Diabetes Mellitus in the US:

Overview
Prevalence
15.7 million Americans (5.9% of the population)
10.3 million diagnosed
5.4 million not diagnosed

Incidence
798,000 new cases diagnosed yearly
Leading cause of

Periodontal
blindness in adults
end-stage renal disease
nontraumatic amputations

disease very common

Healthcare costs $98.2 billion annually

90% to 95% of cases are type 2 diabetes
1.1

1999 PPS

ADA Diabetes Care. 1998;21:296-309.

NIDDK. Diabetes Statistics. NIH Publication No. 98-3926; November 1997 (updated

Incidence of Diabetes, 2007 data

Source: 20032006 National Health and

Nutrition Examination Survey estimates of
total prevalence (both diagnosed and
undiagnosed) were projected to year 2007.

Source: 20042006 National Health Interview Survey

 Type 1: insulin
dependent
diabetes
pancreatic islet cell destruction
with lack of insulin
Early onset
Requires insulin
supplementation

Type I Diabetes Mellitus

High Blood glucose

High Blood glucose

cells destroyed by autoimmune reaction

Detected by cells

Blood glucose remains high

hyperglycemia

Detected by cells
cells release insulin

Peripheral cells
Respond to insulin by
Taking up glucose
Lower blood glucose

cells release insulin

Peripheral cells
Respond to insulin by
Taking up glucose

Lower blood glucose

These steps
do
not happen
because
the cells
have been
destroyed

Insulin Preparations
Type of Insulin
Rapid-acting

Short-acting
(Regular)
Intermediateacting (NPH)

Examples

Onset of Action

Peak of Action

Duration of
Action

Humalog (lispro)

15 minutes

30-90 minutes

3-5 hours

NovoLog (aspart) 15 minutes

40-50 minutes

3-5 hours

Humulin R
Novolin R

30-60 minutes

50-120 minutes

5-8 hours

1-3 hours

8 hours

20 hours

1-2.5 hours

7-15 hours

18-24 hours

Humulin N
Novolin N
Humulin L
Novolin L

IntermediateHumulin 50/50
and short-acting Humulin 70/30
mixtures
Humalog Mix
75/25
Humalog Mix
50/50
Novolin 70/30
Novolog Mix
70/30
Long-acting

Ultralente

The onset, peak, and duration of action of these

mixtures would reflect a composite of the intermediate
and short- or rapid-acting components, with one peak of
action.

4-8 hours

Lantus (glargine) 1 hour

8-12 hours

36 hours

none

24 hours

 Type 2: non-insulin
dependent diabetes
(NIDD)

Disease Progression

Insulin resistance with

insulin deficiency
Adult onset
Initially treated with
lifestyle modifications
(diet and exercise)
If necessary, oral
medications also used
Eventually, insulin also
required

hyperglycemia

Oral Anti-Diabetic Agents:

Sites of Action
Pancreas

Increase
Insulin secretion

Decrease glucose production

Increase
glucose
uptake

Liver

Muscle

From: DeFronzo: Ann Intern Med, Volume 131(4).August 17, 1999.281-303

Sulfonylureas

2nd generation
Glyburide (Micronase)
Glipizide (Glucotrol)
Glimeperide (Amaryl)

Sulfonylureas
Sulfonylureas lower blood glucose by stimulating
insulin release from the pancreatic [beta] cells.

Close K+ channels on pancreatic beta cells, opens Ca++

channels, enhancing insulin secretion

Secondarily, they also decrease hepatic insulin

clearance, resulting in increased serum insulin
concentrations.
Increased circulating insulin levels then feed back to
suppress hepatic glucose production.
Only effective in patients with at least some capacity to
produce insulin not for those patients with type 1
diabetes

Sulfonylureas
Toxicity: hypoglycemia
shaking, sweating, anxiety, loss of
consciousness

blood glucose levels can decrease too

much in some cases, esp. elderly

Sulfonylureas
Interactions with dental drugs:
Corticosteroids (which can cause
hyperglycemia) may decrease effects
Aspirin and NSAIDs (ibuprofen) can increase
effects by plasma protein binding
displacement
Cimetidine (H2 antihistamine) increases
effects of certain sulfonylureas (e.g., Amaryl)
by interfering with metabolism by inhibiting
Cyp4502C9

Oral Anti-Diabetic Agents:

Sites of Action
Pancreas

Increase
Insulin secretion

Decrease glucose production

Increase
glucose
uptake

Liver

Muscle

From: DeFronzo: Ann Intern Med, Volume 131(4).August 17, 1999.281-303

Meglitinides

Repaglinide (Prandin) and Nateglindine (Starlix)

Work like the sulfonylureas by stimulating the

pancreas to make more insulin.
Close K+ channels on pancreatic beta cells, opens Ca++
channels, enhancing insulin secretion

However, unlike the sulfonylureas, this effect only

lasts for a short period of time. Therefore, insulin
levels are high for a limited period of time after taking
the medication.
This medication is taken within 30 min prior to eating,
when insulin is most needed to process the glucose that
will enter the bloodstream after starches and sugars are
digested.

