.0
7.5
5.0
2.5
0
mg/dL
Glucose
mmol/L
Glucose-dependent Effects of GLP-1 Infusion on
Insulin and Glucagon Levels in T2DM Patients
When glucose levels
approach normal
values, glucagon levels
rebound.
Exenatide: HbA1C and Body Weight
Reductions
Preliminary Analysis for Subjects Treated for 2 Years
Two-year data for 82-wk cohort (N=146)
Mean ± SE
Δ A1C (%)
Placebocontrolled
Δ Body Weight (kg)
Open-label Extensions
Baseline A1C: 8.2%
0.0
0
Open-label Extensions
Baseline weight: 100 kg
-2
-0.5
-1.2±0.1%
-1.0
-1.5
0.0
Placebocontrolled
-5.5±0.5 kg
-4
-6
0.5
1.0
1.5
Duration of Treatment (Years)
Kendall D. ADA. 2005.
2.0
0.0
0.5
1.0
1.5
Duration of Treatment (Years)
2.0
Effect of Exenatide vs Insulin Glargine in Pts
with Suboptimally Controlled T2DM on HbA1C
Exenatide, 10 mg BID
8.5
8.2%
Insulin glargine, mean dose at endpoint = 25.0 U/day
A1C (%)
8.0
7.5
7.1%
7.0
6.5
0.0
0
ITT population; Mean ± SE shown
Adapted from Heine R et al. Ann Intern Med. 2005;143:559-569.
12
Week
26
Change in Body Weight—Time Course
Change in Body Weight (kg)
Exenatide
+1.8 kg
Insulin glargine
2
1
Difference of 4.1 kg
between groups
0
*
-1
*
*
-2
*
-2.3 kg
*
*
-3
0
2 4
8
12
Week
*P<0.0001
Adapted from Heine R et al. Ann Intern Med. 2005;143:559-569.
18
26
ITT population; Mean ± SE shown;
*P<0.0001, exenatide vs insulin glargine at
same time point
Effects of Exenatide and Placebo
on Body Weight
Change in Body Weight (kg)
Patients With T2DM Treated With a TZD with or Without Metformin
Exenatide
1.0
Placebo
0.5
0.0
*
-0.5
-1.0
†
-1.5
-2.5
88
4
Weeks
*P <0.01:
†
-2.0
0
†P
†
<0.001
Adapted from Zinman B et al. Ann Intern Med. 2007;146:477-485.
12
16
Liraglutide Is a Long-acting
Human GLP-1 Incretin
Knudsen LB et al. J Med Chem. 2000;43:1664-1669; Degn KB et al. Diabetes. 2004;53:1187-1194.
Changes in HbA1c From Baseline for Liraglutide
1.8 mg vs Comparator and Placebo
Data originally presented as Marre M et al. Diabetes. 2008;57(suppl 1):A4 (LEAD 1); Nauck MA et al. Diabetes.
2008;57(suppl 1):A15 (LEAD 2); Garber A et al. Lancet. 2009;373:473-481 (LEAD 3); Zinman B et al. Diabetologia.
2008;51(suppl 1): A898 (LEAD 4); Russell-Jones D et al. Diabetes. 2008;57(suppl 1):A159 (LEAD 5).
Body Weight Change: Liraglutide 1.8 mg vs
Comparator and Placebo
Data originally presented as Marre M et al. Diabetes. 2008;57(suppl 1):A4 (LEAD 1); Nauck MA et al. Diabetes.
2008;57(suppl 1):A15 (LEAD 2); Garber A et al. Lancet. 2009;373:473-481 (LEAD 3); Zinman B et al. Diabetologia.
2008;51(suppl 1): A898 (LEAD 4); Russell-Jones D et al. Diabetes. 2008;57(suppl 1):A159 (LEAD 5).
Liraglutide Consistently Reduces
Systolic Blood Pressure
Data originally presented as Marre M et al. Diabetes. 2008;57(suppl 1):A4 (LEAD 1); Nauck MA et al. Diabetes.
2008;57(suppl 1):A15 (LEAD 2); Garber A et al. Lancet. 2009;373:473-481 (LEAD 3); Zinman B et al. Diabetologia.
2008;51(suppl 1): A898 (LEAD 4); Russell-Jones D et al. Diabetes. 2008;57(suppl 1):A159 (LEAD 5).
Outline of LEAD 6 Study Design
Buse JB et al. Diabetes Care. 2010 Mar 23.
LEAD 6 14-week Extension: Shifting Patients to
Liraglutide Improves HbA1c Control
Buse JB et al. Diabetes Care. 2010 Mar 23.
LEAD 6 14-week Extension: Shifting Patients to
Liraglutide Improves FPG Control
Buse JB et al. Diabetes Care. 2010 Mar 23.
