PHARM WK 11: DIABETES

04/02/2021

**NINO WILL BE ONLINE FROM 8AM - 9AM DAY OF FINAL**

Diabetes Mellitus: Review…

● Type 1 Diabetes
○ Pancreas is unable to make insulin
○ Beta cells of the Pancreas are destroyed by antibodies
○ Have to be administered insulin → not secreting insulin on their own
○ Insulin-dependent diabetes
● Type 2 Diabetes Mellitus
○ Pancreas is capable of secreting insulin, although in deficient amounts
○ Body is resistant to its own insulin
■ Insulin receptors have become insensitive or resistant to the hormone
■ Minimal amounts of insulin bind to the receptors

What is Insulin’s Job?

● Moves glucose from the bloodstream to the muscle, liver, and fat cells
○ Without insulin → glucose builds up in the bloodstream → hyperglycemia
● Stimulates storage of glucose in the liver and muscle
● Enhances storage of dietary fats in adipose tissue
● Transports amino acids into the cells

Treatment of Diabetes Mellitus

● Balance between
○ Diet
○ Exercise
○ Medication
○ Blood Glucose Monitoring
● Tight Glycemic Control…
○ Maintaining glucose levels within a normal range (roughly 90-110)
around-the-clock.
■ When blood glucose levels are elevated, that’s what increases the
complications of diabetes
○ Goal for glucose levels should be individualized.
○ Risk versus Benefit
■ Risk of tight glycemic control → hypoglycemia

Diabetes Control and Complications Trial (CDDT)

● Patients were placed in a group…
○ “Conventional” Group (2 injections/day)
○ “Intensive Insulin Therapy” Group (4 injections/day)
● After 6+ years…
○ Intensive Insulin Therapy Group…
■ 50% decrease in kidney disease
 ■ 35-57% decrease in neuropathy
■ 76% decrease in ophthalmic complications
● After 17 years…
○ Significant reduction in angina, MI…
● However…
○ Intensive therapy group → 3x as many hypoglycemic episodes requiring
treatment

DM Medication Classes Tables 57-8 & 57-10

● Oral
● Injectable non-insulin
● Insulins

Insulin Therapy
● Primarily administered Sub Q (subcutaneously / SQ / SC)
○ Regular insulin can be administered IV
○ Not administered orally because gastric enzymes would destroy the insulin
● Sources of Insulin:
○ All insulins are produced using DNA technology
○ Human Insulin is identical to human insulin
○ Human Insulin Analog means they have a different time course
■ Can get insulin from pork & beef → don’t use in the US anymore
● Should not be given to pregnant women or children

Types of Insulin
● See Table 57.7, page 684
● Short Duration: Rapid Acting
○ Acts right away → doesn’t last very long
● Short Duration: Short Acting
● Intermediate Duration
○ NPH Insulin
● Long Duration
● Ultra-Long Duration

Short Duration: Rapid Acting Insulin

● Lispro (Humalog)
● Aspart (Novolog)
○ Clear Solution
○ SubQ administration
■ NOT admin via IV
○ May be mixed in the same syringe with NPH
○ May be used in combination with intermediate or long acting insulins
○ Lispro available in u-200 strength
■ Twice as potent (as u-100)
○ Onset: 10 – 30 minutes
○ Peak: 30 – 2.5 hours
 ○ Duration: 3 – 6 hours
***NEED TO KNOW THESE VALUES***
-don’t give insulin until you see FOOD in the patient’s room

Inhaled Insulin: Rapid Acting

● Afrezza
○ Inhaled insulin → rapid acting
■ Same onset, route, & duration as above ^^
○ Approved June 27, 2014
○ New marketing campaign in 2016
○ Rapid Acting Insulin
■ Considered a meal-time insulin
● If patient takes afrezza & doesn’t eat for a bit → they will get
hypoglycemic bc this is rapid acting
■ To be used in conjunction with long term insulin
■ Fairly expensive
○ Cartridges contain 4, 8, or 12 units each
■ Doses are established in these increments
■ For example, a patient needing 16 units of insulin would use two 8-unit
cartridges
○ Enters bloodstream in less than 1 minute
○ Works within ~ 12 minutes

