John Atlee “Jay” Snyder, D.O.
Assistant Professor of Internal Medicine
East Tennessee State University
January 24th 2012
Today’s Goals
 1. To recognize the importance of knowledge of
treatment of diabetics by reviewing the increasing
prevalence of type 2 Diabetes
 2. To review the numerous classes of medicines
currently used for oral management of Diabetes
 3. To recognize strategies used for treatment of
Diabetes
 4. To discuss Diabetes & driving
County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years:
United States 2004
Age-adjusted percent
0 - 6.3
6.4 - 7.5
7.6 - 8.8
8.9 - 10.5
> 10.6
www.cdc.gov/diabetes
County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years:
United States 2005
Age-adjusted percent
0 - 6.3
6.4 - 7.5
7.6 - 8.8
8.9 - 10.5
> 10.6
www.cdc.gov/diabetes
County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years:
United States 2006
Age-adjusted percent
0 - 6.3
6.4 - 7.5
7.6 - 8.8
8.9 - 10.5
> 10.6
www.cdc.gov/diabetes
County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years:
United States 2007
Age-adjusted percent
0 - 6.3
6.4 - 7.5
7.6 - 8.8
8.9 - 10.5
> 10.6
www.cdc.gov/diabetes
County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years:
United States 2008
Age-adjusted percent
0 - 6.3
6.4 - 7.5
7.6 - 8.8
8.9 - 10.5
> 10.6
www.cdc.gov/diabetes
2004 Age-Adjusted Estimates of
the Percentage of Adults† with
Diagnosed Diabetes in Tennessee
Centers for Disease Control and Prevention: National Diabetes Surveillance System.
Available online at: http://apps.nccd.cdc.gov/DDTSTRS/default.aspx. Retrieved 1/20/2012
2005 Age-Adjusted Estimates of
the Percentage of Adults† with
Diagnosed Diabetes in Tennessee
2006 Age-Adjusted Estimates of
the Percentage of Adults† with
Diagnosed Diabetes in Tennessee
2007 Age-Adjusted Estimates of
the Percentage of Adults† with
Diagnosed Diabetes in Tennessee
2008 Age-Adjusted Estimates of
the Percentage of Adults† with
Diagnosed Diabetes in Tennessee
Who will help us stop this
destructive pattern?
 The food industry???
http://www.foxnews.com/entertainment/2012/01/17/paula-deen-reveals-secret-struggle-with-diabetes-teams-up-with-drug-company/
Diabetes vs. Obesity 2008
Centers for Disease Control and Prevention: National Diabetes Surveillance System.
Available online at: http://apps.nccd.cdc.gov/DDTSTRS/default.aspx. Retrieved 1/20/2012
Treating Diabetes
First Line Classes
 Sulfonylureas
 Biguanides
Sulfonylureas (Second Generation)
 Glipizide (Glucatrol, Glucatrol XL)
 Glimepiride (Amaryl)
 Glyburide (Diabeta, Micronase)
 -ionized Glyburide (Glynase) also available
 -ionized doses
≠ to regular Glyburide
Yes Virginia, there is a First
generation Sulfonylurea
Rarely used
 Chlorpropamide (Diabinese)
 Tolazamide
 Tolbutamide
Preference for a specific
Sulfonylurea?
 Second generation?
 Glipizide because of short half-life?
 Glimeperide because of a study showing less
hypoglycemia in the elderly?1
PMID: 19952550/PMID: 8675920
Biguanides
 Metformin (Glucophage)
 Metformin ER (Fortamet/Glumetza/Glucophage XR)
 Riomet
-liquid cherry flavored Metformin
Are there different “generations”
of Biguanides?
 Originally introduced in the 1950’s, the first
biguanides (Phenformin) had a very high frequency of
lactic acidosis & were removed from the market.
 Some critics will argue there is not enough evidence of
lactic acidosis1
 Metformin has a much lower incidence of lactic
acidosis but still enough to warrant a Black Box
warning. (9 cases per 100000 person years)2
1. PMID 20393934. 2. PMID:10372243
Are there other first line meds?