Potential Roles of GLP-1 Mimetics
►
Once-weekly injection of exenatide-LAR in
overweight patients with T2DM who
require initial therapy or combination with
other oral agents
►
Potential treatment for overweight
nondiabetic patients
►
Potential treatment of overweight, insulintreated patients with T2DM
Exenatide LAR 15-Week Study in
T2DM: Results
Baseline HbA1C (mean ± SD) 8.5 ± 1.2%
*Blood glucose
Kim D. Diabetes Care. 2007;30:1487-1493.
Baseline fasting BG 9.9 ± 2.3 mmol/L
Exenatide LAR 15-Week Study in T2DM:
Results—Safety and Tolerability
Placebo
Exenatide
0.8 mg/wk
Exenatide
2 mg/wk
Nausea (mild–moderate) *
15%
19%
27%
Injection site bruising
0%
13%
7%
Injection-site pruritus
15%
6%
7%
Reaction
% patients with exenatide
antibodies
Weight change
67% of all exenatide LAR-treated
patients
-0.04 kg
-0.03 kg
*No vomiting noted
No severe hypoglycemia or withdrawal due to adverse events observed
Kim D. Diabetes Care. 2007;30:1487-1493.
-3.8 kg
Will the DPP-4 Inhibitors Replace GLP1 Mimetics?
►
DPP-4 inhibitors have similar action to GLP-1
agonists but do not result in weight loss;
therefore, for patients in whom weight loss is
needed, GLP-1 agonists are indicated.
►
Lack of weight loss with DPP-4 inhibition is
thought to be due to lesser increase in GLP-1
levels (3x) compared with that of GLP-1
mimetic (10x) or due to lack of PYY* activation
by DPP-4
*PPY = peptide YY (intestinal satiety hormone)
Sitagliptin: Mechanism of Action
Glucosedependent
Ingestion of
food
GI tract
 Insulin
(GLP-1and
GIP)
Pancreas
Release of
active incretins
GLP-1 and GIP
DPP-4
enzyme
Beta cells
Inactive
GIP
 Blood glucose
in fasting and
postprandial
states
Alpha cells
Glucosedependent
 Glucagon
(GLP-1)
Inactive
GLP-1
 Glucose
uptake by
peripheral
tissue
 Hepatic
glucose
production
Incretin hormones GLP-1 and GIP are released by the intestine throughout the
day, and their levels  in response to a meal
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
Sitagliptin: Mechanism of Action (cont)
Ingestion of
food
Pancreas
Release of
active incretins
GLP-1 and GIP
GI tract
Sitagliptin
(DPP-4
inhibitor)
X
Inactive
GLP-1
Glucose
dependent
 Insulin
(GLP-1and
GIP)
DPP-4
enzyme
Beta cells
 Glucose
uptake by
peripheral
tissue
 Blood glucose
in fasting and
postprandial
states
Alpha cells
Glucosedependent
 Glucagon
(GLP-1)
 Hepatic
glucose
production
Inactive
GIP
Incretin hormones GLP-1 and GIP are released by the intestine throughout the
day, and their levels  in response to a meal
Concentrations of the active intact hormones are increased by sitagliptin,
thereby increasing and prolonging the actions of these hormones
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
Role of DPP-4 Inhibitors
►
Approved as single agents or in
combination with a glitazone, sulfonylurea,
or metformin
►
Sitagliptin approved to be used in
combination with insulin
Saxagliptin: Difference from Placebo in
Adjusted Mean Change from Baseline in HbA1c
Rosenstock J et al. Curr Med Res Opin. 2009;25:2401-2411; Hollander P et al. J Clin Endocrinol
Metab. 2009;94:4810-4819; DeFronzo RA et al. Diabetes Care. 2009;32:1649-1655.
Sitagliptin Provides Significant and Progressively
Greater Reductions in A1C
With Progressively Higher Baseline A1C
Inclusion Criteria: 7%–10%
18-Week Study
Reduction in A1C (%)
Mean (%)
<8%
7.37
8<9%
>9%
8.40
9.48
n=96
n=70
n=27
<8%
7.39
Reduction in A1c (%)
Baseline A1C (%)
8<9%
>9%
8.36
9.58
n=130
n=62
n=37
Reductions are placebo-subtracted
Adapted from Raz I et al. and Aschner P et al. ADA 2006.
Placebo-controlled Sitagliptin Add-on to
Glimepiride or Glimepiride/Metformin
Study—Design and Patients
441 Randomized patients
with T2DM age 18–78 yrs
R
A
N
D
O
M
I
Z
A
T
I
O
N
Placebo
Placebo
Sitagliptin 100 mg qd
Sitagliptin
100 mg qd
Stratum 1 Glim (≥4 mg/day) alone
Screening
Period
Stratum 2 Glim + MF (≥1500 mg/day)
Single-blind
Placebo
Double-blind
Week 0
Continue/start
regimen of
glimepiride
± metformin
Week-2
eligible if
A1C 7.5%–10%
Hermansen K et al. Diabetes Obes Metab. 2007;9:733-745.