Short Duration: Slower Acting Insulin

● Regular Insulin
○ Humulin R, Novolin R
■ **regular insulins have an R with them**
● Clear solution
● Administered Sub Q, IV
○ If we need to give IV insulin → we use regular insulin
● May be mixed in the same syringe with NPH
● Available in U 100 and U 500 strength
○ U500 reserved for patients with insulin resistance
○ U500 is never given IV
■ Bc it is way too potent
● Onset: 30 - 60 minutes
● Peak: 1 to 5 hours
● Duration: 6 to 10 hours

Intermediate Acting Insulin

● NPH
○ Humulin N, Novolin N
■ N with insulin → NPH
● Cloudy Insulin
● Typically administered twice daily, only SubQ
 ● Only one suitable for mixing with short-acting and rapid-acting Insulins in the same
syringe
● Onset: 1 to 2 hours
● Peak: 6 to 14 hours
○ This is when the patient is at GREATEST risk for hypoglycemia
● Duration: 16 to 24 hours

Long Duration Insulin

● Insulin Glargine (Lantus) → U-100
● Administered 1x day
○ Can be administered anytime of the day, as long as it is consistent
● Incidence of hypoglycemia is NOT as common with this drug
○ Achieves blood levels that are relatively steady
● Clear solution
● Given SubQ only (SQ / subcutaneously)
● Onset: 1 – 2 hours
● Peak: NONE
● Duration: 24 hours

Ultra-Long Duration Insulin

● Insulin Glargine (Toujeo) (U-300)
● Same as Lantus but 3x more concentrated
● Administered 1x day.
○ Used typically for those who cannot get 24-hour coverage from Long Duration
Insulins
● Clear solution
● Prefilled pens only
● Given SubQ only(SQ / subcutaneously)
● Onset: 6 hours
● Peak: None
● Duration: >24 hours

Insulin Onset, Peak, and Duration

Duration
Insulin Onset Peak
of Action
Rapid Acting 30 minutes–
10–30 minutes 3-6 hours
Lispro (Humalog) 2.5 hours
Short Acting
30–60 minutes 1-5 hours 6-10 hours
Regular
Intermediate Acting
1–2 hours 6-14 hours 12-24 hours
NPH
Long Acting
1-2 hours None 24 hours
Glargine (Lantus)
 Ultra-Long
6 hours None >24 hours
Glargine (Toujeo)

The patient with Diabetes self-administers morning insulin before breakfast…

● NPH 14 units
● Regular 4 units short acting insulin
● What might happen if the patient skips lunch?
○ Hypoglycemia

The patient with Diabetes self-administers long –acting Glargine (Lantus) insulin in the morning.
The patient then administered rapid-acting Lispro insulin before each meal or snack…
● Lantus doesn’t peak
○ Insulin being secreted for the 24 hours → basal insulin dose
■ Small amount of insulin being secreted 24 hours a day
○ Mimics what our body normally does
● Rapid-acting insulin before meals or snacks to make up for the glucose provided by the
meals & snacks

Insulin ADRs
● Hypoglycemia
○ What are the symptoms of hypoglycemia?
■ Headache
■ Dizziness
■ Confusion
■ Slurred speech
■ Nervousness, tremors, sweating
■ Hungry
■ Fatigued
● Lipodystrophy
○ Lump or dent under the skin, abnormal tissue (scar tissue)
○ Caused from frequent injections in the same place
○ Harmless except that it will impair insulin absorption
● Somogyi Effect
○ Also called rebound hyperglycemia
○ Occurs when the blood sugar drops during the night (undetected hypoglycemia),
and the body responds by releasing hormones such as cortisol to increase the
glucose level
○ When the person awakens, they have hyperglycemia (bc of hormones) and
typically do not realize they had hypoglycemia during sleeping hours
○ Treated with bed-time snack +/- possibly adjusting insulin dose
○ Diagnosed by having pt check blood glucose level in the middle of the night
● Dawn Phenomenon
○ This occurs for everyone.
 ■ When we sleep, hormones are released to help maintain and restore cells
within our bodies.
● Growth hormone, cortisol and catecholamines
■ These hormones cause the glucose level to rise.
■ People with Diabetes Mellitus do not have enough insulin to regulate the
blood glucose
■ They have hyperglycemia upon waking
■ Treated with increasing night-time insulin

