Transcript Oral Therapy for Type 2 Diabetes

Some Things You May Be
Interested In With Regard To
Therapy for Type 2 Diabetes
Oliver Z. Graham, MD
Mail-Order Endocrinologist
Department of Internal Medicine
The Agenda
 Dealing
with severe hyperglycemia in
clinic
 Sulfonyureas, Metformin
 The GLP -1 based therapies
 should
we use them?
What about TZDs?
 What should target HA1c be?

A case study
 A 48
YO newly emigrated Mexican man
comes to your clinic with polyuria,
polydipsia and nocturia for the past
month as well as 8 pounds of
unintentional weight loss.
Case study, continued
 Na
140 K 4.4 AG 10 BUN 12 Cr 0.9
 U/A No ketones, ++ Glucose
 Blood sugar 498
 What do you do now?
Dealing with severe
hyperglycemia in clinic
 Per ADA,
insulin indicated as initial
treatment in patients with:
 FBG
> 250
 Random BG > 300
 HA1C > 10
 Ketonuria
 Suspicion of DM type 1
 Is
this realistic for our patients?
Guidelines for management of
hyperglycemia in health centers
 If
abnormal vital signs, ketones in urine,
altered mental status, elevated anion
gap --> send to ER
 Ketonuria in type 2 DM can be
managed in clinic with hydration if
clinically suspect starvation
ketoacidosis (I/O DKA) and electrolytes
normal
Clinical guidelines for management of hyperglycemia,
CCRMC 2005
6
An interesting study….

55 patients with polyuria, polydipsia, weight
loss, BS > 300 treated with high dose SU
alone
 Those
with suspected type 1 DM excluded and
started on insulin immediately (age < 30, lean, no
FH type 2 DM)
 If BS not improved at 1 week --> insulin started

BS decreased
 456
(baseline) --> 202 (1 week) --> 120 (5 months)
 Most had symptomatic improvement in 3 days

HA1c decreased
 18.1 (baseline) --> 8.1 (4 months)
Peters et al, “Maximal Dose Glyburide Therapy…” JCEM, 1996
7
Recommended Initial Doses
of Sulfonylurea Agents
Agent
BS<180
BS>180 Markedly
Symptomatic
Glyburide 1.25
< 65 Years
Glyburide 1.25
>65 Years
2.5
20
1.25
10
Glipizide
2.5
<65 Years
5
40
Glipizide
>65 years
2.5
15
2.5
Interesting SU facts!
 SU
usually reduce FPG by 50-70
 The
higher the HA1c, the more dramatic
the effect
 Should
be started at lowest dose and
can be titrated upward at weekly
intervals to FPG < 120
Glyburide….
 If
patient does not respond to 10
mg/day, unlikely to respond significantly
to a higher dose
 Maintenance doses 20 mg/day not
recommended
 Usually dosed once daily
 Not recommended for GFR < 50 –
“Y use Glyburide?”
Glipizide…
acting than glyburide – if > 15
mg/day given, divide BID prior to meals
 Maximum daily dose is 40 mg/day, but
doses > 10-15 mg/day probably of little
additional benefit for long term tx
 Given its lower potency and shorter half
life, glipizide preferable agent in elderly
patients
 Shorter
Another patient walks in...
 53
YO woman with a history of
hypertension comes into your office.
Her random blood sugar came back at
223. You subsequently confirmed the
diagnosis by a fasting BS of 145.
 You counsel the patient regarding diet
and exercise refer the patient for DM
classes.
 What is your next step?
12
2009 ADA Type 2 Consensus Statement
Diabetes Treatment Algorithm
An American Diabetes Association consensus statement represents the authors’ collective analysis,
evaluation, and opinion at the time of publication and does not represent official association opinion.
Diabetes Care. Published online Oct 22, 2008
Metformin!!
 Drug
of choice in type 2 DM
 Reduction HA1c about 1.5%
 85% of benefit seen from dose 1500
mg/day, little benefit from doses greater
than 2000 mg/day
 May induce modest weight loss
 Risk of hypoglycemia low when used as
monotherapy
How To Titrate Metformin

Tell patient about the possibility of GI side
effects
 Begin with low dose metformin (500 mg)
taken once or twice per day with meals
(before break and dinner) or 850 once daily
 After 5-7 days, if GI side effects have not
occurred, advance dose to 850, or two 500
mg tablets twice per day
 If GI effects appear as dose advanced,
decrease to previous lower dose and
advance at later time
Per ADA consensus statement, 2009
Metformin and lactic acidosis

Unclear exactly why metformin induces lactic
acidosis (ummm… something to do with
Krebs cycle)
 Occurs almost exclusively in patients with




Renal, hepatic or cardiac failure
Dehydration
Hypoxia
Recommended to stop in hospitalized
patients with “the potential to get sick” or ARF
from contrast
 In otherwise healthy patients, risk of LA very
very low (“almost zero”)
Contraindications to
Metformin

Renal failure


Traditional cutoff Creat > 1.4 women, >1.5 men
Recent (not totally accepted) recommendation:



GFR 36-49: Probably safe
GFR < 30-36): Not safe
Other Contraindications (basically more RF
for Lactic Acidosis)




