Diabetes Medications:

An Overview

Eric L. Johnson, M.D.

Assistant Professor
Department of Community and Family Medicine
University of North Dakota
School of Medicine and Health Sciences

Assistant Medical Director
Altru Diabetes Center
Altru Health System
Grand Forks, ND

Objectives
Assess knowledge of usual diabetes
medications
Implement proper medication use per
guideline management
Improve knowledge of side effects and
contraindications of diabetes medications

Diabetes Mellitus
Type 1: Usually younger, insulin at
diagnosis
Type 2: Usually older, often oral agents at
diagnosis
Type 1.5 (Latent Autoimmune),
mixed features
Gestational: Diabetes of Pregnancy
U.S. Prevalence of Diabetes 2010
Diagnosed: 26 million people8.3%
of population (90%+ have Type 2)

Undiagnosed: 7 million people

79 million people have pre-diabetes
CDC 2011
Diabetes Diagnosis
Category FPG (mg/dL) 2h 75gOGTT A1C
Normal <100 <140 <5.7
Prediabetes 100-125 140-199 5.7-6.4

Diabetes >126** >200 >6.5
Or patients with classic hyperglycemic symptoms with plasma glucose >200

** On 2 separate occasions
Diabetes Care 34:Supplement 1, 2011

*IFG=impaired fasting glucose.
Copyright

2000 International Diabetes Center, Minneapolis, USA. All rights reserved. Adapted with permission.
Natural History of Type 2 Diabetes
Years of Diabetes
G
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s
e

(
m
g
/
d
L
)

50
100
150
200
250
300
350
0
50
100
150
200
250
-10 -5 0 5 10 15 20 25 30
R
e
l
a
t
i
v
e

F
u
n
c
t
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o
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(
%
)

Fasting Glucose
Postmeal Glucose
Obesity IFG* Diabetes
Uncontrolled
Hyperglycemia
Insulin Resistance
-cell Function
-Cell Failure
The Ominous Octet
Islet -cell
Impaired
Insulin Secretion
Neurotransmitter
Dysfunction
Decreased Glucose
Uptake
Islet a-cell
Increased
Glucagon Secretion
Increased
Lipolysis
Increased Glucose
Reabsorption
Increased
HGP
Decreased
Incretin Effect
Targets for glycemic (blood sugar) control in
most non-pregnant adults






ADA AACE
A1c (%)
<7* 6.5
Fasting (preprandial) plasma
glucose
70-130 mg/dL <110 mg/dL
Postprandial (after meal)
plasma glucose
<180 mg/dL <140 mg/dL
American Diabetes Association. Diabetes Care. 2010;33(suppl 1)
Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement
at http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf. Accessed January 6, 2006.
AACE Diabetes Guidelines 2002 Update. Endocr Pract. 2002;8(suppl 1):40-82.
*<6 for certain individuals
Goals of Glucose Management
A1C ~ Average Glucose
American Diabetes Association
A1C eAG
% mg/dL mmol/L
6 126 7.0
6.5 140 7.8
7 154 8.6
7.5 169 9.4
8 183 10.1
8.5 197 10.9
9 212 11.8
9.5 226 12.6
10 240 13.4

Formula: 28.7 x A1C - 46.7 - eAG
Diabetes Medications
Diabetes Medications
Many new medications in last decade
Three main categories
Oral agents (pills)- many different kinds old and new
Insulin- newer, more modern insulins
Newer, non-insulin injectable medications
Choices allow individualization of treatment plan
Different medications, different indications,
different situations
Glucose-lowering Potential of
Diabetes Therapies*
Treatment FPG HbA1C

Sulfonylureas 50-60 mg/dl 1-2%

Metformin 50-60 mg/dl 1-2%

a-Glucosidase Inhibitors (Precose) 15-30 mg/dl 0.5-1%

Repaglinade (Prandin) 60mg/dl 1.7%

Thiazolidinediones 40-60 mg/dl 1-2%

Gliptins (Januvia,Onglyza) targets ppd 0.5 - 0.8%


*based on package insert data as monotherapy
Glucose-lowering Potential of
Injection Diabetes Therapies*
Treatment FPG HbA1C

