Transcript Therapeutic Interventions in Type 2 Diabetes A Proactive Clinician’s Pathophysiologic Approach to Therapy in Older Patients with Type 2 Diabetes: A New Paradigm Stan Schwartz MD,

Therapeutic Interventions in Type 2
Diabetes
A Proactive Clinician’s
Pathophysiologic Approach to
Therapy in Older Patients with Type
2 Diabetes: A New Paradigm
Stan Schwartz MD, FACP, FACE
Affiliate, Main Line Health System
Emeritus, Clinical Associate Professor of Medicine
U of Pa.
Lecture Based on Evidence -Based
PRACTICE
EBM=Evidence
Based =
Medicine
Has Led to Students/MDs who don’t Think
Research Evidence
EBM=Evidence
Based
=
Medicine
+
Randomized, Prospective
Publication Trials
Critical Appraisal
Patient-Based
Experience
=Evidence
Based Practice
Clinical expertise
Expert Opinions
Guidelines
Must Marry Evidence, Clinical Reasoning; Art and Science of Medicine
Duggal, Evidence-Based Medicine in Practice,, Int’l j. Clinical Practice,65:639-644,2011
25
FBS- 100-125 = prediabetes, 126 =/> = diabetes
2 hr. ppg 140-199 = prediabetes, 200 =/> = diabetes
HgA1c 5.7-6.4 = prediabetes, 6.5 =/> = diabetes
Type 2 diabetes – the microvascular and
macrovascular burden is already present
at diagnosis
Retinopathy1
ASVD
21%
50%
Nephropathy2
18%
Erectile dysfunction1
20%
Neuropathy1
12%
1. UKPDS Group. Diabetes Res 1990; 13: 1–11.
2. The Hypertension in Diabetes Study Group. J Hypertens 1993; 11: 309–317.
Hyperglycemia Leads to Complications
Hyperglycemia
Spike
Continuous
PPG
A1C
Chronic toxicity
Acute toxicity
Tissue lesion
Diabetic complications
Microvascular
Retinopathy
Nephropathy Neuropathy
Macrovascular
PVD
MI
Stroke
American Diabetes Association.
14 At: http://www.diabetes.org/diabetes-statistics/complications.jsp.
Brownlee M. Diabetes mellitus: theory and practice. Elsevier Science Publishing Co., Inc; 1990:279-291.
Ceriello A. Diabetes. 2005;54:1-7.
Glucose Variability as a predictor of mortality
within different ranges of mean glucose
Higher sugars/ higher Variability
Higher the Mortality
Each of the increments of mean glucose level is subdivided into four quartiles of
glycemic variability.
Q1 represents the lowest quartile; Q4 represents the highest quartile
Hermanides, Critical Care Med,38:838, 2010
BUT MUST AVOID HYPOGLYCEMIA
Especially as Hypoglcemic Unawareness
VERY COMMON;
42% of Type 2 Patients- even greater in the Older Patient
Symptoms Signs of Hypoglycemia
Classic
1.<80
2.Shaky Sweaty, nervous jittery
Hypoglycemic unawareness
1.Awake in AM with headache, nightmare, eerie dream,
sweat
2.Awake with unexpected high- I didn’t eat wrong last night
3.Terrible hunger before meals, sleep
Desouza,DIABETES CARE, VOLUME 33, NUMBER 6, JUNE 2010
Consequences of Hypoglycemia
 Prolonged QT- intervals- Diabetologia 52:42,2009