Phase B
Week 24
Week 80
Summary of Conclusions (24 weeks)
►
Sitagliptin significantly improved A1C when
added to:
●
●
●
►
Overall cohort: Sitagliptin reduced A1C by 0.7%
(P<0.001)
Stratum 1: Glimepiride = -0.6%
Stratum 2: Glimepiride + Metformin = -0.9%
Hypoglycemia rates were similar to those
observed for other AHA when added to SFU
●
●
Sitagliptin + glimepiride = 7.5%
Sitagliptin + glimepiride + metformin = 16.4%
Hermansen K et al. Diabetes Obes Metab. 2007;9:733-745.
Saxagliptin: Drug Interactions
and Use in Specific Populations
►
Drug interactions: Because ketoconazole, a strong CYP3A4/5 inhibitor, increased
saxagliptin exposure, the dose should be limited to 2.5 mg when coadministered
with a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin, indinavir,
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and
telithromycin)
►
Patients with renal impairment: Saxagliptin dose is 2.5 mg/d for patients with
moderate or severe renal impairment, or with ESRD requiring hemodialysis (CrCl
≤50 mL/min). Saxagliptin should be administered following hemodialysis.
Saxagliptin has not been studied in patients undergoing peritoneal dialysis.
Assessment of renal function is recommended prior to initiation of saxagliptin and
periodically thereafter
►
Pregnant and nursing women: There are no adequate and well-controlled studies
in pregnant women. Saxagliptin, like other antidiabetic medications, should be
used during pregnancy only if clearly needed. It is not known whether saxagliptin
is secreted in human milk. Because many drugs are secreted in human milk,
caution should be exercised when saxagliptin is administered to a nursing woman.
►
Pediatric patients: Safety and effectiveness of saxagliptin have not been
established.
Onglyza ® (saxagliptin) [package insert]. Princeton, NJ; Bristol-Myers Squibb; 2009.
Addition of Sitagliptin to Insulin—
Effect on HbA1c at 24 Weeks
►
►
Sitagliptin change from baseline in A1C at
Week 24 -0.59 (P<0.001)
Placebo change from baseline -0.03
Why DPP-4 Inhibitors?
►
Excellent in patients with mild hyperglycemia
requiring insulin secretagogue
►
No contraindication in heart failure and no risk of
edema or lactic acidosis
►
Can be used in renal insufficiency without risk of
hypoglycemia or lactic acidosis
►
No weight gain
►
Immediate activity without causing hypoglycemia
Should DPP-4 Inhibitors
Be First-line Agents?
►
If β-cell-sparing effect shown in rats proves to be
true in humans, DPP-4 inhibitors could become the
preferred first-line agents
►
Appropriate for patients with mild elevation of
glucose with contraindications to other agents that
cause hypoglycemia
►
Should be considered early in overweight patients
►
Should be considered in patients with heart failure
►
Strongly considered in patients with renal failure
Sitagliptin Improved Markers of β-Cell
Function — 24-week Monotherapy Study
0.55
Proinsulin/insulin ratio
80
HOMA-β
Ratio (pmol/L/pmol/L)
75
0.5
70
65
0.45
P<0.001*
P<0.001*
60
55
50
0.4
45
40
0.35
35
0.3
Placebo
Sitagliptin 100 mg
∆ from baseline vs pbo=0.078
(95% CI -0.114, -0.023)
Hatched = Baseline
Solid = Week 24
*P value for change from baseline compared to placebo
Aschner P et al. ADA. 2006.
30
Placebo
Sitagliptin 100 mg
∆ from baseline vs pbo=13.2
(95% CI 3.9, 21.9)
GLP-1 Improves β-cell Mass in Fatty
Zucker Diabetic Rats
β-cell Mass (mg)
β-cell Proliferation (%)
2.5
16
8
4
0
2.0
Apoptotic Beta Cells (%)
Proliferating Beta Cells (%)
Beta-Cell Mass (mg)
12
1.5
1.0
0.5
0
Control
GLP-1treated
30
P<0.05
P<0.01
Control
Adapted from Farilla L et al. Endocrinology. 2002;143:4397-4408.