Exenatide (Byetta) targets ppd 1-1.5%

Liraglutide (Victoza) targets ppd 1-1.5%

Pramlintide (Symlin) targets ppd 1-2%



Insulin Limited by 1.5-3.5%
hypoglycemia



*based on package insert data as monotherapy
ADA/EASD consensus algorithm
to manage type 2
MET: metformin; SU: sulfonylurea. Nathan et al. Diabetes Care 2009;32(1): 193-203
a
SU other than glyburide or chlorpropamide.
b
Insufficient clinical use to be confident regarding safety.
No
No hypoglycemia
Weight loss
Nausea/vomiting
Lifestyle and MET
+ intensive insulin
Lifestyle and MET
+ basal insulin
Lifestyle and MET+ SU
a

At diagnosis:
Lifestyle
+
MET
Step 1 Step 2 Step 3
Lifestyle and MET
+ pioglitazone
No No hypgglycemia
edema/CHF
Bone loss
Lifestyle and MET
+ GLP-1 agonist
b

Lifestyle and MET
+ pioglitazone
+ SU
a

Lifestyle and MET
+ basal insulin
Tier 2: Less well-validated studies
Tier 1:
Well-validated core therapies
Reinforce lifestyle interventions at every visit and check A1C every 3 months until A1C is <7% and
then at least every 6 months. The interventions should be changed if A1C is 7%.
Key Points of
Medication Selection in Type 2
Metformin at diagnosis unless a
contraindication
Second line agents- basal insulin or many
other meds

Oral Diabetes Medications
Sulfonylureas
Oldest oral medications
Stimulate pancreas to secret more insulin
Effective, inexpensive
Glyburide, Glipizide, Glimiperide
Caveats with Sulfonylureas
Hypoglycemia (particularly in elderly)
Premature B-cell exhaustion?
Caution in liver disease, renal disease
Weight gain
Rash
Avoid if anaphylactic to sulfa


Metformin
Improves insulin resistance
Reduced Hepatic Glucose production
Effective, inexpensive
Extremely low incidence of hypoglycemia
Weight neutral or weight loss
Positive effects on lipid profiles
Long term use may result in better CVD
outcomes
Can be combined with virtually all other DM
meds
Caveats with Metformin
Liver Disease
Renal Disease
GI upset
Heavy Alcohol Use
Intravascular Dye Studies (IVP, Angio,etc)
CHF
Not for persons over 80
Can result in B12 deficiency
Thiazolidinediones (TZDs)
Pioglitazone (Actos)
Rosiglitazone (Avandia)
Improves insulin resistance
Extremely low incidence of hypoglycemia
Caveats with TZDs
CHF (or if hx/risk?)
Patients already dealing with edema
Potential weight gain
Renal disease-fluid overload
Current TZDs rare liver disease, not
recommended in active liver disease
Heart disease risk?
(Rosiglitazone-new restrictions)

Gliptins(DPP-IV)
DPP-IV inhibitors
Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Oral agents
Weight neutral or weight loss
Can use with Metformin, Sulfonylurea, TZD, or
insulin (sitagliptin)
Gliptins Caveats, Benefits
Caveats:
Hypoglycemia if used with sulfonyurea or
insulin
Nausea, rash

Benefits:
Few drug interactions; can be renally dosed
Niche Drugs
Colesevelam (Welchol)
- adjunct to lower A1c and LDL
- limited efficacy, cost
Repaglinide (Prandin), Nateglinide (Starlix)
- may replace SU if sulfa allergy
- Prandin may be useful in CKD
Acarbose (Precose), Miglitol (Glyset)
- limited efficacy, GI intolerance, cost
Bromocriptine (Cycloset)
- limited efficacy? Will be marketed
Salsalate
-older NSAID, may lower blood sugar,
no indication yet