Can be of pronged duration IJCP Sup 129, 7/02

Greater with higher catecholamine levels Europace 10,860
 Associated with Angina Diabetes Care 26, 1485, 2003 / Ischemic EKG
changes Porcellati, ADA2010
 Associated with Arrhythmias
 Associated with Sudden Death Endocrine Practice 16, 2010
 Increased Variabilty- explains highest mortality in intensive group had
highest HgA1c in ACCORD ( increases inflammation, ICU mortality,
Hirsch ADA2010)
CV Risk of SU and Insulin
So benefit of both SU/Insulin in
research studies –UKPDS,
DCCT/EDIC
But adverse risk in
‘real world’ use
Pharmacoepidemiology and Drug Safety. 2008;(17):753-759.
Meta-Analysis: Cardiovascular Risk With
Sulfonylurea Plus Metformin
Results With Combination Therapy
• Increased composite cardiovascular risk end point (RR 1.43; 95% CI, 1.10-1.85)
•
•
All-cause mortality alone – not significant
Cardiovascular disease mortality alone – not significant
Relative Risk (95% CI)
Bruno (1999)
1.04 (0.62-1.75)
Olsson (2000)
1.86 (1.33-2.61)
Johnson (2005)
0.96 (0.82-1.12)
Koro (2005)
1.38 (1.13-1.69)
Evans (2006) (A)
2.24 (1.26-3.99)
Evans (2006) (B)
1.86 (1.03-3.35)
Evans (2006) (C)
1.52 (0.84-2.76)
Overall
1.43 (1.10-1.85)
0.25
1.0
4.0
Composite end point: cardiovascular hospitalization or mortality
Relative risk: combination therapy vs. diet, metformin alone, or sulfonylurea alone
Rao AD, et al. Diabetes Care. 2008;31:1672-1678.
RR = relative risk
Higher Mortality Is Associated With Greater
Exposure to Sulfonylurea
There was a greater risk of death associated with higher daily doses and better
adherence for patients who used glyburide (HR = 1.3; 95% CI, 1.2-1.4), but not metformin
(HR = 0.8; 95% CI, 0.7-1.1)
Daily Dose
Monotherapy
group
Glyburide
Adherence
Deaths/1000
person-years
Hazard
ratio
Lower (higher)
53.4 (70.2)
1.32
1.29
1.29
41.5 (37.6)
0.92
0.96
0.84
(n = 4138)
Metformin
(n = 1537)
0
Unadjusted
Adjusted for age, sex, chronic
disease score (CDS), and nitrate use
Adjusted for age, sex, CDS, nitrate use,
physician visits, and hospital admissions
Simpson SH, et al. CMAJ. 2006;174:169-174.
Monotherapy
group
Glyburide
Deaths/1000
person-years
Hazard
ratio
Poor (good)
49.0 (75.8)
1.55
1.34
1.33
37.7 (41.3)
1.10
1.09
0.98
(n = 4138)
Metformin
(n = 1537)
1
2
0
1
2
A retrospective, inception cohort study conducted in 5795 new users of oral
glucose-lowering medications
- Insulin or combination therapy were excluded
- Mean age: 66.3 years
- Mean follow-up: 4.6 years
- Main outcomes: all-cause mortality, death from acute
ischemic event
Sulfonylureas and Ischemic Pre-conditioning
MUST CONSIDER TOTAL COSTIncretin vs Sulfonylureasnot per/pill acquisition costs
‘Complete’ List given 5-20% of patients on Oral Hypoglycemic Agents
1.ER Visits
2.Hospitalizations
3.Mortality
4.Under-recognized- hypoglycemic unawareness
5.Lifestyle Restrictions, diminished quality of life
6.Worry for Spouse, Friends, Co-workers
7.Fear of Hypoglycemic leads to inadequate Control
8.Severe Hypoglycemia Raises the Risk of Dementia
9.Increased cost of increased number SMBG testing
Avoid compartmentalization MD therapy: take care of whole patien
Refer when you know you don’t know, not because of ‘time constraint
My interpretation: given significant life expectancies,
MUST ensure maintenance of Quality of Life; eg: DON’t ‘GIVE UP”