GLP-1treated
Weeks
β-cell Apoptosis (%)
20
P<0.001
10
0
Control
GLP-1treated
Conclusions—GLP-1 Mimetics
►
GLP-1 mimetics are important new therapeutic options that
have important roles in current therapy and major
potential future roles
►
GLP-1 mimetics have excellent glucose-lowering efficacy
and are associated with significant weight loss
►
Combination with glitazones prevents glitazone-induced
weight gain
►
Long-acting GLP-1 mimetics will increase their acceptance
►
β-cell preservation, if proven in humans, may make these
mimetics early treatment options in the future
►
Use in patients with glucose intolerance or simple obesity
for weight reduction needs further evaluation
Conclusions—DPP-4 Inhibitors
►
DPP-4 inhibitors have a major role in diabetes management
►
Ability to use in renal insufficiency, heart failure, and hepatic
disease markedly increases therapeutic options for our
patients
►
Quick onset of action and lack of hypoglycemia may make
these first-line agents in hospitalized patients
►
Excellent agents for the growing population of patients
requiring modest glucose lowering
►
Efficacy is enhanced with increased baseline HbA1C
►
New data support efficacy with sulfonylureas, which will
greatly enhance the usefulness of DPP-4 inhibitors
►
May be used as single agents or in combination with
metformin, glitazones, sulfonylurea, or insulin
Future Management Directions in DM2
►
Longer – acting incretin mimetics
►
Other DPP-IV inhibitors
►
Other agents - e.g., SGLT-2 inhibitors
►
Newer insulin formulations (oral / inhaled)
►
Weight (“girth”) control - medical / surgical
►
DM2 prevention - action in the pre-diabetes
(impaired tolerance) phase
SGLT-2 Inhibitors – Useful Adjuncts?
►
Mechanism of action - sodium-glucose transporter inhibition –
prevents glucose reabsorption in the proximal tubal resulting
in glucose loss (analogous to the apparently benign condition
of renal glycosuria).
Not insulin dependent. Effective in DM2 and DM1.
►
Studies to date - monotherapy and as add on to metformin,
SU’s, TZD’s, DPP-IV inhibitors & insulin – most studies
preliminary
►
Route - oral, daily (contraindicated with severe CKD)
►
Efficacy - HbA1c reduction ~ 0.7-0.8% : weight loss – 1-2 kg
►
Side effects - small(?) increase in U.T.I.’s & genital moniliasis.
No hypoglycemia with monotherapy.
See Lancet 2010;375: 2196-98 & 2223-33
Stamp Out Diabetes!
Investigations • Innovation • Clinical Application
Sequencing Oral Therapy in Type 2 Diabetes:
DPP-4 Inhibitors as Monotherapy or Combination
Therapy with Metformin, Sulfonylureas, and
TZDs—Constructing Outcome-Optimizing Oral
Regimens
Aligning Oral Therapy with Appropriate Patient
Subgroups and Clinical Situations
Alexander Turchin, MD, MS
Assistant Professor, Harvard Medical School
Brigham and Women's Hospital
Boston, MA
Topics
► DPP-4 inhibitors as monotherapy or
combination therapy with metformin,
sulfonylureas, and TZDs - constructing
outcome-optimizing oral regimens
► Aligning oral therapy with appropriate patient
subgroups: how to choose and what to
choose - a systematic, guideline-consistent
approach based on clinical evidence
DPP-IV Inhibitors
Sitagliptin (Januvia)
Saxagliptin (Onglyza)
[Vildagliptin]
[Alogliptin]
• Glucose-dependent stimulation of insulin secretion
• Reduction of gastric emptying
• Reduction of inappropriate glucagon secretion
• Beta-cell proliferation / regeneration
Adapted from: Nauck MA et al. (2009). Diabetes Care 32(S2):S223
Risks & Benefits
EFFICACY
↓A1c 0.7%
(up to 1.5% if starting
A1c higher)
COST
$200 / month*
DPP-IV
inhibitors
SIDE EFFECTS (common)
- none
CONTRAINDICATIONS
- h/o pancreatitis
* Source – drugstore.com
SIDE EFFECTS (putative)
- Pancreatitis
- Pharyngitis
Risks: Immunodeficiency
► DPP-4 is found on the surface of lymphocytes
► It inhibits breakdown of multiple cytokines and
hormones including many involved in immune cell
regulation
BUT
► Meta-analysis of 12 Phase IIb / III trials involving
3,415 patients on sitagliptin vs. 2,724 patients on
placebo showed incidence of infections 34.5% vs.