Alcoholism
Heart Failure (prob safe in stable, well
compensated disease)
Liver disease
Decreased tissue perfusion or hemodynamic
instability
Weight Changes Associated with AntiHyperglycemic Therapies for Type 2 Diabetes
Insulin tx 4 lb increase for every 1% A1c reduction!!
ADA Scientific Meeting 2005 ABS 13-or
GLP –1 based therapies: Exenatide and
Sitagliptin (Byetta and Januvia)



GLP - 1: a gut hormone that is secreted in gut in
response to eating food
 Slow gastric emptying
 Inhibits postprandial glucagon secretion
 Reduction food intake
 Enhance insulin secretion
 Very rapidly degraded in body (2 min)
Exanatide: GLP -1 mimic, but degrades slower in
body
 (derived from Glia Monster saliva)
Sitagliptin: Inhibits GLP -1 degradation
 No
weight gain!
Why use Exenatide
(Byetta)?
 Most
patients gain weight with DM tx
 With
Byetta  WEIGHT LOSS
 12
 A1c
pound loss at 2 years tx
reduction about 1.1%
 ? Animal studies suggest beta cell
regeneration
21
Why not use (Exenatide)
Byetta?

Expensive (1 year -- $2700)
 Long term data not available (lessons from
Avandia & Rezulin…)


Possible association with necrotizing pancreatitis
Nausea very common (50-60%)
 Because slows gastric emptying
CONTRAINDICATED in GASTROPARESIS
 2 injections/day
Who might get Byetta?
 Obese
patients not at A1C target who
are already on metformin, sulfonyurea
or both or glitazone +/- metformin
 Should be patients who HA1c < 8.5 (if
greater than this should be started on
insulin)
Sitagliptin (Januvia)

Reduction HA1c 0.5-0.8
 Weight neutral, well tolerated
 Long term safety not established
 Relatively expensive
 No hypoglycemia when used as
monotherapy
 Think about using it in:



Patients with contraind to SU/Metformin (eg
Januvia safe in renal failure)
Patients who in whom hypoglycemia bad (elderly)
Add on therapy in which you need marginal HA1c
reduction
What about
Thiazolidinediones? (TZD)
0.5 – 1.4 reduction in HA1c
 Weight gain 5-12 lbs at 1 year
 Edema 4-30%
 2 fold increase in CHF
 Small increase fracture rate, decrease BMD in
women
 Rosigliazone (Avandia) – not recommended by ADA
given possible 30-40% increased risk MI per metaanalysis (off CCRMC formulary)
 Pioglitasone (Actos) – 16% reduction death, MI, CVA
(“questionable statistical significance” per ADA),
modest improvement in lipid profile
 Per ADA TZD now second tier drug

Drug Cost Comparison (per month)
Drug and Dose
Glucose Strips (2 per day)
Sulfonylurea
Rapaglinide 2 mg tid
Acarbose 100 mg tid
Metformin 1000 bid
Rosiglitazone 8 mg qd
Pioglitazone 45 mg/d
Sitagliptin
Exenatide
Glargine, 45 U/d
24 hour fitness center
YMCA
Cost/mo
$60
Generic $4-14
Brand $50
$175
$88
Generic $ 4-32
Brand $132
$223
$222
$181
5mcg $230
10mcg $255
$150
$44
$60
When to continue oral therapy
when on insulin
basal insulin  stop TZD, but
continue the SU, Metformin
 Start
 Better
glycemic control with less insulin
requirements, weight gain, hypoglycemia
premeal insulin  stop SU,
Januvia
 Continue Metformin with basal/premeal
insulin therapy
 Start
Generic Oral Hypoglycemic Slide
Change from Drug A to B, C, or D
Add Drug A to B, or B to A
HgA1c
Add Drug C
Add Drug D
Time
2009 ADA Type 2 Consensus Statement
Diabetes Treatment Algorithm
An American Diabetes Association consensus statement represents the authors’ collective analysis,
evaluation, and opinion at the time of publication and does not represent official association opinion.
Diabetes Care. Published online Oct 22, 2008
TYPE 2 DIABETES
SYMPTOMATIC
NO
And very high
YES
Start on
sulfonylurea or
insulin
Start Metformin
Referral for:
•Diet
•HGM
•Sick Day Rules
•Exercise (+/- EST)
•Foot Care
Goal Met
NO
YES
Continue Current Treatment
Add
Medication
Referral for:
•Diet
•HGM
•Exercise
•Foot Care
Consider
transition
to metformin
TYPE 2 DIABETES
Metformin
Thin or no injection
OBESE
Exenatide
THIN
Sulfonylurea
Goal Not
Met
Add Sulfonylurea
(consider TZD)
Goal Not
Met
Sitagliptin
(consider TZD)
Goal Not
Met
•Start insulin – use pens
•Add detemir, glargine or PM NPH (isolated fasting hyperglycemia or insurance)
•? of which existing meds to continue, generally all
•Change to bid premixed insulin
•? of which existing meds to continue, generally just metformin
•Change to basal and with premeal insulin
•? of which existing meds to continue, generally just metformin
Sitagliptin
Goal Not
Met
Add
Sulfonylurea
(consider TZD)
Another case study

A 64 YO man with Type 2 DM comes in to
see you for his first visit.