Greater Survival in Elderly (>75yo) with lower
HgA1c
So…
WHY NOT BE AGGRESSIVE
IN GLYCEMIC CONTROL
IF…
NOT USING
HYPOGLYCEMIC AGENTS
EASD , 9/2010
Not only ‘what’ to eat, ‘how’ to do it;
eg: behavioral advice
NCS diet
100 cal/d rule
Use foods used to eating
What Should Glycemic Goals
Be
In Older Patients
Impact of Intensive Therapy in Type 2 Diabetes
Summary of Major Clinical Trials:
BUT Subset Evaluations Show Reduced CV Outcomes if shorter
duration of DM, without significant pre-existing complications
Initial Trial
Long Term Follow-up
Study
Microvascular
Macrovascular
Mortality
UGDP
↔
↔
↔
UKPDS
DCCT/EDIC*
↓
↓
ACCORD
ADVANCE
VADT
Meinert CL. Diabetes. 1970;19(suppl):789-830.
Goldner MG. JAMA. 1971;218(9):1400-1410.
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865.
Holman RR. N Engl J Med. 2008;359(15):1577-1589.
DCCT Research Group. N Engl J Med. 1993;329;977-986.
Nathan DM, et al. N Engl J Med. 2005;353:2643-2653.
↓
↓
↓
↓
↔
↔
↔
↓
↓
↔
↔
↔
↔
↔
↑(unadj.), ↔ (adj.)
↔
↔
↑- likely due to
Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559.
Patel A, et al. N Engl J Med. 2008;358:2560-2572.
Duckworth W, et al. N Engl J Med. 2009;360.
*T1DM study.
↓
↔
hypoglycemia
and weight gain
But Why was there an apparent increase in
Mortality in ACCORD, lack of benefit in
ADVANCE, VADT
1. Weight Gain-in ACCORD avg 6 lb, 28%>10kg
2. Hypoglycemia
1. ACCORD recorded PRIOR history mild/severe events2. NO DOCUMENTATION OF GLUCOSE AT TIME OF
DEATH
3. Highestst risk in those who tried to get good control but did not
succeed- eg: variability/ hypoglycemia/ weight gain
And YET, ADA Backs-off; Based on
Misinterpretation / Misapplication of
ACCORD, VADT, ADVANCE TRIALS
So given epidemiologic data, CV risk/glucose data and now
ADVANCE, VADT, ACCORD, implications of weight gain and
hypogycemia, what are/ should be goals (SSS)
1. ADA- stayed at <7.0
AACE – stayed at < 6.5
Lowest possible as long as no undue risk of
hypoglycemia and visceral weight gain
2. ADA and AACEa. Start early in DM -
implications for preventionlifestyle and drug therapy of metabolic syndrome and IGT
b. do not aim for aggressive control in those
with significant pre-existing CV disease
Disagree- lowest possible without hypoglycemia, weight gain
3.Modify goals for ‘elderly’
Disagree- lowest possible without hypoglycemia, weight gain
Treatment of Type 2 Diabetes in Older
People:
Based on Pathophysiology
Natural History of Type 2 Diabetes
Age
0-15
Genes
15-40+
15-50+
25-70+
Envir.+
Other
Disease
Macrovascular Complications
Insulin
Resistance
Obesity (visceral)
IR phenotype
Poor Diet
Inactivity
Atherosclerosis
obesity
hypertensionHDL,TG,
HYPERINSULINEMIA
Disability
MI
CVA
Amp
Endothelial dysfunction
pp>7.8
PCO,ED
IGT – OMINOUS OCTET
Type II DM
8 mechanisms of hyperglycemia
 Beta Cell
Secretion
Eye
Nerve
Kidney
Risk of Dev.
Complications
DEATH
ETOH
BP
Smoking
Blindness
Amputation
CRF
Disability
Microvascular Complications
‘Ominous Octect: Pathophysiological Contributions
to Hyperglycemia in Type 2 Diabetes
8.Kidney-
5.Gut
carbohydrate
absorption
1.Pancreatic
insulin
secretion
2.Pancreatic
glucagon
secretion
-
7.BrainInc. Appetite
Insulin
Resistance,
Decrease ,
GLP-1
HYPERGLYCEMIA
4.Liver
-
3.Muscle
Peripheral
glucose
uptake
Hepatic
glucose
production
6.Fat- increased
lipolysis, inc FFA