Non-Insulin Injectable
Medications
Glucagon-like Peptide-1
(GLP-1)
Gut hormone
Stimulates pancreas to secret insulin
Suppresses glucagon action
Many target organs
Weight regulation
Caution in renal or hepatic impairment
GLP-1
Exenatide (Byetta) GLP-1 mimetic
Liraglutide (Victoza) GLP-1 analog
Both available in pen injectors (easy)
Modest weight loss
Combined with other agents except
DPP-IV inhibitors or insulin (exenatide has
basal insulin data)

GLP-1 Caveats
Nausea, vomiting
Pancreatitis
Medullary thyroid carcinoma in rodents
(liraglutide)
Hypoglycemia combined with sulfonyurea
Pramlintide-Synthetic Amylin
(Symlin)
Amylin secreted by normal pancreas along
with insulin to regulate blood glucose
Enhances Postprandial control. Used in
Type 1 and Type 2 patients
Used as adjunct to insulin
Available in pen injector
Possible significant hypoglycemia
Combination Drug Therapy
Consider early if failing monotherapy
Generally additive or synergistic effects
Triple or quadruple non-insulin drug
therapy
-limited benefit in many
-safe for many
Insulin is often a better,more potent choice


Insulin Therapies
Insulin Therapy
All Type 1 patients at diagnosis
All type 2 patients will require insulin if
they live long enough
-7 to 10 years post diagnosis
-A1C >9%
-Function of many non-insulin meds
based on presence of native insulin
Beta-cell function declines as
diabetes progresses
Beta-cell
function (%)
Beta-cell decline exceeds 50%
by time of diagnosis
4 4 12 8 0 8 12
0
50
100
75
25
Type 2 Diabetes
IGT
Years from diagnosis
Postprandial
Hyperglycemia
Diagnosis
Insulin
initiation
Beta-cell function decline over time
Lebovitz H. Diabetes Rev 1999;7:139-153.
Insulin Therapy
Modern insulins safer and
more predictable
Most insulin types come in pen
injectors
Pen injectors easy to use, to teach,
less cumbersome than vials/syringes
Rapid Acting Insulin
Aspart (Novolog)
Lispro (Humalog)
Glulisine (Apidra)
(Human Regular)

Taken with meals and snacks
Bolus insulin
Long-Acting Insulin
Detemir (Levemir)
Glargine (Lantus)
Human NPH (N)
Taken 1 or 2 times daily
Basal insulin
Insulin Time Action Curves
0
20
40
60
80
100
120
140
0 2 4 6 8 10 12 14 16
I
n
s
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E
f
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Hours
18 20
Intermediate (NPH)
Long
(Detemir,Glargine)

Short (Regular)
Rapid (Lispro,Glulisine, Aspart)
adapted from R. Bergenstal, IDC
Basal Insulin in Type 2 Diabetes
Glargine (Lantus), Detemir (Levemir)
Good, potent add-on for improved A1C
Second line agent for many patients
A1C >9, diabetes longer than 5 to 7 years
AACE: ? Weight benefit with Detemir
Pen injectors easy

Basal Insulin in Type 2 Diabetes
Some oral meds may be continued
-metformin, maybe TZD, maybe SU,
maybe gliptin (sitagliptin)
Glargine (Lantus) or Detemir (Levemir)
started at 10 units at HS
Increase 3 units every 3 to 5 days until
fasting blood sugars <110 (or <140)
Most type 2 on 50-80+ units/day
Adding Bolus Insulin in
Type 2 Diabetes
Lispro (Humalog)
Aspart (Novolog)
Glulisine (Apidra)
Pen injectors

Why is bolus insulin important in Type 2?
Fasting and Postprandial Glycemic Excursions
as a Function of A1C
Monnier L et al. Diabetes Care. 2003;26:881-885.
0
20
60
80
2
(7.38.4)
3
(8.59.2)
4
(9.310.2)
5
(>10.2)
1
(<7.3)
40
C
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t
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i
b
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(
%
)