Insulin storage
● Refrigerate unopened insulin vials until needed
○ Should NOT ever be in the freezer
● May be kept at room temperature after it is opened
○ For one month
○ Less irritating to the skin if the insulin is at room temperature
● May be kept in the refrigerator after it is opened
○ For up to three months
● Prefilled syringes should be kept in the refrigerator and used within 1-2 weeks
● Avoid direct sunlight or high-temperature areas (or an area of frequent temperative
changes)

Modes of Administration
● Most commonly Sub Q
● Which insulin(s) can be administered IV?
○ Regular U100
● Which insulin can be administered by inhaler?
○ Afrezza
● Sliding Scale Insulin
○ Adjusted doses dependent on individual blood glucose results.
○ Done often in the hospital
● Insulin Pen Injector
○ Contains a disposable needle and insulin-filled cartridge
○ Insulin dose is obtained by turning the dial to the number of insulin units needed.
○ Can be good for kids and older adults who have trouble manipulating syringe
■ But they’re more expensive
● Insulin Pump
○ Small computerized device
○ Includes a tube placed under the skin
○ Can deliver both basal insulin and bolus doses with meals

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Treatment of Type 2 Diabetes

● Is it possible that the patient with Type 2 DM will use insulin? → yes
○ T2D → progressive disorder
○ May also use insulin when they’re sick, injured, times of stress (like in hospital)
 ● Goal in treatment of Type 2 DM…
○ Glycemic control
○ Prevention of long-term complications
○ Weight loss***
■ Most type 2 diabetic patients are overweight
○ Lipid management

Treatment Approach: Type 2 DM

● Four Step Approach (2017 ADA Recommendations)
● Step 1:
○ Newly diagnosed
○ Lifestyle changes + Metformin
● Step 2 (as disease progresses):
○ Continue lifestyle changes & Metformin
○ One additional drug (often sulfonylurea)
● Step 3:
○ Progress to a 3 drug regimen
● Step 4:
○ Include insulin in the regimen
● Should start at step 1 and proceed through steps as needed
○ If A1C is >7.5, should start at step 2
○ Most patients → if A1C is less than 7.5, start at step 1
Antidiabetic Agents Used in the Treatment of Type II DM
**See Prototype Drugs, page 682
● Oral Agents
○ Biguanides
○ Sulfonylureas
○ Meglitinides (Glinides)
○ Thiazolidinediones (Glitazones)
○ Alpha-glucosidase inhibitors
○ DPP4 Inhibitors (Gliptins)
● Non-Insulin Injectable Agents
○ Incretin Mimetics
○ Amylin Mimetics

Biguanides – Metformin (Glucophage)

