Oral Anti-diabetic Medications

Mario Skugor, MD FACE

Endocrine and Metabolic Institute
Cleveland Clinic
Insulin
secretaguages
Insulin
sensitizers
Incretin
based
therapies
Alpha-
glucosidase
inhibitors
CNS acting
Long acting

Sulphonylureas
Liver

Metformin
PPD-4
inhibitors
Acarbose Bromocriptine
Short acting

Meglitinides
Muscle and Fat

Thiazolidinediones
Miglitol
Other
Bile acid sequestrants
Orlistat
CLASSES OF ORAL ANTIDIABETIC MEDICATIONS
In development
Dual PPAR gamma agonists
SGLT-2 antagonists
Insulin
secretaguages
Insulin
sensitizers
Incretin
based
therapies
Alpha-
glucosidase
inhibitors
CNS acting
Long acting

Sulphonylureas
Liver

Metformin
PPD-4
inhibitors
Acarbose Bromocriptine
Short acting

Meglitinides
Muscle and Fat

Thiazolidinediones
Miglitol
Other
Bile acid sequestrants
Orlistat
CLASSES OF ORAL ANTIDIABETIC MEDICATIONS
In development
Dual PPAR gamma agonists
SGLT-2 antagonists
Canagliflozin just approved.
METFORMIN
French lilac used in folk
medicine for centuries.

Synthesized in 1920s

In 1950 Metformin was used to
treat influenca and noted to
lower blood glucose to
physiologic levels.
METFORMIN
In 1957 first clinical trial of diabetes treatment was
published in France

Approved in 1958 in UK, 1972 in Canada and in
1995 in US.
METFORMIN
Suppression of hepatic gluconeogenesis through
activation AMP-activated protein kinase (AMPK).

Improves glucose uptake in muscle and fat.

Causes weight loss in some individuals.

Improves menstrual cycle and fertility in PCOS

May improve NASH.

May reduce risk of range of different carcinomas
METFORMIN
Comes in 500, 850 and 1000 mg pills.
Extended release pills are available (but more
expensive)
Usual dose is 1000 mg twice a day.
Main side effects is abdominal cramping and diarrhea
Metformin extended release is better tolerated by
some patients
Even mild renal failure (Cr>1.4 in males and >1.5 in
females) is contraindication for use

Metformin Bottom line
Clearly the first line.
Cheap
Improves physiology
Has other benefits.
Unfortunately, significant proportion of patients has
contraindications or cannot tolerate it.
SULPHONYLUREAS
Marcel Janbon and co-workers discovered
hypoglycemic effect of sulfonylurea in 1942.

They were studying sulfonamide antibiotics and
discovered that the compound sulfonylurea
induced hypoglycemia in animals
Sulphonylureas
First sulfonylurea for treatment of DM introduced in 1955.
General structure:
Sulphonylurea
First generation Binds to the proteins in the blood.

Tolbutamide
Chlorpropamide
Tolazamide
Acetohexamide
Carbutamide
Sulphonylurea
Second generation Not bound to serum proteins.

Glipizide
Glyburide (glibenclamide)
Gliclazide

Glibornuride
Gliquidone
Glisoxepide
Glyclopyramide


Sulphonylurea
Third generation
Glimepiride

SUFONYLUREAS
Sulfonylurea
Advantages
Fast acting
Once a day dosing
Gliclazide may be particularly beneficial
Disadvantages
Risk of hypoglycemia
Weight gain
Possible problems with ischemic preconditioning

Glicilizide
Inhibits platelet aggregation
Associated with lower mortality from malignant
neoplasms.
Improves repair of DNA damage caused by oxidative
stress in tissue cultures.
Sulfonylureas Bottom line
Fast acting
Older ones are cheap
Do not improve physiology
Hypoglycemia is significant risk
Require strict regime of diet
Meglitinides
Nategelinde
Repaglinide

Act on same potassium channel as sulfonylurea but
bind to different part of the molecule.

