Diabetes-

eat a meal, beta cells in pancreas will produce insulin which picks up glucose from blood &
stores it in tissues; pancreas also secretes glucagon which promotes higher glucose levels
(glucagon for people who are severely hypoglycemic & can’t be given IV dextrose, etc; there are
other ancillary mechanisms that regulate glucose as well)

Type I versus type II diabetes-

Type 1: childhood/ autoimmune, body attacks & destroys own beta cells; underproduce or don’t
produce insulin; tx is insulin replacement; polydipsia, polyuria, polyphagia (lotsa peeing, very
thirsty, very hungry) Hyperglycemia beyond 400-500, sx of confusion, cardiovascular collapse,
long-term damage

Type 2: tissues are resistant to effects of insulin, not a lack of insulin until late-stages, usually
developed in middle age, result of obesity/diet, no sx while body is compensating, elevated
insulin in body & then will no longer sustain & drop levels; latter part of disease less efficient/no
production of insulin in pancreas

Factors affecting glucose control

Diagnostic Criteria:

A1C ≥6.5%
OR
Fasting plasma glucose (FPG)
≥126 mg/dl (7.0 mmol/l)
OR
Two-hour plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT
OR
A random plasma glucose ≥200 mg/dl (11.1 mmol/l)

2. Epidemiology- Estimated 23.6 million adults in the United States; 5.7 million are undiagnosed.
Ped diabetes estimated in 57 million Americans

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Predictive Factors for Developing Type 2 DM - Metabolic syndrome
NCEP criteria: (3 or more are present)
1. Increased body weight & Waist circumference >40” in men, >35” in women
2. High triglycerides >150
3. Low HDL- Less than 40 in men or less than 50 in women
4. Insulin resistance- Fasting >100 or DM treatment
5. Hypertension- BP >130/>85 or on treatment
• The prevalence of metabolic syndrome is 20% of the population >20 years old and 40%
greater than 50 years old – and it is increasing!
• The risk of developing diabetes increases with the number of factors present. With 3
factors the risk is approximately 7-9 X more likely to develop diabetes as compared to having
no factors present.
• A public health strategy is to reduce metabolic syndrome in order to prevent diabetes.

Home blood glucose testing

3. Outcomes
Microvascular: nervous system damage, retinopathy, nephropathy
Macrovascular: coronary artery disease, stroke

4. Therapeutic goals (ADA)

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Alternative goals are based on specific patient factors- other co-existing diseases present, may
want to remain at lower A1C (ex- CA with mets) Long-term benefits examined

Key studies of diabetes treatment

The DCCT and the UK Prospective Diabetes Study

UKPDS Key findings:

Conventional vs intensive control:
12% decrease in any diabetes endpoint
25% decrease in microvascular endpoints
16% decrease in MI
21% decrease in retinopathy at 12 years
33% decrease for microalbuminuria at 12 years

Sulfonyulurea vs Insulin:
No differences in glucose control
No differences in risk reduction
No increased evidence of cardiac effects with sulfonylureas
No evidence of increased atheroma formation with insulin

Metformin:
Vs conventional therapy
32% risk reduction in any diabetes endpoint
42% decrease in any diabetes related death
36% reduction in mortality
39% reduction in myocardial infarct
Metformin may be advantageous in obese type 2 diabetics.

In hypertensive diabetics either beta blockers or ACE inhibitors had equal effects in
reducing BP and diabetes related endpoints.

Treatment goals: beta blockers ok in type 1 diabetics, but not if have hypoglycemia since they
are usually using intense insulin

Ideal Goal – Normal A1c of less than 6

Tight control (HgbA1c less than 7)

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 70-105 before meals
<150 2 hrs postprandial

Practical control (HgbA1c less than 8)

90-140 before meals
<180 2 hrs postprandial
fasting less than 140
no value less than 60

Reasonable control in older patients

HgbA1c less than 9 and minimize DM symptoms.