 Sitagliptin (Januvia) is a DPP4 previously used as an
adjunct that has now been approved as a
monotherapy.
 Insulin. Very poor control/renal failure/etc but that’s a
“whole ‘nother presentation.”
So which medicine have we started
in the past??
 Sulfonylurea or Metformin?
Cardiac concerns?
 Old study (1970) with first generation sulfonylurea
Tolbutamide showed increased cardiovascular
mortality.1
 Some belief that this still persists with all sulfonylureas
including second generation.2
1. PMID: 992232. 2. PMID :22250169
Are they Overweight/Obese?
 Sulfonylureas increase insulin release from the
pancreas & thus can cause weight gain
Are they Overweight/Obese?
 Metformin helps with weight loss by:
 -reduction of GI absorption of glucose.
 -stimulation of anerobic glycolysis. (lactic acid)
 -inhibition of gluconeogenesis.
 -stimulation of glucose uptake in the liver.
 -increasing insulin receptors.
Dosing=Start low & go slow.
 Start Sulfonylureas at lower doses & increase slowly
due to concern of hypoglycemia.
 Start Metformin at lower doses & increase slowly due
to concern of GI side effects. May even start with PM
or HS dosing, then increasing to BID. (To sleep
through the bloating sensation) Also consider the
extended release formula.
 Max dose Sulfonylurea varies medicine to medicine
 Max daily dose Metformin…
2550mg/day
Renal failure?
 Metformin contraindicated due to concerns of lactic
acidosis.
 Metformin should be held in anticipation of
procedures when IVP dye is used.
 Sulfonylureas are excreted by the kidneys & may build
up in the bloodstream, thus causing hypoglycemia.
Rare adverse anemias
 Metformin- Megaloblastic anemia
 Sulfonylureas- Aplastic anema, hemolytic anemia &
pancytopenia
Cost
 Most first line options on $4/month $10/3month lists
or even free depending on the pharmacy.
Example: Walmart $4 List
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Diabetes
Chlorpropamide 100mg tab* . . . . . . . . . . . . . . 30 . . . . . 90
Glimepiride 1mg tab . . . . . . . . . . . . . . 30 . . . . . 90
Glimepiride 2mg tab . . . . . . . . . . . . . . 30 . . . . . 90
Glimepiride 4mg tab . . . . . . . . . . . . . . 30 . . . . . 90
Glipizide 5mg tab . . . . . . . . . . . . . . . . 30 . . . . . 90
Glipizide 10mg tab* . . . . . . . . . . . . . . . 60 . . . . . 180
Glyburide 2.5mg tab . . . . . . . . . . . . . . . . . . . . 30 . . . . . 90
Glyburide 5mg tab (blue) . . . . . . . . . . . .30 . . . . . 90
Glyburide 5mg tab (green) . . . . . . . . . . . 30 . . . . . 90
Glyburide, micronized 3mg tab . . . . . . . . . . . . 30 . . . . . 90
Glyburide, micronized 6mg tab . . . . . . . . . . .. 30 . . . . . 90
Metformin 500mg tab . . . . . . . . . . . . . . . . . . . . 60 . . . . . 180
Metformin 850mg tab . . . . . . . . . . . . . . . . . . . . 60 . . . . . 180
Metformin 1000mg tab* . . . . . . . . . . . . . 60 . . . . . 180
Metformin 500mg ER tab* . . . . . . . . . . . 60 . . . . . 180
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*Prices may be higher in CA, HI, MN, MT, PA, TN and WI.