Short acting taken 0-30 min before meal.

Risk of hypoglycemia is small


Meglitinides Bottom line
Useful in small number of patients for relatively short
period of time.
Allow for some flexibility in timing of the meals.
TZD-s actually Pioglitazone
The proliferator-activated receptor gamma (PPAR-)
and to a lesser extent PPAR- agonist in the muscle,
adipose tissue, and the liver.
Pioglitazone reduces insulin resistance in the liver and
peripheral tissues.
Pioglitazone decreases the level of triglycerides and
increases HDL without changing LDL and total
cholesterol.
Pioglitazone - 15 - 30 - 45 mg pills

Peripheral edema is main side effect.

More hospitalizations for CHF in studies with all
TZD-s

Effect is maintained when combined with metformin
and incretin based therapies.
Pioglitazone
Thiazolidinediones and bladder cancer.

Colmers IN, et al. CMAJ 2012I:10.1503
TZD-s and fracture risk

Toulis KA, et al. CMAJ, 2009, 180 (8) 841-842
TZD-s and fractures
TZD-s are associated with fractures in females over 50
years of age.
In men risk is increased if TZD-s are used with loop
diuretic
Bilik D, et al. JCEM. 2010 (10) 1210.
Bottom line on Pioglitazone
Benefits are still higher than risks.
There is some evidence that lower dose is not
associated with risk of bladder cancer.
However at this time Metformin and PPD-4 inhibitors
are clearly ahead of Pioglitazone as choices for
treatment.

Incretins
Gut-derived hormones, secreted in response to nutrient ingestion,
that potentiate insulin secretion from islet cells in a glucose-
dependent fashion, and lower glucagon secretion from islet cells
Two predominant incretins:
Glucagon-like peptide1 (GLP-1)
Glucose-dependent insulinotropic peptide (GIP)
(also known as gastric inhibitory peptide)
Incretin effect is impaired in type 2 diabetes
Known as GLP-1 deficiency
Incretin system and DPP-4 physiologic action
Native GLP-1 is rapidly degraded by DPP-IV
Human ileum,
GLP-1 producing
L-cells
Capillaries,
DPP-IV (Di-Peptidyl
Peptidase-IV)

Adapted from: Hansen et al. Endocrinology 1999;140:53565363.
Double immunohistochemical staining for DPP-IV (red)
and GLP-1 (green) in the human ileum
Slide Source:
Lipids Online Slide Library
www.lipidsonline.org
Glucagon-Like Peptide1 Normalizes
Postprandial Hyperglycemia in Patients
with Type 2 Diabetes
Nauck MA et al. Acta Diabetol. 1998;35:117-129.
Time (h)
P
l
a
s
m
a

g
l
u
c
o
s
e

(
m
g
/
d
l
)

0
300
100
50
150
200
250
2 3 4 1 0 1
Infusion
GLP-1 [7-36 amide]
1.2 pmol/kg/min
Placebo
Liquid meal
0
300
100
50
150
200
250
2 3 4 1 0 1
Infusion
GLP-1 [7-36 amide]
1.2 pmol/kg/min
Placebo
Liquid meal
P
l
a
s
m
a

g
l
u
c
o
s
e

(
m
g
/
d
l
)

Healthy subjects T2DM patients
Time (h)
Slide Source:
Lipids Online Slide Library
www.lipidsonline.org
Continuous Glucagon-Like Peptide1
Infusion Reduces Appetite over 6 Weeks
All data for patients treated with glucagon-like peptide1 (n = 10).
No changes in these parameters were observed in the saline group.
0
100
200
300
400
500
Mean (SE)
AUC for
Visual
Analogue
Score (mm)
vs Time (h)
Time (wk)
6 1 0
Zander M et al. Lancet. 2002;359:824830.
Time (wk)
*Prospective food intake
*Hunger
*Satiety
*Fullness
*p<.05
Slide Source:
Lipids Online Slide Library
www.lipidsonline.org
Glycemic Control with GLP-1 Receptor
Agonists in Head-to-Head Clinical Trials
*Significant difference
vs comparator GLP-1
receptor agonist
1
Buse JB et al. Lancet. 2009;374:39-47 |
2
Drucker DJ et al. Lancet. 2008;372:1240-1250 |
3
Blevins T, et al. J Clin Endocrinol Metab. 2011;96:1301-1310 |
4
Buse JB et al. Presented at
47th EASD Annual Meeting, Lisbon, Portugal, 14 September 2011.
Trial:
Size (N):
Study length (weeks):
LEAD-6
1