Prevention
Age
0-15
Genes
15-40+
15-50+
25-70+
Envir.+
Other
Disease
Macrovascular Complications
Insulin
Resistance
Obesity (visceral)
IR phenotype
Poor Diet
Inactivity
Atherosclerosis
obesity
hypertensionHDL,TG,
HYPERINSULINEMIA
Disability
MI
CVA
Amp
Endothelial dysfunction
pp>7.8
PCO,ED
IGT – OMINOUS OCTET
Type II DM
8 mechanisms of hyperglycemia
 Beta Cell
Secretion
Eye
Nerve
Kidney
Risk of Dev.
Complications
DEATH
ETOH
BP
Smoking
Blindness
Amputation
CRF
Disability
Microvascular Complications
Treat Pre-Diabetes to Prevent DM
72%
Diabetes Mellitus Reduction (%)
80
70
60
62%
58%
58%
55%
55%
50
42%
41%
40
31%
30
25%
20
10
0
Diabetes Prevention Clinical Trials
FINNISH=Tuomilehto J, et al. N Engl J Med 2001; 344: 1343-50
DA QING=Pan XR, et al. Diabetes Care. 1997; 20: 537-44
DPP=Diabetes Prevention Program. Nathan DM, et al. N Engl J Med 2002; 346:393-403
STOP-NIDDM=Study TO Prevent Non-Insulin-Dependent Diabetes Mellitus. Chiasson JL, et al. Lancet 2002; 359:2072–77
TRIPOD=Troglitazone in the Prevention of Diabetes. Buchanan T, et al. Diabetes 2002; 51(9): 2796-2803
XENDOS=XEnical in the Prevention of Diabetes in Obese Subjects. Torgerson JS, et al. Diabetes Care 2004; 27 (1): 155-61
Finnish-Diet+ Exercise
Da Qing – Diet +
Exercise
DPP-Lifestyle
DPP-Metformin
STOP-NIDDM
TRIPOD
XENDOS
DREAM
PIOPOD
ActNOW
Prevention Increased with Use of Incretin
9 m,
105 pts
Alter the Natural History of Diabetes
Age
0-15
15-40+
15-50+
25-70+
Envir.+
Other
Disease
Genes
Macrovascular Complications
Obesity(visceral)
IR Phenotype
Inactivity
Atherosclerosis
Obesity
HypertensionHDL,TG,
Insulin
Resistance Poor Diet
HYPERINSULINEMIA
MI
CVA
Amp
Endothelial Dysfunction
pp>7.8
PCO,ED
 -Cell Secretion
Risk of
Complications
Disability
IGT
ETOH
BP
Smoking
Eye
Nerve
Kidney
DEATH
Type 2 DM
Blindness
Amputation
CRF
Disability
Microvascular Complications
ADOPT: Treatment effect on primary
N = 4351
outcome
Hazard
40
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
30
Cumulative
incidence of
monotherapy
failure*
(%)
Metformin
20
Rosiglitazone
10
0
0
1
2
3
4
5
Years
*Time to FPG >180mg/dL
Kahn SE et al. N Engl J Med. 2006;355:2427-43.
Exenatide: Sustained A1c Reductions
Mean  A1c (%)
0.5
0.0
0
Time (wk)
10
20
30
40
50
70
80
Baseline A1C
Placebo BID (N = 128)
8.3%
8.3%
Exenatide 5 mcg BID (N = 128)
8.3%
Exenatide 10 mcg BID (N = 137)
-0.5
-1.0
-1.5
-2.0
60
Open-Label Extension
Placebo-Controlled Trials
Kendall D, et al. American Diabetes Association Scientific Sessions. June 2005
90
Natural History of Type 2 Diabetes
Insulin Resistance
Age
0-15
Genes
15-40+
15-50+
25-70+
Envir.+
Other
Disease
Macrovascular Complications
Insulin
Resistance
Obesity (visceral)
IR phenotype
Poor Diet
Inactivity
Atherosclerosis
obesity
hypertensionHDL,TG,
HYPERINSULINEMIA
Disability
MI
CVA
Amp
Endothelial dysfunction
pp>7.8
PCO,ED
IGT – OMINOUS OCTET
Type II DM
8 mechanisms of hyperglycemia
 Beta Cell
Secretion
Eye
Nerve
Kidney
Risk of Dev.
Complications
DEATH
ETOH
BP
Smoking
Blindness
Amputation
CRF
Disability
Microvascular Complications
The Adipocytokine Syndrome: A New
Model for Insulin Resistance and ßCell Dysfunction
Liver
Obesity
IR
Diabetes
ASVD
Atherothrombosis
Artery
CRP, PAI-1
FFA
Visceral
fat cells
Resistin, TNFa
FFA, TNFa, Leptin
Brain
Muscle
Pancreas
Metformin
 Advantages