● Drug of choice for initial therapy in most patients with type 2 Diabetes
○ Usually prescribed immediately after diagnosis
● May be given alone, or in combination with another antidiabetic agent
● New studies are showing that Metformin can prevent diabetes in high risk persons
● Metformin can be used in pregnancy
○ Traditionally only insulin was used in pregnancy
○ Studies have shown Metformin to be equally effective
● MOA:
○ Increases binding of insulin to receptors
○ Decreases the hepatic production of glucose
 ○ Reduces slightly the glucose absorption in the gut
○ Does NOT promote insulin release
■ Does NOT cause hypoglycemia (no risk for it as an ADR)
● Safe to use in patients who occasionally skip meals or eat at irregular intervals
○ Bc it does not promote insulin release
● ADRs
○ Decreases appetite
■ Actually a benefit with many type 2 patients
○ May cause nausea and diarrhea
○ Will not cause hypoglycemia
○ Metformin and Lactic Acidosis
■ Metformin poses the risk of lactic acidosis
● Metformin-induced lactic acidosis has a mortality rate of 50%!
■ With good kidney function, this complication is extremely rare
■ In patients with renal insufficiency, Metformin can rapidly accumulate to
toxic levels and lead to lactic acidosis
● Metformin should be avoided in patients with renal insufficiency
● Consumption of alcohol increases the risk of lactic acidosis
■ IV contrast media that contains iodine may lead to acute renal failure
■ Metformin in combination with contrast media may lead to lactic
acidosis
○ Metformin (Glucophage) should be withheld for 48 hours prior to, and
following administration of contrast media used for diagnostic procedures!

Sulfonylureas
● First oral hypoglycemic available (first drug used for type 2 diabetes)
● MOA
○ Stimulate the release of insulin → can cause hypoglycemia
● Some also increase cellular sensitivity to insulin
● Divided into 1st and 2nd generation categories
○ Both generations are equally effective
○ Second generation agents are more potent, have a longer duration of action, and
have fewer drug-drug interactions
○ Second generation agents have replaced the first-generation agents
● **See table 57-11, page 695
● Second Generation
○ Glipizide
■ (Glucotrol)
○ Glyburide
■ (DiaBeta & Micronse)
○ Glimepiride
■ (Amaryl)
● Sulfonylureas ADRs
○ Hypoglycemia
■ Bc they cause the pancreas to release more insulin
■ Most likely with kidney and liver dysfunction
 ○ If taken with alcohol (EtOH), can cause a disulfiram-like reaction
(Antabuse-like)
■ Flushing, palpitations, nausea
■ Alcohol also enhances the hypoglycemic response
○ Beta-Blockers will diminish the benefit of Sulfonylureas
○ Should be avoided in pregnancy
■ Teratogenic in animals

Alpha-Glucosidase Inhibitors
● Example: Acarbose (Precose, Glucobay)
● MOA:
○ Delays absorption of carbohydrates
■ Acts by blocking the enzyme in the small intestine responsible for
breaking down complex carbohydrates into monosaccharides
■ Does NOT work systemically → systemic side effects rare
● ADRs
○ Will NOT produce hypoglycemia
○ GI side effects common
■ Flatulence, cramps, abdominal distention, diarrhea
○ Can decrease absorption of iron
■ May lead to anemia

Meglitinides (Glinides)
● Examples:
○ Repaglinide (Prandin)
○ Nateglinide (Starlix)
● MOA:
○ Stimulates the release of insulin
● Equal efficacy to the sulfonylureas
● Quick onset, peak, and short duration of action
○ Enables the client to take the medication immediately before eating and skipping
medication if he/she does not eat
○ Patient should eat within 30 minutes of taking med
■ Eating can be more flexible
● Hypoglycemia is a potential adverse effect

Thiazolidinediones (Glitazones)
● Decreases insulin resistance
● Contraversial
● Pioglitazone (Actos)
○ Most common prescribed from this class
● Rosiglitazone (Avandia)
○ Troubled past…
○ Has been withdrawn from the market in Europe
○ At one time had FDA restrictions on prescriptions,
■ Restrictions have now been lifted
 ● Both drugs are contraindicated in clients with heart failure
○ Can expand blood volume and cause edema

Dipeptidyl Peptidase-4 Inhibitors (DPP-4 Inhibitors) (“Gliptins”)

● Example: Sitagliptin (Januvia)
● MOA:
○ Enhances the action of the Incretin Hormones
● What are Incretins??
○ Hormones that are released after eating
○ Stimulate the pancreas to release insulin
■ Stimulate insulin release
○ Inhibits glucagon secretion
○ Slow gastric emptying
○ Suppress appetite
● ADRs
○ Pancreatitis (rare)
■ Should be taught the signs of Pancreatitis
● Severe abdominal pain → if they develop this after taking these
meds, contact provider ASAP
○ Hypersensitivity Reactions (rare)