464
26
DURATION-1
2

303
30
DURATION-5
3

254
24
DURATION-6
4

912
26
-0.8
-1.5
-0.9
-1.3
-1.1
-1.9
-1.6
-1.5
-2.0
-1.5
-1.0
-0.5
0.0
A
1
C

C
h
a
n
g
e

(
%
)
*
*
*
EXN BID
LIRA
EXN QW
Slide Source:
Lipids Online Slide Library
www.lipidsonline.org
Comparison of Incretin Modulators
GLP-1 Analogues DPP-4 Inhibitors
Administration route Injection Oral
GLP-1 Sustained Meal-related
Effect on A1C
Effects on body weight
Side effects
Nausea,
Rare: pancreatitis
(Well tolerated)
Nasopharyngitis, skin rashes,
Stevens-Johnson syndrome
-cell function
GLP-1=glucagon-like peptide1; DDP-4=dipeptidyl peptidase4
DPP 4 inhibitors
Sitagliptin
Saxagliptin
Linagliptoin
Alogliptin
Vildagliptin marketed in EU

More in development
Gemigliptin

DPP4 inhibitors
All taken once a day
Sitaglipitin 100 mg daily
50 mg if Cr 1.7-3.0 for men and 1.5-2.5 for women
25 mg in ESRD
Saxagliptin 5 mg per day
2.5 mg in renal impairment
2.5 if taken with cytochrome P450 inhibitors
(ketoconazole)
Linagliptin 5 mg daily
Sitagliptin - example

DPP-4 inhibitors
Side effects are minimal
Acute pancreatitis is seen
Linagliptin 15.2/10.000 patients
Placebo 3.7/10,000 patients

Saxaglipin No data but some postmarketing cases
are reported

Sitagliptin There is 88 cases in 2.5 years in
postmarketing reporting.
DDP-4 inhibitors Bottom Line
Very well tolerated
Improve physiology
Expensive
So far, no serious adverse effects with long term use.
No increased risk of pancreatic caner.


Alpha-Glucosidase inhibitors
Acarbose - 25, 50 or 100 mg tablets
Miglitol - 25, 50 and 100 mg tablets
They block intestinal enzyme breaking sugars to
monosaccharides.
This slows down and blocks some of carbohydrate
absorption.
Postprandial peak is diminshed and Hba1c
improves.
Alpha-Glucosidase inhibitors

Alpha-glucosidase inhibitors
Taken with each meal.
Side effects are flatulence and diarrhea
This can be diminished with low carb, high fiber diet
and slow titration of the dose form 25 mg to 100 mg
per day.
Very low risk of hypoglycemia
Alpha-glucosidase inhibitors Bottom line
Very useful if tolerated
Relatively cheap.
Bromocriptine
Bromocriptine mesylate given within 2 hours of waking
up in the morning improves glycemic control by
unknown mechanism.
It is given in escalating dose starting with 0.8 mg and
increasing by 0.8 mg every week to maximal tolerated
dose.
Therapeutic dose is between 1.6 to 4.8 mg per day.
Very low risk of hypoglycemia.
About 25% of patients experience some nausea.
Bromocriptine

Bromocriptine

Bromocriptine Bottom line
Useful if tolerated.
Still expensive
Many patients are discuoraged by need to use 2-6 pills
at once (In US only 0.8 mg pill is available).