INSULIN

1. Human insulin
2. Types of insulin

Insulin name Onset Peak Duration

Regular 0.5-1 hr 2-5 hr 6-8 hr
NPH 1-2 hr 6-12 hr 18-26 hr
(Lente, semilente and ultralente taken off the market)

Newer insulins:
lispro insulin: very quick onset; short duration of action.
insulin aspart: ditto
insulin glulisine (Apidra) ditto
insulin glargine (Lantus): very long acting insulin
insulin detemir (Levemir) also very long acting

3. Dosing strategies
In type 1 you want to provide basal control (Glargine or Detemir) & quick-acting insulin; another
strategy includes the pump for continuous delivery, boluses for when eating

In type 2, can begin 2 ways- if pt is failing oral meds, begin with nighttime dosing NPH or can
start immediately with insulin/ morning NPH, possibly single dose to last entire day or can be
split between morning & evening (to control lunch/dinner hyperglycemia, can add regular insulin
to regiment; can buy pre-mixed)

Single dose
Split dosing
Mixed insulin
Insulin pumps
4. Adjusting insulin dosing

Work backwards from glucose results to when the insulin should be having its peak
effect:
_8_________________12___________________6_____________________
AM NPH Dinner glucose
AM regular Lunch glucose
Evening regular ->Bedtime

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 Evening NPH -> fasting glucose

5. Tight control strategy

Baseline long acting
PLUS regular before meals (adjusted)
6. Initiation of insulin in type 2 diabetes (combination with oral drugs)
7. Patient education, administration technique, storage, supplies (syringes, swabs),
hypoglycemia management
8. Inhaled insulin (Exubera) – off the market in 2008, will Oralin arrive soon?

ORAL ANTI-DIABETIC MEDICATIONS

Oral Sulfonylureas

1. Pharmacology
√ Stimulates beta cells to release insulin
√ Increases tissue sensitivity to insulin
√ ~ 1.5-2% drop in A1c with proper titration

2. Dosing

Drug Total Daily Dose Frequency

Tolbutamide (Orinase) 500 - 3000 mg BID - TID
Tolazamide (Tolinase) 100 - 1000 mg QD - BID
Chlorpropamide (Diabenese) 100 - 500 mg QD
Glipizide (Glucotrol) 2.5 - 40 mg QD-BID
Glyburide (Diabeta, Micronase) 1.25 - 20 mg QD-BID
Glyburide Prestab (Glynase) 1.5 - 12 mg QD- BID
Glimepiride (Amaryl) 1 - 8 mg QD - BID

3. Adverse effects
Hypoglycemia
Rarely: hepatitis, allergic reactions, rash, nausea, SIADH, antabuse reactions
Primary and secondary failure to oral sulfonylureas

4. Drug Interactions

5. Patient education

Metformin (Glucophage®) – only drug in its class (phenformin in 60’s associated with lactic
acidosis) Contraindicated in decreased renal function & risk of accumulation

The higher the A1C level, the quicker the reduction when given Metformin (11.5-8 in one
month for instance)

1. Pharmacology:
√ Increased glucose uptake by muscle
√ Decreased hepatic glucose production
√ Decreased intestinal glucose availability

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 Pharmacokinetics:
Bioavailabiltiy = 50-60%
Excreted unchanged in urine
Half-life = 6 hrs

2. Clinical Efficacy Summary:

The US Pivotal Trial:

143 patients given metformin versus 146 patients given placebo
length: 29 weeks
fasting plasma glucose: 189 vs 244 mg/dl
HgA1c 7.1% versus 8.5%

The US metformin + glyburide study

632 patients already on oral sulfonylureas who did not have acceptable fasting
plasma glucose on maximal glyburide dose (20 mg/day). They were randomized
to continue glyburide, switch to metformin or receive the combination of both
drugs for a 5 week titration phase followed by 24 weeks maintenance.

Patients receiving combination therapy had significant decreases in both fasting

plasma glucose (187 vs 261 mg/dl) and HgA1c (7.1% vs 8.7%)

3. Adverse Effects and Other Cautions

GI: diarrhea, nausea, abdominal pain, anorexia, metallic taste. May be transient and dose
related. Minimize with gradual dose titration.
HEMATOLOGICAL: Lowered vitamin B-12 levels, usually asymptomatic. There are
very rare cases of megaloblastic anemia.

THE ISSUE ABOUT LACTIC ACIDOSIS

Symptoms are vague: GI complaints, altered sensorium, tachypnea.

Incidence is about 0.03 cases/1000 patient-yrs of treatment

At highest risk are patients with decreased renal function who might accumulate the drug.
Do not use in patients with decreased renal function. Withhold in situations with
anticipated decreases in renal function: surgery, trauma, dehydration, use of
iodinated contrast media, excessive alcohol use.

Avoid use in patients with significant hepatic disease as lactic acid is cleared by the liver.

