10/12/2015
Introduction to Meds for Diabetes Mellitus
Diabetes can occur either because (1) theres too little insulin
synthesized and released from the beta cells of the pancreas (type
1 diabetes)
Or because insulin receptors become insensitive and glucose
transport into the cell is impaired (type 2 diabetes)
o Most people with type 2 diabetes also experience reduced
insulin secretion over time.
Goals of pharmacotherapy for Diabetes Mellitus
Primary goal for pharmacotherapy for diabetes is to maintain tight
control of plasma glucose levels.
Maintaining near normal levels of glucose helps prevent long term
complications and treats hypertension and hyperlipidemia.
Categories of pharmacotherapeutic agents for Diabetes.
Agents that stimulate insulin release
Agents that stimulate insulin receptors
Agents that decrease/delay glucose absorption
Insulin replacement
Agents that suppress glucagon
Glucagon to counteract excess insulin
Agents to prevent complications of diabetes
Agents to treat complications of diabetes
Type 2 diabetes accounts for more than 90% of pts with diabetes.
o Can be prevented though with diet, exercise and weight
control
Agents that stimulate insulin release
People with type 2 diabetes are typically obese at the time of
diagnosis
They usually have enough insulin levels
o Development of type 2 diabetes often preceded by years of
hyperinsulinemia due to consumption of large, frequent
meals.
o Over time, the insulin receptors downregulate and they
become insulin resistna
Drugs stimulating insulin release were ONCE the mainstay of drug
therapy for type 2 patients.
o Today, they are step 1 drugs only for people with type 2 who
are lean (small minority of pts)
Single-drug therapy isnt effective long-term, and many obese pts
take other drugs as well
Agents stimulating insulin release include
o Sulfonylureas: first and second generations
o Meglitinidies: repaglinide (prandin) and nateglinide (Starlix)
SUFLONYLUREAS: insulin receptor stimulators
Chemically related to sulfonamide antibiotics
They increase beta-cell insulin release and decrease gylcogenolysis
(breakdown glycogen into glucose)
Increase insulin receptor sensitivity after long-term use
Two generations of sulfonylureas
o Both gens have equal therapeutic effects, but second gen is
more potent and has following advantages
Longer duration of action
Less likely to cause disulfiram-like reactions with alcohol
Less likely to be involved in cross-sensitivity with
allergic reactions to sulfonamides
Less potential for fluid retention (they have diuretic
properties)
Less risk of UVA/UVB photosensitivity
Potential adverse effects and drug interactions
o Hypoglycemia
o Displacement from plasma proteins by other drugs
Drugs like warfarin, NSAIDS, and sulfonamides compete
to bind to albumin.
The resulting increase free levels of the sulonylurea
may result in hypoglycemia.
o Inhibition of hepatic metabolism by other drugs
Drug inhibitors like cimetidine, omeprazole, and
antifungal drugs can reduce hepatic biotransformation
of sulfonylureas may result in hypoglycemia
Increased free levels of
o Decreased action from drugs that cause hypokalemia
Drugs like thiazide diuretics and oral corticosteroids
deplete potassium, as do drugs and diets high in
sodium.
Hypokalemia impairs insulin release and insulinreceptor function
o Decreased action from drugs that cause hyperglycemia
Corticosteroids, estrogen-based contraceptives, thiazide
diuretics, nicotinic acid, phenytoin, and some Ca-2+
chnl blockers can increase blood glucose levels.
Therefore, sulfonylureas can be less effective
o Reduced efficacy with long-term use
Sulfonylrueas continue to stimulate insulin secretion
even when the pt is fasting.
Over time, this leads to a pancreatic burn out and
reduces capacity of the pancreas to make insulin
MEGLITINIDES: insulin receptor stimulators
About as effective as sulfonylureas and share same MOA.