32.9% (NS)
► Incidence of nasopharyngitis was 7.1% vs. 5.9% (NS)
From: Williams-Herman, D et al. (2008). BMC End Dis 8(14)
Risks: Pancreatitis
► 88 cases of pancreatitis in patients on sitagliptin
have been reported to the FDA by 09/2009
BUT
► Retrospective study of 786,656 patients including
patients with h/o chronic pancreatitis and other
pancreatitis risk factors
► 15,826 patients on sitagliptin
► Incidence of pancreatitis increased in patients
with diabetes; no difference for sitagliptin
From: Garg R et al. (2010). Diabetes Care online 08/03/10
The Rest - Daily
Sulfonylureas
Thiazolidinediones
(TZD)
Metformin
Efficacy
(A1c)
-1.5%
-1.0%
-1.5%
Cost*
(1 month)
$4§
$250
$4§
Side effects
Hypoglycemia
Weight gain
CHF
Weight gain
Bone loss
GI
All are approved as monotherapy or in combination with each other
* Source – drugstore.com if not specified otherwise
§ Wal-Mart
The Rest – with Meals
Glinides
α-glucosidase
inhibitors
Efficacy
(A1c)
-1.5%
-0.7%
Cost*
(1 month)
$200
$100
Side effects
Hypoglycemia
Weight gain
GI
All are approved as monotherapy or in combination with each other
* Source – drugstore.com if not specified otherwise
ADA Consensus Algorithm
At diagnosis:
lifestyle +
metformin
lifestyle +
metformin +
basal insulin
lifestyle +
metformin +
intensive insulin
lifestyle +
metformin +
sulfonylurea
lifestyle +
metformin +
pioglitazone
lifestyle +
metformin +
sulfonylurea +
basal insulin
lifestyle +
metformin +
GLP-1 agonist
Adapted from: Nathan DM et al. (2009). Diabetes Care 32(1):193
Less well
validated
therapies
ACE / AACE Algorithm
Patient Preference: Efficacy
sulfonylurea
DPP4
inhibitor
metformin
TZD
αglucosidase
inhibitors
glinide
Patient Preference: Cost
TZD
metformin
DPP4
inhibitor
sulfonylurea
αglucosidase
inhibitor
Patient Preference: Weight
sulfonylurea
metformin
DPP4
inhibitor
αglucosidase
inhibitor
TZD
Patient Preference:
Hypoglycemia Avoidance
sulfonylurea
DPP4
inhibitor
αglucosidase
inhibitor
metformin
TZD
glinide
Investigations • Innovation • Clinical Application
Questions?
Alexander Turchin, MD, MS
aturchin@partners.org
Investigations • Innovation • Clinical Application
Cardiovascular, Metabolic, and Renal
Considerations: Optimizing Efficacy and
Safety of DPP-4 Inhibitor Therapy in High
Risk Patients
Evidence-Based Therapy for T2D in Patients with CV
and/or Renal Risk Factors or Dysfunction
Derek LeRoith, MD, PhD, FACP
Chief, Division of Endocrinology, Diabetes and Bone Disease
Director, Metabolism Institute,
Mount Sinai School of Medicine
New York, NY
No A1C threshold is apparent
–
Finnish study by Kuusisto et al;UKPDS epidemiologic analysis; EPIC-Norfolk Study
Impaired glucose tolerance (IGT) and postprandial hyperglycemia are CV risk factors
–
Funagata Diabetes Study,;Honolulu Heart Program; DECODE Study; Rancho Bernardo Study
Mortality in Multiple Risk Factor
Intervention Trial (MRFIT)
Risk Factor
Diabetes
(n = 5163)
No Diabetes
(n = 342,815)
Relative
Risk*
CVD
85.13
22.88
3.0
CHD
65.91
17.03
3.2
6.72
1.75
2.8
12.99
4.08
2.3
160.13
53.20
2.5
Stroke
Other CVD
Other
*Age-adjusted rate per 10,000 person-years. Relative risk adjusted for age, race, income, systolic BP, and
smoking.
Savage PJ. Ann Intern Med. 1996;124:123-126.
“Ticking Clock” Hypothesis: Glucose Abnormalities
Increase CV Risk, Even Before Dx DM
Nurses’ Health Study, N = 117,629 women, aged 30–55 years; followup 20 years (1976–1996)
Relative
risk of MI
or stroke*
No diabetes
Before
diabetes
diagnosis
After
diabetes
diagnosis
Diabetes at
baseline
*Adjusted
n = 1508 diabetes at baseline
n = 5894 new-onset diabetes
Hu FB et al. Diabetes Care. 2002;25:1129-34.
7-year incidence of
cardiovascular events (%)
High Risk of Cardiovascular Events
in Type 2 Diabetes
50
45
40
35
30
25
20
15
10
5
0
No diabetes
Type 2 diabetes
-
+
-
+
Myocardial
infarction
Haffner, NEJM 1998, 229-234
-
+
-
Stroke
+
-
+
-
+
Cardiovascular
deaths
Prior myocardial infarction
DCCT/EDIC: Incidence of
Any CVD Event
EDIC observation
0.12
Cumulative incidence
Conventional treatment
0.10
EDIC A1C mean 8.2%
42%
Risk reduction
P=0.02
0.08
0.06
0.04
0.02
Intensive treatment
EDIC A1C mean 8.0%
0.00
0 1 2 3
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Years since entry into studies
DCCT=Diabetes Control and Complications Trial.
EDIC=Epidemiology of Diabetes Interventions and Complications.
DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-2653.