4. Dosing: Available in 500, 850 and 1,000 mg tablets. Start at either 500 BID or 850 QD.
With 500 mg tablets increase by one tablet every week until control is achieved or a maximum
2,500 mg dose is reached. With 850 mg tablets increase by one tablet every other week until
response or a maximum dose of 2,550 mg is reached. Higher doses are split. Also available in
SA tablets dosed QD/BID (Glucophage XR)

5. New formulations: Fixed combination with glyburide: Glucovance

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 Avandamet (metformin plus rosiglitazone)

6. Place in Therapy- Comparable glucose control to oral sulfonylureas. Positive metabolic

changes and no weight gain suggest best used in significantly overweight patients. Guidelines
recommend this drug for use in most type 2 patients as 1st drug.

Alpha Glucosidase Inhibitors-

Acarbose (Precose®)

1. Pharmacology- A reversible inhibitor of alpha glucosidase: slows down

breakdown of complex carbohydrates thereby preventing post-prandial glucose surge. Acarbose
works intraluminally; almost no drug is absorbed systemically.

2. Clinical Efficacy Summary- Achieves a 0.5-1% reduction in HgA1c

3. Adverse Effects and Other Cautions- Abdominal pain, diarrhea and flatulence are
common. These adverse effects are related to increased delivery of undigested carbohydrate to
the large colon. They tend to abate with time and are minimized by gradual titration.
Note that excessive intake of disaccharides will increase GI side effects. Maltose and sucrose
have a relatively fast transit time through the intestine and will reach the large colon where they
will be fermented by colonic bacteria. Gas and cramping will result. Advise patients to avoid
consuming concentrated sucrose (cake with frosting) and maltose (beer).

There is no risk of hypoglycemia from acarbose used alone. However, hypoglycemia

may develop during combination therapy with oral sulfonylureas. In these cases, it is important
to remind patients that plain glucose should be used to correct hypoglycemia. Sucrose (table
sugar) will not work fast enough because of the enzymatic inhibition with acarbose.

4. Dosing- Available in 50 and 100 mg tablets. Start with 25 mg (1/2) tablet TID
and increase at 4-8 week intervals using 1 hr postprandial glucose measurements as a guide. The
maximum recommended dose is 100 mg TID. Acarbose must be taken with the first bite of food
(start of the meal).

5. Place in Therapy- As an adjunct to dietary changes for type II diabetes mellitus.

Usefulness may be limited in some cases by non-serious but bothersome GI side effects.

Miglitol (Glyset)

1. Pharmacology- Reversible inhibitor of alpha glucosidases; slows down the

breakdown of complex carbohydrates thereby preventing postprandial glucose surge.

2. Clinical Efficacy Summary- In 2 US studies the postprandial glucose surge was

reduced by 63-66 mg/dl with a 50 mg TID dose. Hemoglobin A1c was reduced by 0.58 to
0.69%. Also studied in combination with sulfonylureas. Additional blood sugar lowering seen
with combination.

3. Adverse Effects and Other Cautions: Abdominal pain, diarrhea and flatulence
are common. Similar to acarbose. Same cautions.

The Miglitinides: Repaglinide (Prandin)

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Pharmacology: Causes pancreatic beta cells to release insulin. While similar in effect to
sulfonylureas, it is more quickly acting and has a short duration of action. It is taken before
meals.

Clinical Efficacy Summary: As monotherapy lowers Hgb A1c by up to 1.9%. In comparison to

sulfonylureas it has approximately the same efficacy.

Adverse Effects: Hypoglycemia - relatively rare

Place in Therapy: as an alternative to sulfonylureas particularly for patients with significant

postprandial hyperglycemia

Phenylalanine derivative (similar to repaglinide)

Nateglinide (Starlix) - also used for postprandial hyperglycemia control

Typical dose is 120 mg tid just before meals

Thiazolidenediones (“Glitazones”)

1. Mechanism of Action: Partially reverses insulin resistance. Works at the level of

the nucleus by modifying gene expression and protein production.

2. Indications: Used in combination with sulfonylureas or metformin and as

monotherapy although the latter is generally not recommended at this time.

3. Clinical Efficacy Summary: Troglitazone was removed from the US market on

3/21/00.

Pioglitazone

Monotherapy: 0.3-1.6% decrease in Hgb A1c - greater effect in therapy naive

patients. Effects are sustained for at least 1 year.
Combination: Sulfonylurea + pioglitazone = 0.9 - 1.3% HgbA1c drop.
Metformin + pioglitazone = 0.8% drop in HgbA1c
Insulin + pioglitazone = 0.7 to 1.0% drop in HgbA1c

Rosiglitazone

Monotherapy: 0.3-0.7 decrease in HgbA1c; effects sustained for 1 yr.