Example: Target $4 List
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Diabetes
CHLORPROPAMIDE 100 MG* - Tablet 30 90
GLIMEPIRIDE 1 MG - Tablet 30 90
GLIMEPIRIDE 2 MG - Tablet 30 90
GLIMEPIRIDE 4 MG - Tablet 30 90
GLIPIZIDE 5 MG - Tablet 30 90
GLIPIZIDE 10 MG* - Tablet 60 180
GLYBURIDE 2.5 MG - Tablet 30 90
GLYBURIDE 5 MG - Tablet 30 90
GLYBURIDE MICRO 3 MG - Tablet 30 90
GLYBURIDE MICRO 6 MG - Tablet 30 90
METFORMIN 500 MG - Tablet 60 180
METFORMIN 850 MG - Tablet 60 180
METFORMIN 1000 MG* - Tablet 60 180
METFORMIN ER 500 MG* - Tablet 60 180
More on strategy later…
Second-line/Add on Therapy
 Alpha-glucosidase inhibitors
 Beta cell stimulators
 TZD’s
 GLP-1’s
 DPP4’s
 Others
Alpha-glucosidase inhibitors
 Acarbose (Precose)
 Miglitol (Glyset)
 Prolong digestion of carbohydrates & reduce peak glucose
levels by blocking oligosaccharide binding to the brush
border.
 Taken with first bite of the meal & has additive effects
when combined with sulfonylurea.
 Side effects:
-GI related. Worse with Acarbose (including elevated LFT’s
& ileus)
Oral Beta cell stimulators
 Repaglinide (Prandin) technically a Meglitinide
 Nateglinide (Starlix) technically amino acid derivative
 Action similar to sulonylureas, working in a glucose
dependent fashion but still with the risk of hypoglycemia.
 Have a very short half-life & must be taken with meals.
 Some consideration as first line therapy in renal failure
 Side effects:
- URI symptoms & GI side effects. Rare cardiac ischemia with
Prandin & rare accidental injury with Starlix
Thiazolidinediones
(TZD’s/Glitazones)
 Pioglitazone (Actos)
 Rosiglitazone (Avandia)
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Very good for additional control.
Agonists of PPAR–gamma.
Work at the tissue level to increase insulin sensitivity.
Side effects:
-may cause or worsen heart failure
-rare hepatotoxicity
-fractures (in women only)1
-Bladder cancer2
1. PMID: 17363747. 2. PMID: 21515844.
Incretin Mimetics (GLP-1’s)
 Exanatide (Byetta)
 Liraglutide (Victoza)
 Lixisenatide (Lyxumia) soon to be released
 Works as a glucogon-like peptide (GLP-1) to increase glucose
dependent insulin secretion, decrease excessive glucagon secretion,
slow gastric emptying & decrease appetite.
 $$$ & bid injections. If willing to do injections why not just do insulin??
 Side effects:
-Suppresses appetite
-Associated with pancreatitis
-Rarely associated with acute renal failure
-Injection site concerns?
Dipeptidyl peptidase-4 inhibitors
(DPP4’s)
 Sitagliptin (Januvia)
 Saxagliptin (Onglyza)
 Linagliptin (Tradjenta) recently released
 By blocking DPP4, incretins including GLP-1 are
increased & effect is similar to incretin mimetics.
 Side effects:
-URI symptoms
-pancreatitis
Cancers with GLP-1’s/DPP4’s
 With known risk for pancreatitis in Exanatide &
Sitagliptin, a review also found an increased risk for
pancreatic cancer with these medicines
 Also thyroid cancer in Exanatide
PMID: 213343333
PMID: 213343333
Bile acid sequestrants
 Colesevelam (Welchol)
 Cholesterol medicine shown to improve glucose
control/lower A1C.
 Side effects:
 -GI (including obstructions starting at the esophagus
& ending with fecal impaction)
 -Oral blisters/severe rash
Amylin analogues
 Pramlintide (Symlin)
 Increased risk of hypoglycemia (especially with
insulin)
The elephant in the room…
 INSULIN
Combination meds
 Too many to count!!!!
 If on multiple medicines, see if there is an option.
 Only Sulfonylureas & Beta cell stimulators (&
insulin/amylin) can cause hypoglycemia. However,
additional medicines may enhance the hypoglycemia
caused by sulfonylureas.