Effective, 2% HbA1c (1% with extended-release metformin)

No initial weight gain or modest weight loss (UKPDS)

Advantageous lipid profile

No hypoglycemia when used alone or with TZD, incretins

Decreases MIs (39% UKPDS obese subgroup,retrospective analysis)

Decreases AGEs, improved endothelial dysfunction

Potential decrease in some cancer risk

Cheap
BUT

GI side effects on initiation

Risk of lactic acidosis: Don’t use if…

Cr >1.4 female, >1.5 male

Cr Clearance <40 (age >80), blood levels increase

Cr Clearance <40, lactic acidosis cases seen
TZD MECHANISM OF ACTION
Effect of Meds on Fat Topography
IR, TG, FFA
Insulin, BP,
Inflam.
En Dys.
TZD
Intra-muscular
fat
IR, TG, FFA
Insulin, BP
Inflam.
En Dys.
Subcutaneous
fat
Intra-abdominal
fat
Intra-hepatic
fat
Direct PPAR effect on vascular cells to
decrease endothelial dysfunction and inflammation
Pioglitazone
 ADVANTAGES
Improves insulin resistance (fat/muscle), decreases insulin conc.,
improves endothelial dysfunction , dysfibrinolysis, BP, decreased
microalbumin, improved beta-cell function, treats PCOS and
steatohepatitis
Lipids (GLIA study)

Advantage to pio - decrease TG, decreased # of buoyant LDL
particles, decrease non-HDL chol.
May use in renal insufficiency , elderly

No hypoglycemia used alone or with metformin , incretin mimetics

Potential to delay or prevent DM and progression; lower secondary
failure rate than SU/met

Pio decreased prospective composite endpoint (MI,CVA, death) 16%
in PROactive trial (Can’t assume class effect) , dec. risk second MI/
ACS, decreased risk second stroke 47%
Pioglitazone in Dysmetabolic Syndrome,
Prediabetes, Type 2 Diabetes
 Safety

No liver toxicity

Increased distal fractures in women

Edema-renal sodium and total body water retention
- can be prevented/minimized (patient selection, NAS diet)
- treated with spironolactone, amilioride, triamterene

Weight gain not an obligatory side effect- studies- portion control/ education
freq.

Bone loss in women = risk/benefit evaluation for each patient

CHF not a cardiac issue except more susceptible with diastolic dysfunction
–function of renal sodium and total body water retention
-Can be prevented/reduced- low salt diet/ patient selection;
ranolazine
No Increase Risk
of Bladdder Cancer
at 8 years in K-P
Prospective Study
Natural History of Type 2 Diabetes
Insulin Secretion
Age
0-15
Genes
15-40+
15-50+
25-70+
Envir.+
Other
Disease
Macrovascular Complications
Insulin
Resistance
Obesity (visceral)
IR phenotype
Poor Diet
Inactivity
Atherosclerosis
obesity
hypertensionHDL,TG,
HYPERINSULINEMIA
Disability
MI
CVA
Amp
Endothelial dysfunction
pp>7.8
PCO,ED
IGT – OMINOUS OCTET
Type II DM
8 mechanisms of hyperglycemia
 Beta Cell
Secretion
Eye
Nerve
Kidney
Risk of Dev.
Complications
DEATH
ETOH
BP
Smoking
Blindness
Amputation
CRF
Disability
Microvascular Complications
Clinical Consequences of Abnormal First- phase Secretion
and Elevated Post-Prandial Sugars, ie: treat PPG

PPG increases
– Variability
– Microvasular disease and adverse pregnancy outcomes
– ASVD risk factors
– adverse CV outcomes

Treating elevated PPG leads to
– Reduce Pregnancy Outcomes
– Reduce micro/macrovascular risk// CV Outcomes
– Prevent Diabetes
The Pathogenesis of Type 2 Diabetes
Beta-Cell Workload Outpaces Beta-Cell Response
Healthy Subjects (n = 14)
Type 2 Diabetes (n = 12)
Carbohydrate Meal
 Beta-Cell
Workload
 Beta-Cell

Response
 Beta-Cell

Workload
Euglycemia
Hyperglycemia
Euglycemia
Mean (SE)
Incretin Effect, Normal and with Diabetes
Incretins

Gut-derived hormones, secreted in response to nutrient ingestion, that
potentiate insulin secretion from islet
-cells

Stimulation of insulin secretion is glucose-dependent.

Incretins only work when glucose levels are above basal levels- THUS , NO
HYPOGLYCEMIA if not on secreatogogue or insulin
Two predominant incretins
– glucagon-like peptide-1 (GLP-1)
– glucose-dependent insulinotropic peptide
([GIP] also known as gastric inhibitory peptide)
Holst JJ et al. Diabetes. 2004;53(suppl 3):s197-s204;
Meier JJ et al. Diabetes Metab Res Rev. 2005;21:91-117.
GLP-1 Actions Extend Beyond the Pancreas:
Address 6 of 8 Aspects of the Ominous Octet +
Improves Cardiac Function
Neuroprotection
Heart
Stomach
Appetite
Cardio-protection
5
Brain
Cardiac output
6
Gastric emptying
Pancreas
GLP-1
4
Liver
Production of glucose
Insulin synthesis
1,2
3
Muscle
Insulin sensitivity
INC. PDX-1
-cell proliferation
Insulin secretion:
glucose-Dependent
Glucagon secretion
-cell apoptosis
9-37, dec. ox. stress
Adapted from Drucker DJ. Cell Metab. 2006;3:153-165., Brownlee EASD,2007
S
e
c
t
i
o
n
Mechanism of Incretins
12,
12.2
Ingestion of
food
GI tract
DPP-4
inhibitor