20 years
Legacy Effect of Earlier Glucose Control
After median 8.5 years post-trial follow-up
Aggregate Endpoint
1997
2007
Any diabetes related endpoint
RRR:
P:
12%
0.029
9%
0.040
Microvascular disease
RRR:
P:
25%
0.0099
24%
0.001
Myocardial infarction
RRR:
P:
16%
0.052
15%
0.014
All-cause mortality
RRR:
P:
6%
0.44
13%
0.007
RRR = Relative Risk Reduction, P = Log Rank
10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Eng J Med 2008; 359
Cardiovascular Safety: Exenatide BID
►
Meta-analysis of clinical trials for exenatide twice daily
● No increased risk of CV events
● Relative risk (95% CI) = 0.69 (0.46 - 1.04) versus pooled
comparators
►
Retrospective, comparative analysis of large health insurance
database
●
●
Exenatide-treated (n = 21754) versus non-exenatide-treated (n =
361771)
Significantly lower risk of CV event for exenatide-treated patients
• Hazard ratio (95% CI) = 0.81 (0.68-0.95); P = .011
• Lower risk despite greater inherent CV risk due to higher rates of
hyperlipidemia, hypertension, obesity, and prior CAD
Shen L, et al. Diabetes. 2009;58(suppl 1):366-OR.
Best JH, et al. Presented at the ADA 70th Scientific Sesions; 712-P.
Cardiovascular Safety: Liraglutide
►
US FDA analyses of clinical trial data identified no excess
risk of CV events versus comparators (active or placebo)
►
Liraglutide Effect and Action in Diabetes: Evaluation of
Cardiovascular Outcome Results (LEADER) trial
●
●
Designed to assess CV safety and satisfy FDA guidelines for
T2DM treatments
Scheduled to begin Autumn 2010
FDA briefing materials – liraglutide. http://www.fda.gov/ohrms/dockets/ac/09/briefing/
2009-4422b2-01-FDA.pdf; Update on FDA Advisory Committee meeting on
liraglutide for the treatment of type 2 diabetes.
http://www.novonordisk.com/include/asp/exe_news_attachment.pdf?s
AttachmentGUID=1c87137d-806f-41bc-832a-e5a74aa86164;
LEADER trial press release. http://press.novonordisk-us.com/index.php?s=43&item=250.
CV Safety With DPP-4 Inhibitors:
Sitagliptin
►
Over 10,000 patients with T2DM, treated with sitagliptin
100 mg/day or placebo (non-exposed), up to 2 years.
►
The patients were from trials using sitagliptin as
monotherapy, or in combination with metformin,
sulfonylurea, pioglitazone or insulin.
►
Incidence rates of adverse events in the Cardiac
Disorders Systems Order Class was ~4% per 100 Patient
years, in both the sitagliptin and non-exposed patients.
Williams-Herman D, et al.BMC Endocr Disord. 2010 Apr 22;10:7.
Cardiovascular Safety in
Saxagliptin Clinical Trials
Data from 8 randomized, double-blind, phase 2b/3 trialsa
Major adverse cardiovascular events (MACE)b
Acute cardiovascular events (ACE)c
0.44
(0.24, 0.82)
Saxagliptin
n (%)
Comparator
n (%)
ACE
38 (1.1)
23 (1.8)
MACE
23 (0.7)
18 (1.4)
All deaths
10 (0.3)
12 (1.0)
CV deaths
7 (0.2)
10 (0.8)
Event type
MACE
ACE
0.59
(0.35, 1.00)
0
0.5
1
1.5
2
Cox Proportional Hazard Ratio
(95% confidence interval)
a
Wolf R, et al. ADA 69th Scientific Sessions.
Late Breaking Abstract Handout. 2009;8-LB:LB3.
Saxagliptin exposure: n = 3356 (3758 patient-years);
comparator exposure: n = 1251 (1293 patient-years).
b Stroke, myocardial infarction, cardiovascular death.
c Includes revascularization.
Summary of Incretin Actions on Different Target Tissues
Neuroprotection
Appetite
Brain
Stomach
Heart
Gastric emptying
Cardioprotection
Cardiac output
GLP-1
Liver
GI tract
Insulin biosynthesis
b cell proliferation
b cell apoptosis
Insulin sensitivity
Muscle
Glucose production
Drucker D. J. Cell Metabolism 2006
Insulin secretion
Glucagon secretion
Position Statementa Regarding ACCORD,
ADVANCE, and VADT Results
►
Clinical implication = individualized goals and care
►
General A1C goal of < 7%
●
●
►
A1C goals closer to normal for some patients
●
●
►
For microvascular disease prevention
Reasonable for macrovascular risk reduction, pending more
evidence
Short diabetes duration, long life expectancy, no significant CVD
Levels reached without significant adverse treatment effects
Less stringent goals for some patients
●
History of severe hypoglycemia, limited life expectancy,
advanced micro- or macrovascular complications, extensive
comorbid conditions, long-standing diabetes with difficulty
achieving glycemic goals
aAuthored
by the American Diabetes Association, American College of
Cardiology Foundation, and American Heart Association.
Skyler JS, et al. Diabetes Care. 2009;32:187-192.
Risk of Hypoglycemia in Type 2 DM
►
Hypoglycemia associated with use of sulfonylureas and
insulin.
►
Severe hypoglycemia is clinically evident, however, mild to
moderate hypoglycemia maybe asymptomatic and remain
unreported.
►
When unreported, asymptomatic hypoglycemia maybe
detrimental to patients.