Benzoic Acid Derivatives:

Meglitinides
Drug Interactions:
3A4 substrate:
Repaglinide metabolism is inhibited by drugs which
inhibit cyt. P4503A4: antifungal agents like
ketoconazole and miconazole, and macrolide antibiotics
like erythromycin and clarithromycin
Extensively bound to plasma proteins:
NSAIDs may potentiate its actions via plasma protein
displacement, increasing free plasma levels

Adverse effects: hypoglycemia

Biguanides:

Metformin (Glucophage)
Drug of choice for newly diagnosed type 2
patients
Works by reducing the amount of glucose that
is made and output by the liver and
increasing the amount of glucose taken up
and used by target tissues.
Increases insulin sensitivity, thereby
decreasing the insulin resistance that is often a
problem in patients with type 2 DM.

Biguanides:

Metformin (Glucophage)
Advantage vs. sulfonylureas: not an insulin
secretagogue, thus no hypoglycemia.
The main concern with biguanides is that people
with kidney, liver or heart disease can develop a
serious, sometimes fatal condition called lactic
acidosis (rare with metformin).
Signs of lactic acidosis include labored breathing,
muscle cramps and dizziness or drowsiness.

Understanding the benefit of

metformin use in cancer treatment
Ryan JO Dowling, Pamela J Goodwin and Vuk Stambolic
BMC Medicine20119:33

Abstract
Biguanides have been developed for the treatment of hyperglycemia
and type 2 diabetes. Recently, metformin, the most widely prescribed
biguanide, has emerged as a potential anticancer agent.
Epidemiological, preclinical and clinical evidence supports the use of
metformin as a cancer therapeutic. The ability of metformin to lower
circulating insulin may be particularly important for the treatment of
cancers known to be associated with hyperinsulinemia, such as those
of the breast and colon. Moreover, metformin may exhibit direct
inhibitory effects on cancer cells by inhibiting mammalian target of
rapamycin (mTOR) signaling and protein synthesis. The evidence
supporting a role for metformin in cancer therapy and its potential
molecular mechanisms of action are discussed.

Metformin as an anticancer drug?

Metformin Combination Medications

Glipizide/metformin (Metaglip)
Linagliptan/metformin (Jentadueto)
Sitagliptan/metformin (Janumet)
Repaglinide/metformin (Prandimet)
Pioglitazone/metformin (Actoplus Met)

Metformin (Glucophage)
Potential Dental Drug interactions:
Cimetidine (H2 blocker) may increase plasma
levels by decreasing renal clearance,
Corticosteroids may decrease effect via
hyperglycemic effect of their own.
Not plasma protein bound, so plasma levels
not altered by aspirin, NSAIDs. (advantage vs.
sulfonylureas)

Alpha-glucosidase Inhibitors:
Acarbose (Precose), Miglitol (Glyset), Vogilbose (Voglib)
This diabetes medication is taken with food at the
beginning of a meal and
slows down the digestion and absorption of sugars
and starches in the small intestine
Alpha-glucosidase hydrolyzes oligosaccharides to glucose and
other sugars

This, in turn, leads to blood glucose levels rising

slower after a meal, thus allowing impaired insulin
response or sensitivity to keep up
Clinical Advantage:
not known to cause hypoglycemia

Thiazolidinediones

Rosiglitazone (Avandia) and Pioglitazone (Actos)

.
Action: Lower blood glucose by improving target
cell response to insulin, without increasing
pancreatic insulin secretion.
These drugs decrease insulin resistance
Dependent on the presence of insulin for activity.
2D6 inhibitors: can decrease the effectiveness of
codeine by decreasing its conversion to morphine
New combination forms:
ActoplusMet: Actos plus Metformin
DuetAct: Actos plus Glymepiride
Avandamet: Avandia and Metformin
Avandaryl: Avandia and Glymepiride

Avandia in the News

Sept. 15, 2006 Research suggests that Avandia (rosiglitazone)

prevents the onset of Type 2 diabetes in a large proportion of
high-risk patients. The drug also restored normal blood glucose
concentrations in about half of treated patients

May, 2007: Study Shows 43% More Heart Attacks With Avandia

July, 2007: FDA advisory panel: Keep Avandia, but add

safeguards

Aug, 2009: (British Medical J) Avandia linked to increased rate

of heart failure

Aug. 2009: (Arch.Int.Med) TZDs associated with increased risk

for fractures

Pioglitazone (Actos)
Due to safety issues
with Avandia, many
doctors switched to
Actos
Increased risk of
bladder cancer!