Repaglinide (prandijn) and nateglinide (Starlix) differ from sulf. In
different ways
o Short half-life
So theyre taken immediately before a meal or as long
as 30 minutes after eating to treat postprandial (aftermeal) hyperglycemia)
o Less likely to cause hypoglycemia
Hypoglycemia only occurs if patient takes drug and
doesnt eat
o Less likely to cause pancreatic burnout
Low drug level between meals allow the pancreas to
rest and recover, delaying or preventing the burnout
o Metabolized by CYP3A4
BIGUANIDES: stimulate insulin receptors
Metformin (Glucophage)
o Chemically related to a naturally occurring substance called
guanidine.
o Plants containing guanidine were used in medieval times to
treat diabetes
o Metformin requires sufficient levels of insulin to exert its
action so its used to treat only type 2!
o Recommended that all pts taking long-term oral
corticosteroids take metformin as well.
Corticosteroids deplete potassium and cause muscle
catabolism (breakdown) which can cause hyperglycemia
and insulin resistance.
Metformin has shown that it can prevent this!
o Studies have also shown that metformin can prevent type 2
diabetes in pts at high risk for disease when COMBINED with
lifestyle changes
Metformins actions
o Increases number of insulin receptors
o Increases insulin receptor sensitivity
o Increases cellular uptake of glucose
o As a result of increased receptor sensitivity, it reduces hepatic
gluconeogenesis (formation of glycogen from fatty acids and
protein)
o Reduces GI glucose absorption
Metformins advantages
o Doesnt cause hypoglycemia
o Decreases plama lipids
o Decreases blood pressure in obese pts
o Decreases weight in obese
o Not bound to plasma proteins
o Not metabolized in liver
Adverse effects
o Increases risk of lactic acidosis
Can be avoided if pt has normal renal and hepatic
function, doesnt have sepsis, dehydration, or acute
heartfailure and avoids alcohol
o Should be avoided with renal impairment
o Alcohol potentiates effect of metformin on lactate metabolism
Limit to 1 drink/day
o Decreases absorption of folate and vitamin b12
o Metformin withheld before administering contrast agent
Can cause acute renal failutre in pts undergoing
radiologic studies in which contrast agent is given
d/c 2 days before and after contrast agent is
administered
o Causes GI distress and metallic taste
THIAZOLIDINEDIONES: pioglitazone and rosiglitazone.
Glitazones (get in the zone with glitazones) activate a gene that
decreases insulin resistance in pts with type 2.
o They increase insulin receptor sensitivity and number.
o Decrease hepatic gluconeogenesis.
o Have none of metformins side effects and no effect on hepatic
liver enzymes
THINGS TO REMEMBER:
o Glitazones cause fluid retention and edema
Contraindicated in pts with heart failure, bc edema
aggravates dyspnea and fatigue.
Also causes macular edema
o Pioglitazone increases HDL and decreases triglycerides
These lipid effects can decrease heart disease risk
(most common cause of death in type 2 pts)
Rosiglitazone doesnt have these lipid benefits because
it increases triglycerides and doesnt increase HDL as
much.
BOTH drugs increase LDL slightly.
o Check alanine transaminase at baseline and every 3-6 months
o Glitazones associated with increased risk of fractures in the
distal extremities in women
o Rosiglitazone now has FDA warning that the drug increases
cardiovascular risks.
Restricted to pts already on the drug and wish to
continue with it and pts who dont wanna use
pioglitazone and cannot control their blood glucose with
other agents.
Agents that decrease/delay glucose absorption
Alpha-glucosidase inhibitors: ACARBOSE (Precose), MIGLITOL
(glyset)
o Drugs work by inhibiting the intestinal brush-border enzyme
that breaks off glucose molecules from carbohydrates before
absorption.
o As a result, carb absorption is slower and the postprandial
increase in plasma glucose is less.
o Minimal systemic effects (less than 2% is absorbed)
Important points
o Adverse effects are flatulence, cramps, abdominal distention,
and diarrhea.
Gas produced by fermented carbs via gi bacteria
o Iron absorption reduced
Iron supplememnts needed!
o Sugar cant be used to treat hypoglycemia
A-g inhibitors dont cause hypoglycemia, but it may
happen when taken with sulfonylurea
When this happens, glucose is the answer, not sugar
Avoid use with metformin
o A-G inhibitors decrease metformin absorption.
o The combined GI SE of both drugs are poorly tolerated
Monitor liver function in pts taking acarbose
o Every three months
Insulin replacement
Now insulin is made with the use of recombinant DNA technology in
a weakened form of E.Coli.