►
Asymptomatic hypoglycemia maybe more prevalent in older
patients.
Chico A et al Diabetes Care 26: 1153-1157. 2003
Matyka K et al Diabetes Care 20: 135-141. 1997.
Monami M, et al. Eur J Endocrinol. 2009;160:909-917.
Buse JB, et al. Lancet. 2009;374:39-47.
aHypoglycemia
requiring third-party assistance.
Risk Factors and Consequences of
Hypoglycemia in Type 2 Diabetes
►
Risk factors1
●
●
●
●
●
►
Use of insulin secretagogues and insulin therapy
Missed or irregular meals
Advanced age
Duration of diabetes
Impaired awareness of hypoglycemia
Consequences2,3
●
●
Suboptimal glycemic control
Other health effects
1. Amiel SA et al. Diabet Med. 2008;25:245–254.
2. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.
3. Cryer PE. J Clin Invest. 2007;117:868–870.
Hypoglycemia May Be a Barrier to Glycemic
Control in Patients With Type 2 Diabetes
►
Hypoglycemia is an important limiting factor in
glycemic management and may be a significant
barrier to treatment adherence
►
Fear of hypoglycemia is an additional barrier to
control
●
A study in patients with type 2 diabetes showed
increased fear of hypoglycemia as the number of
mild/moderate and severe hypoglycemic events
increased
Amiel SA et al. Diabet Med. 2008;25:245–254.
45
20
Patients with hypoglycaemia** (%)
Hypoglycaemia, events/patient/year*
Current Treatments Increase
Risk of Hypoglycemia
15
10
5
39
40
35
p<0.05 glibenclamide
vs. rosiglitazone
30
25
20
15
10
12
10
5
0
0
Glargine
*All symptomatic hypoglycaemic events
NPH
Rosiglitazone Metformin
Glibenclamide
** Patients self-reporting (unconfirmed) hypoglycaemia
Riddle et al. Diabetes Care 2003;26:3080; Kahn et al (ADOPT). NEJM
2006;355:2427–43
Hypoglycemia Risk
With GLP-1 Receptor Agonists
►
Meta-analysis
● 15 trials with exenatide BID or liraglutide versus active
comparators or placebo
● Low risk of hypoglycemia except in combination with SUs
►
Significantly less minor hypoglycemia with liraglutide than with
exenatide in head-to-head comparison
● Liraglutide or exenatide + MET and/or SU
● Major hypoglycemiaa: 2 events in patients treated with
exenatide + SU
aHypoglycemia
Monami M, et al. Eur J Endocrinol. 2009;160:909-917.
Buse JB, et al. Lancet. 2009;374:39-47.
requiring third-party assistance.
Hypoglycemia Risk With
DPP-4 Inhibitors
Any Hypoglycemia (Mantel-Haenzel Odds Ratio With 95% CI)a
Placebo-Controlled
Active
Trials
Comparators
0.01
0.10
1.0
10.0
Vildagliptin
Monotherapy
Add-on to SU/Insulin
Sitagliptin
Monotherapy
Add-on to SU/Insulin
DPP-4 Inhibitors
Sulfonylureas
Thiazolidinediones
Hypoglycemia risk similar to placebo
a
Monami M, et al. Nutr Metab Cardiovasc Dis.
Published online June 8, 2009; doi:10.1016/j.numecd.2009.03.015.
Logarithmic scale.
Age-related Decline in Renal Function
in Patients with Type 2 diabetes
Dosing GLP-1 Receptor Agonists in
Renal Insufficiency
Degree of Renal
Insufficiency
Mild
(GFR > 50 mL/min)
Exenatide BID
No change
Moderate
Use caution during initiation or
(GFR ≥ 30-50 mL/min) dose escalation
Severe
(GFR < 30 mL/min)
•Should not be used in patients
with severe renal impairment
or end-stage renal disease
•Use with caution in patients
with renal transplantation
Liraglutide
Use with caution due to
limited clinical experience in
this population. No dose
adjustment recommended.
Use with caution due to
limited clinical experience in
this population. No dose
adjustment recommended.
Use with caution due to
limited clinical experience in
this population. No dose
adjustment recommended.
Byetta (exenatide) [prescribing information]. http://pi.lilly.com/us/byetta-pi.pdf.
Victoza (liraglutide) [prescribing information]. http://www.victoza.com/pdf/PI_(1_Column_Format).pdf.
Dosing DPP-4 Inhibitors in
Renal Insufficiency
Degree of Renal
Insufficiency
Sitagliptin
Saxagliptin
Mild
(GFR > 50 mL/min)
100 mg per day
5mg per day
Moderate
(GFR ≥ 30-50
mL/min)
50 mg per day
No adjustment
Severe
(GFR < 30 mL/min)
25 mg per day
2.5 mg per day
Saxagliptin and Sitagliptin
in Elderly Patients
Saxagliptin
5 mg/day vs placebo
Participants
A1C change
(relative to placebo)
AEs
Hypoglycemia
Sitagliptin
100 mg/day vs placeboa
•Patients ≥ 65 yearsb
•Monotherapy and
combination therapy
•N = 274
•Patients ≥ 65 years
•Monotherapy
•N = 206
- 0.55%
- 0.7%
Similar to placebo
Similar to placebo
None reported
Similar to placebo
Barzilai N, et al. Diabetes. 2009;58(suppl 1):587-P.