Future medicine options
 Weekly/Depot Byetta shots.
 More “me too” drugs such as DPP4 meds Vildagliptin
& Alogliptin.
 Bromocriptine mesylate (Cycloset) is a dopamine
agonist on the market with unknown mechanism of
improved diabetic control. More meds like this soon?
 Other PPAR agonists. PPAR alpha, beta, or
combinations with gamma. (TZD’s only gamma)
Future medicine options
 Dapaglifozin
 Works as a SGLT2 inhibitor. Works at sodium-glucose
cotransporter 2 in kidneys to prevent glucose being
reabsorbed & thus to be lost to the urine.
 Increased incidence of UTI’s
 Increased incidence of bladder cancer
 ?Increased incidence of breast cancer
PMID: 22262072
Even more combination meds
 Juvisync (Januvia & Simvastatin) approved recently
Which medicine do we start?
Recent systematic review in the
Annals of Internal Medicine
 “..overall guideline quality was poor with respect to the
rigor of the guideline development process,
particularly in use of systematic methods to identify
evidence. In addition, most guidelines were
susceptable to bias because they lacked a description
of editorial independence from funders and guideline
developers failed to report potential conflicts of
interest.”
PMID: 22213492
Recent systematic review in the
Annals of Internal Medicine
 “11 guidelines met the inclusion criteria. Seven
guidelines agreed with the conclusion that metformin
is favored as the first-line agent”
 The American Diabetes Association has also recently
clarified its preference for metformin
Which medicine to add on?
 New England Journal of Medicine interactive clinical
decisions survey January 2008
 Patient on Metformin & Glipizide with fasting
morning glucose of 110-140 & HbA1C of 8.1%
 Adding Pioglitazone, NPH before bedtime or
Exanatide twice daily
PMID: 18272888
Results
 6455 votes cast
 Pioglitazone 1625 votes
 Exanatide twice daily 1587 votes
 NPH before bedtime 3243 votes
Staying up to date
 Don’t forget to check the American Diabetes
Association’s website in the beginning of every January
for updates on recommendations.
Question
 A patient with poorly controlled DM2 comes in the
office for a follow-up & yearly physical. The patient
notes that if they were placed on insulin, they would
no longer be able to work in their current profession &
they would be fired…
What is your patient’s job?
 A. Nurse
 B. Teacher
 C. Carpenter
 D. Truck driver
 E. Chef
Answer
 D. Truck driver
Diabetes & driving
But wait a minute!!
 From the “Instructions for the Medical Examiner”
section of the Medical Examination Report for
Commercial Driver Fitness Determination:
 “CMV drivers who do not meet the Federal diabetes
standard may call (202) 366-1790 for an application for
a diabetes exemption”
 Diabetes Exemption Team (202) 366-4001
Insulin & Truckers Timeline
 1986: ADA & others petitioned to grant waivers on a case
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by-case basis
1993: Waiver program granted for those with safe driving
history & endocrinologist/ophthalmologist approval.
1996: Appeals court ruled the program illegal (Advocates
for Highway and Auto Safety v Federal Highway
Administration)
2003: Federal waiver process established with an exemption
for for interstate commerce
Now: Most states are adopting similar process to Federal
rule for their CDL’s
http://www.fmcsa.dot.gov/facts-research/research-technology/tech/TB-02-01-1.htm
ADA Guidelines
 An entire section for Diabetes & Driving
 “...people with diabetes should be assessed
individually, taking into account each individual's
medical history as well as the potential related risks
associated with driving.”
 Potential medical-legal ramifications
Today’s Goals
 1. To recognize the importance of knowledge of
treatment of diabetics by reviewing the increasing
prevalence of type 2 Diabetes
 2. To review the numerous classes of medicines
currently used for oral management of Diabetes
 3. To recognize strategies used for treatment of
Diabetes
 4. To discuss Diabetes & driving
Thank You!