Divided into categories
o Short acting
Rapid onset/short duration
Slower onset/short duration
o Intermediate acting
o Long-acting
o
Rapid onset/short duration
Lispro, aspart, glulisine
o All clear solutions that are injected sub-Q 15 minutes before
or immediately after a meal to control postprandial glucose.
o Used in both type 1 and type 2 diabetes.
o In people with type 1 diabetes, additional intermediate or
long acting insulin MUST be taken to provide glycemic control
between meals and at night
o Pts with type 2 may need an oral hypoglycemic.
Humalog (lispro)
o Acts within 15-30 minutes and lasts 3-6 hours.
o Regular insulin takes 30-60 minutes to take effect
Novolog (aspart)
o Acts within 10-20 minutes and lasts 3-5 hours
Apidra (glulisine)
o Fastest onset, 10-15 minutes
o Duration is 3-5 hours
MIX WITH NPH INSULIN ONLY
Slower onset/short duration
Given sub q injection, infusion, im injection and inhalation.
IV use is not FDA approved
o This is not FDA approved because insulin adsorbs to IV
infusion sets in an unpredictable manner
Regular insulin takes about 30-60 minutes to take effect b/c insulin
molecules aggregate under the skin and this slows absorption
o Peaks in 1-5 hours and lasts 10 hours
Slower onset/intermediate duration: NPH, Detemir
NPH
o Conjugated with a large protein that decreases the absorption
of insulin
o Some important points about NPH insulin
NPH injected sub Q 2x/day to control blood sugar
between meals and during the night
Only longer acting insulin that can be mixed with shortacting insulin
Cloudy
Available without prescription
Allergic reactions to protamine possible
DONT GIVE IV
Levemir (Determir)
o Rx only insulin anolog
o Amino acid removed and fatty acid chain attached.
Causes levemir to form strongle bound aggregates that
slow its absorption
Fatty chain causes levemir to bind strongly to plasma
albumin; which slows delivery to tissues.
SUB Q INJECTIONS 2X DAY
Dont give IV, dont mix, clear and colorless.
Long duration
Lantus (insulin glargine)
o Differs from regular insulin by 3 amino acids.
o One amino acid replaced with glycine
o Two arginines added to the end of protein chain.
o Has at least a 24 hour duration of action and can be taken
sub q once a day (at bedtime)
o Risk of hypo/hyperglycemia is less than that with regular
insulin because release of insulin glargine from injection site
is slow and constant.
o Doesnt produce peaks!
o Dont prefill syringes with lantus; its acidic and reacts with
plastic.
Mixing insulin solutions
Rules
o Only NPH can be mixed with short duration insulins
Lispro, aspart, glulisine, regular insulin
Draw up short-duration insulin first to avoid
contamination with NPH.
Mixture stable for 28 days.
Insulin pumps
Portable insulin pumps deliver a constant basal infusion of insulin
thru sub q needle placed in abdomen.
Pt pushes button to deliver bolus doses with meals
b/c short-duration insulin is used, pump should not be removed for
more than 1-2 hours
infusion set and needle location must be changed every 1-3 days
b/c insulin microdeposits may form at infusion site, reducing insulin
absorption.
Storage of insulin
unopened vials: store at room temperature until expiration date;
dont store below 36 degrees F
opened vial: store at room temp for as long as 1 month and in
fridge for as long as 3 months
mixtures in prefilled syringes
o store in fridge for as long as 1 week with the needle pointing
up
o agitate gently to resuspend the insulin before administering.
o LANTUS IS NOT TO BE PREFILLED.
Incretin mimetics: pramlintide (symlin), exenatide (byetta)
Incretin hormones, GLP-1 and gastric inhibitory polypeptide (GIP)
are released by intestinal mucosa in response to increased blood
glucose levels.