Incretin
Mimetic
Glucose
dependent
 Insulin
(GLP-1and
GIP)
Pancreas
Release of
active incretins
GLP-1 and GIP
X
Inactive
GLP-1
DPP-4
enzyme
Beta cells
 Blood glucose in
fasting and
postprandial states
Alpha cells
Glucosedependent
 Glucagon
(GLP-1)
Inactive
GIP
 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.
Incretin Mimetics are resistant to DPP-4 inactivation
Concentrations of the active intact hormones are increased by DPP-4 inhibition, thereby increasing and prolonging
the actions of these hormones.
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
8-10x
2-4x
Twice insulin inc., glucagon drop
mmol/L
Glucose-Dependent Effects of GLP-1 on Insulin
and Glucagon Levels in Patients With Type 2
15.0
Diabetes
250
*
*
*
*
*
*
*
0
pmol/L
250
200
150
100
50*
*
*
*
*
*
*
*
20
15
15
*
*
*
10
*
When glucose levels
approach normal values,
insulin levels decreases.
pmol/L
pmol/L
40
30
20
10
0
20
10
5
0
–30
GLP-1
0
0
Glucagon
Placebo
*P <0.05
Patients with type 2
diabetes (N=10)
mU/L
Insulin
200
150
100
50
mg/dL
12.5
10.0
7.5
5.0
2.5
Glucose
5
Infusion
0
60
When glucose levels
approach normal values,
glucagon levels rebound.
0
120
180
240
Minutes
Adapted with permission from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag.
exenatide
82WEEK WEIGHT Dec.Not correlated to nausea
74
Change in A1C, %
Changes in Glycemia and Weight in
3 Studies of Exenatide vs Insulin
Heine
et al1
Barnett
et al2
Heine
et al1
Barnett
et al2
Nauck
et al3
-0.9%
-1.1%
-1.4%
-1.0%
10
9
8
7
6
ADA
GOAL
-1.1%
-1.4%
Glargine, Once Daily
Change in Weight, kg
Nauck
et al3
Insulin Aspart, 70/30
Exenatide
4
3
2
1
0
-1
+1.8 kg
+2.3 kg
+2.9 kg
-2
-3
1. Heine R, et al. Ann Intern Med. 2005;143:559-569.
2. Barnett AH, et al. Clin Ther. 2007;29:2333-2348.
3. Nauck MA, et al. Diabetologia. 2007;50:259-267.
-2.3 kg
-2.2 lb
-2.5 kg
75
Easy to Initiate:
31- g tips don’t hurt!!
All MDs should poke themselves!!!
• After first use, BYETTA can be kept at a room temperature not to exceed
77ºF (25ºC)
• Initiate with 5-mcg BID fixed dose, prefilled pens
• increase dose to 10 mcg BID, based on glycemic / weight response and
tolerability
• Take BYETTA with first bite , (and only 1 hour before a meal when tolerates
10 Pen)
No dosage adjustments based on meal size or exercise
• No additional glucose monitoring required
Nausea Story
Observations
– The most common AEs associated with exenatide (vs placebo) in three 30-week, placebocontrolled clinical trials were nausea (44% vs 18%), vomiting (13% vs 4%), diarrhea (13% vs
6%),
– 5 years later, monotherapy study was only 19%;
eg: learned how to use it- stop eating when full
– Both exenatide/liraglutide, nausea decreases over time
– Exenatide-QW 1/3 risk of nausea as liraglutide 1.8 mg/d
– Etiology Oversenstive hypothalamic sensitivity
 Slower gastric emptying; patients keep eating after first sense of fullness
 High fiber, high fat meals
– In Hospital-
– TEACH PATIENTS TO STOP EATING AT FIRST SENSE OF FULLNESS!!
– Patients eat slowly, decreased speed of eating, decreased quantity of eating, less fatty meals
•The ~1 % hypothalamic nausea can be treated with metochlopromide/ ondansetron-Diabet Med. 2010
Oct;27(10):1168-73. doi: 10.1111/j.1464-5491.2010.03085.x.
GLP-1 Receptors on rodent C- cells, but not on Human C-Cells
Endo, 2010
Exenatide-QW carries same warning