A1C (%) Quintiles
Postprandial hyperglycemia
Fasting hyperglycemia
Adding Bolus Insulin in
Type 2 Diabetes
1 injection basal/1 injection bolus
good 2 injection program-
better than split basal
90/10 rule (90% basal, 10% bolus)
Start with largest meal of the day
Add other meal doses later
Usually stop TZD, always stop SU
Easy with pens

Premix Insulins
70/30, 75/25, 50/50
Combine R or rapid acting with NPH or an
NPH-like component
Certain applications may be appropriate
Limitation: change 2 insulins at once
Case Studies
Case #1
42 y/o Hispanic female with hx of GDM 6
years ago, term 10 lb 5 oz male infant
Not seen for follow-up in 3 years
FBS done at annual pap/px is 149

Does this patient have type 2 diabetes?
What next?
Case #1
Diagnosis of diabetes generally requires
two abnormal values
Patient at high risk for type 2
GDM is a pre-diabetes condition
Repeat FBS three days later.
Case #1
Repeat FBS 135

Dx: type 2 diabetes (FBS >126 on two
separate occasions)


What should be done next for this patient?
Case #1
Patient had tubal ligation after last delivery
Start metformin 500mg BID, advance to
850-1000 mg BID
Most newly-diagnosed patients should
start metformin (current ADA
recommendation)
Case #1
Diabetes Educator and Dietician
SBGM with appropriate targets
Check fasting lipids, monitor Blood
Pressure

Case Study#2
54 y/o white male
Diagnosed with type 2 diabetes after 2
fasting blood sugars of 154 and 142
Also has high blood pressure and
cholesterol disease (common in type 2)
Case Study #2
Metformin 500 mg prescribed twice daily,
titrated to 1000mg BID
ASA 81 mg daily
Referred to Diabetes Educator and
Dietician for meal planning
Recommend developing graduated
exercise plan (exercise prescription)
Six months after diagnosis, A1C = 6.8%
(target <7%)

Case Study #2
Three years later, patients A1C has risen
to 8.4% (target <7%)
Blood pressure and cholesterol effectively
treated
Now what?
Case Study #2
Choices include
Adding a basal insulin once daily
Adding any other oral agent
Adding exenatide twice daily or liraglutide
once daily
Any of these are good choices
Choice may be made on individual factors
Case Study #2
Patient chose additional oral agent
(sitagliptin), but others would be OK
A1C:
6 months later = 7.4% (target <7%)
3 years later = 8.1% (target <7%)

Now what?
Case Study #2
Sitgliptin, metformin continued
Basal insulin started with titration
Eventually added bolus insulin with largest
meal (90/10 rule)
Likely will add bolus with other meals
over time
Medication Combinations
Sulfonylureas: Virtually any in type 2
Metformin: Virtually any in type 2
TZD: Virtually any in type 2
Gliptins: metformin, TZD, insulin (sitagliptin)
Insulin: metformin, TZD, sulfonylurea, amylin,
sitagliptin
Amylin: only in insulin regimens
Exenatide/Liraglutide: metformin, sulfonyureas,
TZD
Medication Indications
Type 1 Diabetes: Insulin, amylin (amylin
only in combination with insulin)
Type 2 Diabetes: All oral agents,
exenatide, liraglutide, amylin, insulin
(amylin only in combination with insulin)
Prediabetes: none (yet), case by case,
i.e., PCOS
Summary
Diabetes is common
Understand Medications and Indications
Type 1 diabetes: Insulin regimen (pumps)
Type 2 diabetes: Lots of choices, but
nearly all will need insulin eventually

Acknowledgements
North Dakota Department of Health, Karalee Harper
Centers for Disease Control
Office of Continuing Medical Education, UNDSMHS,
Mary Johnson
Department of Family and Community Medicine,
UNDSMHS, Melissa Gardner
Brandon Thorvilson, UNDSMHS IT
Disclosure: Novo Nordisk Speakers Bureau
Contact Info/Slide Decks/Media

e-mail

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ejohnson@altru.org

Phone
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