Combination: Metformin + rosiglitazone = 0.6 to 0.8% decrease in Hgb A1c

4. Adverse Effects and Other Cautions:

Adverse effects during clinical trials:
Pioglitazone
Upper Respiratory Tract Infection 13 .2
Headache 9 .1
Sinusitis 6 .3
Myalgia 5 .4

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Tooth Disorder 5 .3
Diabetes Mellitus Aggravated 5 .1
Pharyngitis 5 .1
Others: Increased intravascular volume, resumption or increase in fertility in women of child
bearing age.
Issues of hepatotoxicity:
Troglitazone: higher incidence (1.9% in LFT’s during studies, many reported cases of
hepatic failure). Removed from the US market for this reason.
Pioglitazone and Rosiglitazone have similar incidence of LFT elevation as placebo
during premarketing trials and thus far no clearly documented cases of hepatic failure.
Recommended monitoring: Every 2 months for the first year and the periodically thereafter.
Edema and heart failure: glitazones are now contraindicated.
The rosiglitazone (Avandia) scare of 2007; requirement for REMS in 2010

4. Dosing:

Pioglitazone: Monotherapy: 15-30 mg/day. Maximum 45 mg/day

Combination with metformin or sulfonylurea: use 15 - 30 mg and beware of need
to adjust doses of other antidiabetic medication.

Rosiglitazone: Monotherapy or combination with metformin: 4 mg/day. May increase to 8

mg/day.

Newer therapies for diabetes management:

Introduction to the amylin system

a. Incretin mimetics and insulin secretion signaling

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 b. GLP-1 and related compounds – basic pharmacology
Glucagon-like peptide 1 belongs to a group of hormones secreted by specialized
intestinal cells in response to a meal. Collectively termed incretins, they signal to the pancreas
prompting release of insulin and amylin

The activity of GLP-1 is terminated by dipeptidyl peptidase-4.

c. Exenatide (Byetta) and Luraglitide (Victoza)
Exenatide is a 39 amino acid peptide found in the salivary venom of the Gila
monster. It is a GLP-1 agonist but it is resistant to inactivation by DPP-IV.
Luraglitide is an analog of exenatide that is longer acting; injected once daily as
compared to exenatide twice daily.
Effects: enhanced insulin secretion, suppression of glucagons, slows gastric
emptying, decreased food intake and body weight.
d. Pramlintide (Symlin): synthetic amylin for type 1 DM

e. DDP4 inhibitors: Sitagliptin (Januvia) and Saxagliptin (Onglyza)

Indicated as monotherapy or in combination with metformin or glitazone
Efficacy summary: Lowers A1c by 0.5% – 0.9%
Dose: Sitagliptin100 mg once daily – reduce to 50 mg with moderate renal
dysfunction or 25 mg with severe renal dysfunction; saxagliptin 2.5 – 5 mg once daily – reduce to
2.5 mg daily with renal dysfunction.
Side effects to date: nonspecific URI, nasopharyngitis, headache.
Place in therapy?

Beyond the incretins

- Bromocriptine (Cycloset)
A dopamine receptor agonist that regulates blood glucose in type 2 diabetes. Exact mechanism of
action is unknown but it probably involves regulation of other hormones such as growth
hormone.

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Available as 0.8 mg tablets given once in the morning. Target dose is 1.6 to 4.8 mg/day. A1c
response is rather small.

Place in therapy is unknown at this point.

- Coveselam: This is a lipid lowering drug; a bile acid binding resin

But, it has also received approval for type 2 diabetes. Mechanism of action is unknown but it
probably slows down carbohydrate absorption.
About a 0.5% reduction in A1c
Dose is 3 tablets BID or 6 QD

General Guidelines for management of type 2 diabetes

American Diabetes Association; published yearly. View at: http://www.diabetes.org; follow the
links to health professionals and click on practice guidelines

Therapeutic Considerations

1. Diabetes care encompasses more that hypoglycemic or antidiabetic drug therapy

a. Dietary/weight management
b. Glucose testing
c. Preventing end-organ damage
d. Comorbidity management (HTN, lipids, etc.)

2. The role of ACE inhibitors/ARB’s in diabetic renal disease. There is some

evidence ACE’s delay DM onset in pre-diabetes patients.

3. Recommendations for the use of aspirin in diabetics- consider for those with
significant CV risk defined as Framingham score of 10% or larger. (This is an important change
that began in 2010)

4. Lipid disorder management in diabetes – as in other patients but TG can be a

major issue. TG tend to correct as BG normalizes

5. Hypertension – target is 130/80 or better

Diabetes care – the big challenge for coordinated multidisciplinary care: Metformin is first
choice, then insulin or sulfidameria; after this use combos of those, then other tx’s

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