Non-Insulin Injectable Agents for Type II DM

● Amylin Mimetic
○ Indicated for Type 1 and Type 2 DM
○ Pramlintide
● Incretin Mimetics
○ Type 2 DM only
○ Exenatide (Byetta)
○ Exenatide Once Weekly (Bydureon)

Incretin Mimetic: Exenatide (Byetta)

● Self-Administered SubQ (SQ)
● Used in combination with Metformin or a sulfonylurea
● ADRs
○ Pancreatitis
■ Patients should be instructed on symptoms
● Severe abdominal pain
● Should be instructed to stop the medication with symptoms &
notify provider
○ Hypoglycemia is an adverse effect when combined with the Sulfonylurea, but
NOT with Metformin
■ Sulfonylurea dose needs to be decreased when treatment regimen includes
Exenatide
Amylin Mimetic: Pramlintide (Symlin)
● Drug used to supplement the effects of mealtime insulin in patients with Type 1 and 2
Diabetes
● MOA:
○ Will decrease postprandial (after meal) glucose levels and reduce glucose
fluctuations
● ADRs
○ Hypoglycemia
■ Within 3 hours of injection
■ Insulin doses may need to be reduced

Other medications used in the patient with Diabetes

● ACE Inhibitor/ ARB
○ Reduce the risk of Diabetic Nephropathy progression
○ Prescribed if Albuminuria is present (would indicate kidney problems)
○ May also be prescribed for Hypertension in diabetic patients without Albuminuria
■ Want to protect the kidneys
● Statins
○ Reduce high levels of cholesterol
○ Have been shown to reduce cardiovascular events in patients even with normal
cholesterol levels
○ Can stabilize the atherosclerotic plaques → reduce CV events
● Colesevelam
○ Bile Acid Sequestrant
■ Used in the treatment of high cholesterol
○ Also shown to reduce blood glucose levels
○ Non-absorbable → work only in the GI tract
■ Promotes excretion of bile acids and other substances
○ Seeing more frequently in type 2 diabetics
○ ADRs
■ Constipation
■ Bloating
■ Indigestion
■ Nausea

Treatment of Hypoglycemic Reaction

● Mild Hypoglycemia (Fully conscious)

○ Oral carbohydrate followed by protein foods
■ Life savers, candy, glucose tablets, sugar cubes…
■ Skim milk is often recommended
● Offers the carbohydrate with the protein, easily absorbed, & has
protein in it
○ Nothing should be administered by mouth if the swallowing or gag reflex is
suppressed
 ○ Do NOT want to give a candy with fat in it → fat delays the absorption
○ Carb raises blood glucose level
○ Protein helps maintain (keep) blood glucose level up

● Moderate to Severe Hypoglycemia

○ IV Dextrose (Glucose) (preferred)
■ D50%, D25%, D10%
● Hypertonic solutions
○ Parenteral Glucagon
■ Available by prescription
■ Prefilled syringes
● Administered IM, SubQ (SQ) or IV
■ Releases stored glucose from the liver
● Goes to liver first
■ Requires 10 minutes to start elevating blood sugar
● About 20 minutes to peak & start doing well
■ Patient may vomit after glucagon administration, if unconscious, turn
him/her on her side
■ Drug of choice if we don’t have access to an IV or IV fluids or IV
dextrose

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● If patient could only take one -- lisinopril vs HCTZ → take HCTZ

○ Aspect of protecting the kidney
● Statins pose a risk for rhabdomyolysis
● Lisinopril & low BP can mimic hypoglycemia
● Sulfonylureas, esp Glyburide → can be an issue if the patient doesn’t eat
○ If not eating with it, greater risk of hypoglycemia
○ d/t increased insulin release in the pancreas
● Metformin & glyburide
○ Important to check blood glucose level

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