Maheux P, et al. Presented at the 2009 European Association
for the Study of Diabetes Meeting. Present No. 766.
Except in cases of dose adjustment for renal
insufficiency.
b Pooled analysis of clinical trial data.
a
Investigations • Innovation • Clinical Application
Case Studies in Oral Therapeutics for
Type 2 Diabetes—Clinical Decisions and
Real World Outcomes
Program Chairman
Charles Faiman, MD, FRCPC,MACE
Past Chairman
Consultant Staff
Department of Endocrinology, Diabetes and Metabolism
Cleveland Clinic Foundation
Case Study #1
►
47-year-old male with type 2 diabetes mellitus
diagnosed 5 years ago, returns for a follow-up visit.
►
He reports feeling well. For exercise, he walks his
dog daily for about a mile. He feels he could “do
better with his diet”; he has seen a nutritionist and
diabetes educator, but says he lacks motivation.
Case Study #1
►
On exam he has a BMI of 36, Pulse 74,
BP 130/80. Rest of the exam is normal
►
His current meds are metformin 1000 mg bid,
glyburide 10 mg bid, lisinopril 10 mg daily,
simvastatin 40 mg daily, and ASA 81 mg daily.
►
Downloaded meter reveals BG testing about once
daily; BG range 55-320, average 162 mg/dl.
►
A1C 7.8 %, serum creatinine 1.1 mg/dl , LDL-C
66 mg/dl
Case Study #1
What is your recommendation for him?
1. Add basal insulin
2. Stop glyburide and start basal bolus
insulin treatment
3. Add pioglitazone (Actos) 45 mg daily
4. Add sitagliptin (Januvia) 100 mg
daily
5. Do not change drug therapy and
refer back to the diabetes educator
6. Add exenatide (Byetta) bid
Case Study #2
► 67-year-old woman with DM-2, hypertension,
obesity, rheumatoid arthritis and COPD presents
with A1c of 7.6%. Her BMI is 34.2 and she is
looking to lose weight. She tried metformin
previously but did not tolerate due to side effects.
► Candidate for DPP-IV monotherapy
► Alternatives: α-glucosidase inhibitor
► Other options
Case Study #3
► 82-year-old man with hypertension,
hypercholesterolemia, ischemic cardiomyopathy
and NYHA class III heart failure presents with a
newly diagnosed DM-2 and A1c of 7.4%.
► Candidate for DPP-IV monotherapy
► Alternatives: α-glucosidase inhibitor
► Other options
Case Study #4
► 59-year-old man with DM-2 treated with metformin,
hypertension, dyslipidemia, prostate cancer and
osteoporosis presents with A1c of 7.9%. He was
previously taking glyburide but had several episodes of
severe hypoglycemia (had to be assisted in treatment)
and discontinued it 3 months ago. He has a hectic work
schedule (marketing executive) and is not always able
to have meals at regular times.
► Candidate for DPP-IV as 2nd line agent (after metformin)
► Alternatives: α-glucosidase inhibitor
► Other options
Case Study #5
► 52-year-old man with no past medical history
presents with newly diagnosed DM-2. His A1c is
9.1%. He is adamant in refusing to consider
injectable medications.
► Candidate for DPP-IV as 3d line agent (after
metformin + sulfonylurea and / or TZD)
► Alternatives: α-glucosidase inhibitor
► Other options
Case Study #6
73-year-old African-American female - T2DM for the past 5 years
PM History: GI intolerance with metformin
Longstanding hypertension
MI at age 65, ejection fraction 40%
Meds:
Glimepiride 4 mg, Aspirin 325 mg, Metoprolol 50 mg
Rosuvastatin 10mg, Furosemide 20mg, Lisinopril 10mg daily
Vitals:
BMI 29, BP 130/80
Bloods:
TCHOL 193, LDL 70, HDL 58, TG 81
FPG 127 mg/dl, A1C 7.5%
Creatinine 1.4 mg/dl, GFR 49 ml/min
What’s the next step in managing her diabetes?
Case Study #6
What’s the next step in managing her diabetes?
The following should not be used in this patient,
except one class:
A. Metformin
B. Sulfonylureas
C. Thiazolidinediones
D. Incretin mimetics/ DPP-IV inhibitors
E. Insulin
Case Study #6
What are some of the major risk factors in treating
Type 2 diabetic patients?
1. Cardiovascular disease
2. Renal Failure
3. Aging
4. Hypoglycemia