Patient Types/ Situations
0.Treat Late Post-Prandial Hypoglycemia
1. Prevention / Delay of DM
2. Cardiovascular- as above, likely reduced CV outcomes with
weight neutrality, no undue hypoglycemia
3. Guideline based
4. Approach to Weight reduction in Diabetes
5. Type 1/ Type 2 on insulin (on/off label)
6. Discontinue Insulin
7. Hospital/ stress/ steroid dm
Insulin Secretagogues:
Sulfonylureas and “Glinides”
X
Safety and Efficacy
-Decreases HbA1c approx 1–2%(sfu, repaglinide)(0.51.0%,neteglanide)
-Adverse events:
Wt gain,
sulfa allergy (sfu,rare),
-cell apoptosis (sfu)
Main risk = hypoglycemia , inc ischemia risk(~50% less w/repaglinide,75% less with
neteglanide)
Increase Cancer vs Metformin
Abnormal ischemia pre-conditioning
SO WHY USE SOMETHING THAT DESTROYS BETA-CELLS
THAT YOU’D LIKE TO SAVE
Davies MJ. Curr Med Res Opin. 2002;18(Suppl 1):s22-30.
SGLT2-I
40-50% efficient as hepatic glucose production increased;
Obviate with incretin Rxyielding up to 1% drops
Durable up to 1 year
cana
cana
cana
Minimize by- push PO intake, fastidious bathroom habits; urinate after intercourse
before sleep
If baseline BP low- cut back or d/c diuretic or antihyperetensive
Watch K+, if older, eGFR 45-60, on ACE / spironolactone
Other Meds with Glycemic Benefit
Fast-acting Bromocryptine
central dopaminergic effect on
decreasing peripheral sympathetic tone
decreasing insulin resistance
Decreases CV outcomes 50% in 1 year
Colsevelam
lipid benefit
(Ranolazine)
Decrease angina ( or equivalent)
Decreases arrhythmia
Improves diastolic dysfunction, thus-decreases edema of
Pio-,
Decreases HgA1c, FBS in glucose dependent fashion , no
hypoglycemia
RANOLAZINE CAN BE USED IN PATIENTS WITH
CAD AND DIABETES
.
●
Ranolazine affects Na+ channel function in cardiomyocytes,
and is likely to do the same in beta-cells
●
Ranolazine is approved for treatment of ischemic anginal-equivalents
●
Ranolazine significantly and dose- dependently reduces HbA1c.
●
The magnitude of HbA1c lowering by ranolazine is correlated with the levels of HbA1c and
FPG at baseline.
●
Ranexa does not increase the incidence of hypoglycemia compared with placebo
●
Ranexa does not increase the incidence of:
─
Weight gain
─
Cardiovascular adverse events
─
Dyslipidemia (LDL, HDL, total cholesterol, and
triglycerides)
─
No Clinically relevant changes in blood pressure or heartTimmis
rateAD, et al. Eur Heart J 2006;27:42-48
Therapy for Type II
Diabetes
Targets for Glycemic Control
ADA
ACE
<7.0
<6.5
Fasting/Preprandial (mg/dL)
(plasma equivalent)
90-130
<110
Postprandial (mg/dL)
<180*
<140
A1C (%)
Normal: 4-6%
(2-hour)
* Peak
Goals for individual patients may vary.
Aim for the Lowest A1C Possible without
Hypoglycemia.
American Diabetes Association. Clinical Practice Recommendations. Diabetes Care. 2004,27:S15-S35
The American Association of Clinical Endocrinologists. Medical Guidelines for the Management of Diabetes Mellitus. Endocr Pract. 2002; 8(Suppl. 1):
40-82
Inc PPG
increases
Microand
macrovascular
disease
Thus , to get to glycemic goals, one must control PPG as well as FBS.
(incretins, alpha-glucosidase inhibitors, TZDs)
Reduce Variability and
Prevent Build-up of Metabolic Memory
Augers for Avoiding Step-Care Therapy; use Early CombinationTherapy
Non-Insulin Therapy for
Type II Diabetes
Concurrent Therapy