New Developments
Incretin Mimetics
Insulin Enhancers: DPP-4
inhibitors
Glucose renal reabsorption
inhibitors: SGLT2 inhibitors

INCRETINS PLAY AN ACTIVE ROLE IN MEDIATING PANCREATIC

BETA-CELL AND ALPHA-CELL RESPONSES IN HEALTHY INDIVIDUALS

New Developments: Incretin Mimetics

Exenatide is a synthetic version of

exendin-4, a hormone found in the
saliva of the Gila Monster

Exenatide (Byetta) was the first of

a new class of medications
approved for the treatment of Type
2 diabetes. Can be used alone or in
combination.

It is an incretin mimetic, which has

glucoregulatory effects.

It basically is a synthetic GLP1

agonist that lasts longer than
natural GLP because it is not
subject to rapid inactivation by
DPV-IV

GLP: glucagon like peptide

Exenatide (Byetta)
The medication is injected subcutaneously twice per day
30-60 min. prior to eating using a specially designed
pen.
Typical human responses to Exenatide plus eating
include
improvements in the initial rapid release of internal insulin,
suppression of glucagon release by the pancreas,
and reduced appetite; all behaviors more typical of
individuals without blood sugar control problems.
Plus, patients lose weight on other meds, they gain

Negligible problems with hypoglycemia

Bydureon once a week injectable form of Exenatide

Byetta Side Effects

Nausea
Acute pancreatitis:
Thyroid cancer risk- FDA may add Black Box Warning
DDI:
can reduce plasma concentrations of acetaminophen and
antimicrobials by slowing absorption by decreasing gastric
emptying, but no evidence yet as to whether this is
clinically relevant

Liraglutide (Victoza)
Victoza introduced Feb. 2010:
benefits unique to Victoza vs. Byetta:
Once-daily injection
More flexible dosing: Byetta must be dosed at least
one hr before the morning and evening meal,
whereas Victoza can be injected anytime during the
day
Claimed better glucose control and a lower incidence
of nausea than Byetta
Pancreatitis risk may be lower, but FDA advises
caution in patients with a history of pancreatitis
Carries FDA Black Box warning regarding potential
risk of thyroid cancer

Dulaglutide (Trulicity)
Incretin Mimetic synthetic
GLP-1 receptor agonist
Approved Sept. 2014 as an
adjunct to diet and exercise for
the management of Type-2
diabetes
Injected once a week
FDA warning concerning thyroid
cancer risk

INCRETINS PLAY AN ACTIVE ROLE IN MEDIATING PANCREATIC

BETA-CELL AND ALPHA-CELL RESPONSES IN HEALTHY INDIVIDUALS

Insulin Enhancers: Dipeptidyl

Peptidase-4 Inhibitors

Incretin,
GLP1

Stimulate
insulin
release

Lower
blood
glucose

Inhibits
glucagon
release

DPP-4
enzymes
inactivate
GLP1

DPP-4 inhibitors block

DPP-4 and decrease
glucose

DPP-4 inhibitors:
Sitagliptin (Januvia), approved 2006, Saxagliptin
(Onglyza), approved 2009, Linagliptan (Tradjenta) FDA
Approved 2011
Taken orally (unlike Byetta)
Competitive inhibition of DPP-4 potentiates the
secretion of insulin and suppresses the release of
glucagon by the pancreas
May be used as monotherapy or in combination with
Metformin
Do not cause weight loss like the incretin mimetics

SGLT: sodium glucose transporter

SGLT2 Inhibitors

Examples: Invokana (canagliflozin), Jardiance

(empagliflozin), and Farxiga (dapagliflozin)

Lower blood sugar by reducing glucose reabsorption from the

glomerular filtrate in the kidney by inhibiting sodium-glucose
transport protein 2 (SGLT2)

This mechanism is independent of insulin secretion and target

tissue insulin sensitivity and is thus useful in patients with
diminished beta-cell function

No risk of hypoglycemia

5/15/2015: The U.S. Food and Drug Administration (FDA) is warning

that the type 2 diabetes medicines canagliflozin, dapagliflozin, and
empagliflozin may lead to ketoacidosis, a serious condition where
the body produces high levels of blood acids called ketones that may
require hospitalization.

DKA: diabetic ketoacidosis

Summary of Antidiabetic Agents

Drug

Type

Glucoregulatory Effects

Insulin/Insulin analogues

Insulin replacement

Correct insulin deficiency

Sulfonylureas

Insulin secretagogues

Increase insulin secretion

Insulin sensitizers

Decrease glucose release,

increase peripheral
sensitivity

Insulin secretagogues

Increase insulin secretion

Insulin sensitizers

Decrease glucose release,

increase peripheral
sensitivity

Starch blockers

Retard carbohydrate
absorption

Enhance insulin
release

Decrease glucose release

Decrease incretin
breakdown

Decrease glucose release

(Glyburide)

Biguanides
(Metformin)

Meglitinides
(Prandin)

Glitazones
(Avandia, Actos)

A-glucosidase inhibitors
(Precose)

Incretin mimetics
(Byetta, Victoza)

DPV-IV inhibitors
(Januvia, Onglyza)

The End