Incretin GLP-1 suppresses glucagon secretion
Both incretin hormones, GIP and GLP-1, increase insulin synthesis
and release
Glucagon is a major counterregulatory hormone with effects that
are opposite of insulin
o Secreted by alpha cells in pancreas
o Stimulates glyocgenolysis (breakdown of glycogen and
glucose)
o Inhibits glycogen synthesis.
o Results in increase of plasma glucose.
o Also relaxes smooth muscle in GI.
Both drugs injected at mealtimes
PRAMLINTIDE (symlin)
o Synthetic analog of amylin (peptide hormone released
w/insulin from pancrease)
o Suppress glucagon secretion and delay gastric emptying.
o Prescribed in pts whom insulin therapy fails to achieve
glucose control
EXENATIDE (byetta)
o Synthetic analog of GLP-1.
o Slows gastric emptying and inhibits postprandial glucagon
secretion.
o Also stimulates postprandial insulin release and is used in
type 2 pts whose diabetes isnt well controlled with
metformin or sulfonylurea
o Weekly injections shown to be effective as twice daily
injections
Side effects
o Hypoglycemia
o Nausea
o Reduced absorption of oral drugs
Take oral drugs 1 hour before adminstration
o Avoided in end-stage renal disease
Pancreatitis
o Byetta associated with risk of pancreatitis
Agents that inhibit the breakdown of incretin hormones
Sitagliptin
o Inhibits an enzyme named DPP-4 that breaks down incretin
hormones.
o Results in levels of GLP-1 and GIP incretin increased.
o This allows more insulin production and release in response to
meals and decreased gluconeogenesis in liver.
o Sitagliptin is used alone or with metformin or ER-metformin
No increased risk of hypoglycemia found with sit.
Compared to placebo and the risk for GI effects is low.
o Eliminated primarily by kidneys
Saxagliptin
o New DPP-4 inhibitor with similar effects as sit.
o Undergoes both hepatic CYP3a4/3a5 metabolism and renal
elimination.
o Therefore affected by drugs that undergo hepatic metabolism
Glucagon to counteract excess insulin
Can be injected IM, sub q or IV to counteract insulin overdose
Agents
Ineffective if person has no glycogen reserves because of starvation
Glucagon is second choice and should be used only if oral glucose is
ineffective or if IV glucose cant be given.
Used mostly when pt unconscious.
to prevent complications of Diabetes
Cardiovascular disease
o Statins (HMG CoA Reductase Inhibitors)
Cardio. Disease most common cause of morbidity and
mortality in pts with type 2
Statins reduce cardiovascular events in pts with
diabetes regardless of their LDL levels.
o Low dose ASA
Take 75-162mg /day as an antiplatelet agent for
primary prevention of heart attack and CVA
Nephropathy
o ACEi/ ARBs
Pts with both types of diabetes are at high risk for
neprohpathy.
Nephropathy most common cause of death in
type 1 diabetes.
Monitoring for microalbuminuria is key to early
identification.
Antihypertensive drugs in ACE inhibtors and ARB
protect against diabetic nephropathy.
Theses are Drugs of choices in treating hypertension in
pts with diabetes
Slows onset of type 2 diabetes in pts at a high risk
Neuropathic ulcers
o Becaplermin (regranex)
Diabetic foot ulcers most common reason for
hospitalization of pts with diabetes(and reason for 85%
of amputations in U.s)
Attracts repair cells like monocytes and fibroblasts to
the wound and stimulates granulation tissue
Effective only if there is adequate blood supply to the
ulcer
o Atorvastatin
Very high dose of this drug (80 mg) improves healing of
foot ulcer and decreases recurrence of new ulcers
Neuropathic pain
o Gabapentin
Not fda approved, but treats pain associated with
diabetic neuropathy.
SE includes dizziness, peripheral edema, blurred vision,
drowsiness.
FDA approved for treating diabetic peripheral
neuropathy.
o Pregabalin
Pts take smaller dose and less SE
o Weight gain is possible
o Increased blood sugar and Hb1 ac should be monitored
closely.