The ABCs of Diabetes Care:
Recommended Goals
A1C
ADA recommends < 7.0% in general, < 6.0% in selected individuals
AACE/IDF recommend ≤ 6.5%
Blood pressure
< 130/80 mm Hg
Cholesterol
LDL-C: < 100 mg/dL (< 70 mg/dL in very high-risk patients)
HDL-C: > 40 mg/dL in men and > 50 mg/dL in women
Non–HDL-C: < 130 mg/dL (< 100 mg/dL in high-risk patients)
Triglycerides: < 150 mg/dL
American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12-S54.
AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13(suppl 1):3-68.
IDF Clinical Guidelines Task Force. Diabet Med. 2006;23:579-593.
Treating the ABCs Reduces
Diabetic Complications
Strategy
Blood glucose control
Blood pressure control
Lipid control
1 UKPDS
Complication
▪ Heart attack
 37%1
▪ Cardiovascular disease
 51%2
▪ Heart failure
 56%3
▪ Stroke
 44%3
▪ Diabetes-related deaths
 32%3
▪ Coronary heart disease mortality
35%4
▪ Major coronary heart disease event
55%5
▪ Any atherosclerotic event
37%5
▪ Cerebrovascular disease event
53%4
Study Group (UKPDS 33). Lancet. 1998;352:837-853.
L, et al. Lancet. 1998;351:1755-1762.
3 UKPDS Study Group (UKPDS 38). BMJ. 1998;317:703-713.
4 Grover SA, et al. Circulation. 2000;102:722-727.
5 Pyŏrälä K, et al. Diabetes Care. 1997;20:614-620.
2 Hansson
Reduction of
Complication
Steno-2- Synergy in CareTreating Glucose, BP, Lipids
Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes,
Treating Defronzo’s Octet: WITHOUT HYPOGLCEMIA
Match Patient Characteristics to Drug Characteristics
5.Gut CHO
Absorption:
8.Kidney-
SGLT2
-
Incretin,
Pramlintide,
Glucosidase inh.
1.Pancreatic
insulin
Secretion:
Incretin, ranolazine
2.Pancreatic
glucagon
Secretion- Incretin
7.BrainTZD,INCRETIN
bromocryptine
HYPERGLYCEMIA
De
-
-
3.MuscleTZD, Incretin
4.Liver
Hepatic glucose
production:
Metformin, incretin
Peripheral
glucose
uptake
6.Fat- TZD, metformin
The New ADA Guidelines for Type 2 Diabetes:
AKA- David Nathan’s Regimen-
DNR- COST BASED
Revised Treatment Algorithm
At diagnosis:
Lifestyle + metformin
STEP 1
Tier 2†
Tier 1*
HbA1C >7.0%
STEP 2
Add basal
insulin
STEP 3
Add
sulfonylurea
Add GLP-1
agonist
Add pioglitazone
± SU
Intensive insulin
NOT Glyburide, chlorpropamide
NOT Rosiglitazone
Addressing Cost- One Patient at a Time
New ADA Guidelines- 4/20/12
SU most prominent
Added back
glyburide
Inzucchi,
Diabetologia
4/20/12
AACE/ACE: Recommendations Based on A1C at
Diagnosis
Lifestyle Modifications
A1C 6.5%-7.5%
A1C 7.6%-9.0%
If under
treatment
Monotherapy
Dual therapy
Insulin plus
other
agent(s)*
Dual therapy
A1C > 9.0%
Triple therapy
Triple therapy
If drug
naive
Insulin plus
other
agent(s)*
Triple therapy
*Pramlintide can be used with prandial insulin, but insulin secretagogues should
be discontinued with multidose insulin
AACE: American Association of Clinical Endocrinologists
Rodbard HW, et al. Endocr Pract. 2009;15:540-559.
And the GUIDELINES SHOULD REFLECT
THIS!!
Summary for DM Care In
Older Patients
 Treat aggressively- benefit on cost and complications
 Treat elements of pathophysiology

Resistance-glycemia,endothelial dysfunction,lipids,BP,coag.

Secretion-first phase,incretin,importance of PPG

Multi-hormonal issues

Use SIDE-BENEFITS of the various agents
 Treat to new goals using combinations that make pathophysiologic
sense
 Guidelines should help pick right drug(s) for right patients