Bile acid sequestrants
Colesevelam
Cholestyramine
Colestid

Mechanism is unknown
In db/db mice these drugs increase metabolic
utilization of glucose in peripheral tissues which
corelates with decrease in muscle long chain
acylcarnitine content
Meissner M, et al. PLOS 2011 (6)11 e24564.
Coleselavam

Cholestyramine

Colesevalam

Colesevalam

Orlistat

Effect on weight

Effects on Hba1c

Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.
Targeting the Kidney
Chao, EC & Henry RR. Nature Reviews Drug Discovery. 2010;9:551-559.
Renal Glucose Transport
Rationale for SGLT2 Inhibitors
SGLT2 is a low-affinity, high capacity glucose transporter
located in the proximal tubule and is responsible for 90% of
glucose reabsorption
Mutation in SGLT2 transporter linked to hereditary renal
glycosuria, a relatively benign condition in humans
Selective SGLT2 inhibitors have a novel & unique mechanism of
action reducing blood glucose levels by increasing renal
excretion of glucose
Decreased glycemia will decrease glucose toxicity leading to
further improvements in glucose control
Selective SGLT2 inhibition, would also cause urine loss of the
calories from glucose, potentially leading to weight loss
Brooks AM, Thacker SM. Ann Pharmacother. 2009;42(7):1286-1293.
Canagliflozin
*P.001 vs. placebo calculated using LS means Rosenstock J, et al. Abstract 77-OR. ADA 2010.
Metformin + Canagliflozin Dose-Ranging Study
Mean Baseline
A1C (%)
7.71 8.01 7.81 7.57 7.70 7.71 7.62
*
*
*
*
*
*
Changes from Baseline in Body Weight
in Phase 3 Dapagliflozin Studies
Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg
Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010;
Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224; Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233.
Canagliflozin Trials
Symptomatic genital infections in 3-8%
canagliflozin arms
2% placebo
2% SITA
Urinary tract infections in 3-9% canagliflozin arms
6% placebo
2% SITA
Hypoglycemia in 0-6% canagliflozin arms
2% placebo
5% SITA


Rosenstock J, et al. Abstract 77-OR. ADA 2010.
Treatment and cancer risk
metformin
sulphonylurea
metformin + sulpha
insulin
No treatment
Treatment and colorectal cancer risk
metformin
sulphonylurea
metformin + sulpha
insulin
Treatment and pancreatic cancer risk
metformin
sulphonylurea
metformin + sulpha
insulin
ADOPT and RECORD Trials
ADOPT and RECORD Trials
METFORMIN
METFORMIN
Are all sulphonylureas the same?
Retrospective cohort study
Glibenclamide treated N-378
Gliclizide treated N-190
5 year follow up
Cancer mortality higher for
glibenclamide after
adjustments for age and sex,
BMI, metformin and insulin
treatment- HR 3.56 (1.1-11.9)

Are all sulphonylureas the same?
Matched case-control study
195 diabetic patients with incident malignancy
195 matched diabetic patients with no malignancy
Matched for sex, age, BMI, duration of diabetes, Hba1c,
smoking and alcohol abuse
Exposure to antidiabetic drugs over last 10 years was
analyzed.
Are all sulphonylureas the same?
Possible mechanism
New Classes Presently in Development
Long-acting GLP-1 receptor agonists
Ranolazine
11 Hydroxysteroid Dehydrogenase (HSD)- 1 inhibitors
Fructose 1,6-bisphosphatase inhibitors
Glucokinase activators
G protein-coupled Receptor (GPR)- 40 & -119 agonists
Protein Tyrosine Phosphatase (PTB)- 1b inhibitors
Camitine- Palmitoyltransferase (CPT)- 1 inhibitors
Acetyl COA Carboxylase (ACC)- 1 & -2 inhibitors
Glucagon receptor antagonists
Salicylate derivatives