Meds: Nifedipine, ASA, lovastatin, metoprolol,
70/30 insulin BID
PMH: DM 2 dx 15 years ago





+ Diabetic Retinopathy
Creatinine 2.3, 1.4 g/dl protein/day
PE BP 167/94, BMI 36
HA1C 8.3
LDL 145
What
is your target HA1c?
Some big DM studies you
may be familiar with
 Recent
trials that evaluated HA1c with
focus on cardiovascular mortality
 ACCORD,
ADVANCE, VA Diabetes
 Prior
trials that evaluated HA1c with
less stringent HA1c goals mostly that
demonstrated improvement in
microvascular complications
 DCCT
(Type 1 DM), UKPDS (Type 2)
The ACCORD Trial (2008)
 10,251
patients x 3.5 years (terminated
early)
 Inclusion criteria: H/O CVD event or
significant CVD risk
 Average 62 years old
 Baseline HA1c 8.1
 Achieved Median HA1c 6.4 (intensive)
vs 7.5 (control)
ACCORD TRIAL
Outcomes
Primary outcome (MI, stroke, CV
Death) reduced in intensive
Glycemic group (not statistically
Significant)
BUT:
Significant increase in
all cause death and CVD disease!
(1.41 vs 1.14% per year
257 vs. 203 deaths over 3.5 yrs
HR 1.22)
Why did more people die in with intensive
glucose control in ACCORD?
 No
?
one really knows
Severe hypoglycemia increased risk of
CV death
 ? Weight gain
 ? Med interactions
 ? Rapid reduction of HA1c by 2%
ADVANCE Trial (2008)

11,140 Patients x 5 years
 History of major or microvascular disease or
at least one other RF for vascular disease
 Average age 66, baseline HA1c 7.2
 Median HA1c 6.3 (intensive) vs 7.0 (control)
 No difference in overall mortality or
macrovascular events
 Most significant finding: reduced
development of macroalbuminuria
VADT - Veterans
Administration Diabetes Trial
•1742 Enrollees
•97% male
•Mean age 60.4
•BMI 31.3
•Majority had
multiple CV risk
factors
•72% HTN
•40% macrovascular
dx
•62% retinopathy
•43% neuropathy
VADT - Veterans
Administration Diabetes Trial
 Primary
Endpoint: NO DIFFERENCE
IN CARDIOVASCULAR DISEASE
OUTCOMES, but overall LESS
PATIENTS DIED THAN PREDICTED
 Standard:
29.3%
 Intensive: 27.4%
 Why
(predicted – 40%)
(predicted – 31.6%)
was mortality better than
expected?
Probable answer: Statin, ASA, really good BP control
So what does this all mean?

Based on ACCORD, ADVANCE, VA trial no
clear evidence aggressive reduction HA1c
results in improvement mortality or
macrovascular complications at 3-5 years
 BUT --- Recent data from UKPDS (10 years
followup) suggest long term reduction in MI
with improved glycemic control
 Very clear correlation between reducing
microvascular events and improved glycemic
control

DCCT trial: Getting HA1c from 9% to 7% resulted
in 60% reduction in retinopathy, nephropathy and
neuropathy at 6.5 years
Feel proud of any HgA1c
reduction


From “horrible control” to “poor control” – pat yourself
on the back!!
43
So just tell me what to do!

Target HA1c < 7% for the majority
 Consider a lower HA1c in younger, healthier,
newly diagnosed patients
 Higher target HA1c if life expectancy < 5
years, severe hypoglycemia, advanced
microvascular or macrovascular
complications, other significant co-morbid
conditions
 Aggressive tx with ASA, statin, and BP
control
ADA consensus statement, 2009
To really make a difference,
go beyond the HA1c
 Blood
pressure:
 <130/80
in most, consider <125/75 in those
with > 1 g/day protienuria

Statin use:
LDL < 100 in most
 LDL < 70 in established vascular disease or
mult risk factors


Consider ASA for primary prevention:
> 40 years old, FH, tob use, obesity,
albuminuria, hyperlipidemia (per ADA, not
great evidence)
 Not recommended in < 30 yo

45
The main points
 Sulfonyureas
 Can
probably be given safely in severe
hyperglycemia with type 2 DM
 Avoid glyburide in elderly, renal failure
 Glyburide > 10 mg/day, glipizide > 15
mg/day prob not too effective
 Metformin
 Use
in initial therapy in all DM 2
 Can possibly be used up to GFR > 35
 New recommendations: consider rapid
titration
46
More main points
 ALL non-generic
DM meds are
expensive
 GLP -1 drugs: sexy, no weight gain, but
long term data lacking
 Consider exenatide in your obese
patients
 Sitagliptin not particularly potent, but
well tolerated
 TZDs -- associated with weight gain,
fracture risk, now “second line” drug
47
Even more points!!
 Target
HA1c < 7% in most, higher in
those with multiple comorbidities, less
in younger patients
48