Insulin

 
Insulin

    NOTE: If you encounter a medical term or value you are not familiar with, check Acronyms and Definitions below for more information.
   
Medical studies - information on the different types of medical studies and terminology used in describing studies is available here.
      ______________________________________________________________________________

      Acronyms and Definitions
        - ADA - American Diabetes Assoc
        - FDA - U.S. Food and Drug Admin.
        - Glucose = Blood sugar
    
   - Glycogen - glucose molecules joined together so that they can be stored for future use
        - OTC - Over-the-counter
      ______________________________________________________________________________
_____________________________________________ 
DRUGS IN CLASS

  Insulin classes
    - Insulins are categorized by how quickly they act (onset of action) and by how long they act (duration)
    - See the StraightHealthcare Insulin Chart for specific characteristics of each insulin (duration, onset of action,
       peak effect, availability, mixing, storage and expiration)

  Rapid-acting insulins
     • Humalog
® (Insulin lispro)
     • Novolog
® (Insulin aspart)
     • Apidra
® (Insulin glulisine)

  Short-acting insulins
     • Humulin R
® (Regular)
     • Novolin R
® (Regular)

  Intermediate-acting insulins
     • Humulin N
® (NPH)
     • Novolin N
® (NPH)
     • Insulin Aspart Protamine (in Novolog Mix
® 70/30)
     • Insulin Lispro Protamine (in Humalog Mix
® 75/25, 50/50)

  Long-acting insulins
     • Lantus
® (Insulin glargine)
     • Levemir
® (Insulin detemir)

  Combination products
    • Novolin
® 70/30 - 70% Novolin N and 30% Novolin R
    • Humulin® 70/30 - 70% Humulin N and 30% Humulin R
    • Humalog Mix® 75/25 - 75% Insulin lispro protamine and 25% insulin lispro
    • Humalog Mix® 50/50 - 50% Insulin lispro protamine and 50% insulin lispro
    • Novolog Mix® 70/30 - 70% Insulin aspart protamine and 30% insulin aspart
_____________________________________________ 
MECHANISM OF ACTION

  Definitions
     ▪ Glucose = blood sugar
    
Glycogen = glucose molecules joined together so that they can be stored for future use

  Physiology
   
- Insulin is a natural hormone secreted by the Beta-cells (also referred to as "islet cells") of the pancreas
    - Insulin is secreted in response to rising blood sugars (after consuming food)
    - Insulin acts primarily on the liver, fat tissue, and muscle tissue

  Liver effects
    - In the liver, insulin stimulates the formation of glycogen from glucose
    - Insulin inhibits the breakdown of glycogen into glucose

  Muscle and fat tissue effects
    - In muscle and fat tissue, insulin promotes the uptake of glucose from the blood stream
     
Muscle tissue converts glucose into glycogen
     
Fat tissue converts glucose into fatty acids for storage as triglycerides
   - Insulin inhibits the release of amino acids from muscle
   - Insulin inhibits the release of free fatty acids from fat tissue [1]

  Types of insulin
    - Insulin can be modified structurally or combined with other chemicals in order to change its
      pharmacological properties (onset of action and duration of action)
    - See PROPERTIES OF DIFFERENT INSULINS below for a description of each insulin
_____________________________________________ 
EFFECTIVENESS

 
Type 1 diabetes
   
- Humans cannot live without insulin
    - Type 1 diabetics do not make insulin and therefore must replace it with insulin injections
    - Type 1 diabetes - full review of Type 1 diabetes

  Type 2 diabetes
    - Type 2 diabetics secrete insulin, but they do not secrete enough to control their blood sugars
      Type 2 diabetics can take medications that do the following:
       
▪ Stimulate more insulin secretion
        ▪ Increase liver, fat, and muscle tissue sensitivity to insulin
    - When these medications are not effective, Type 2 diabetics often have to use insulin
    - Type 2 diabetes - full review of Type 2 diabetes

_____________________________________________ 
COMMON AND/OR SIGNIFICANT SIDE EFFECTS

  Low blood sugar (hypoglycemia)
    - Too much insulin can cause hypoglycemia
    - Hypoglycemia - review of hypoglycemia and its treatment

  Changes in fat tissue (lipodystrophy)
    - At sites where insulin is repeatedly injected (abdomen, upper arm, thigh), fat tissue may undergo changes
   
Lipoatrophy
      - Lipoatrophy is thinning of fat tissue at the sites of injection
      - Lipoatrophy is thought to be caused from an immune reaction
      - Lipoatrophy is not common anymore with the introduction of purified, human insulins (insulin used to
         come from pig and cow pancreases) [7]
   
Lipohypertrophy
      - Lipohypertrophy is thickening of the fat tissue at the sites of injection
      - Lipohypertrophy is characterized by soft bumps that form underneath the skin
      - In some studies, lipohypertrophy occurs in up to 50% of diabetics who inject insulin [3,4]
       Factors associated with the development of lipohypertrophy include:
        ▪
Years of insulin use
        ▪ Frequency of injection site change
        ▪ More daily injections [3,4]
      - Sites of lipohypertrophy often lose sensation, causing diabetics to prefer these sites which can
         make the problem worse
      - Treatment for lipohypertrophy is to rotate injection sites and hope for regression
      - If regression does not occur, liposuction may be necessary to remove cosmetically unacceptable growths [2]

  Injection site reactions
    - Localized redness, itching, pain, and swelling may occur at the injection site (about 2-3% of patients)
    - These reactions tend to begin 8 - 12 hours after insulin injection and peak at 24 - 48 hours
    - These reactions typically resolve in a few weeks
    - Rotating the site of injection can help [5]

  Low potassium (hypokalemia)
    - Insulin causes cells to take up potassium thus lowering blood levels of potassium
    - This is typically only an issue when insulin is given intravenously [6]

  Insulin antibodies
    - All insulins have the potential to induce an immune response
    - The immune response can lead to the production of antibodies against the insulin
    - This was a larger issue with older insulins (derived from pigs and cows), but modern insulins still have
       the potential for antibody production
    - Theoretically, insulin antibodies might decrease insulin effectiveness and increase insulin resistance
    - Studies evaluating this effect have not found an association between the presence of insulin antibodies
       and insulin resistance (decreased effectiveness) [7]

  Weight gain
    - Insulin therapy can induce weight gain in many patients (4 - 9 pounds on average)
    - This effect is due to the increased utilization of glucose by the body [8]

  Swelling of the feet and legs (edema)
    - In rare cases, insulins may cause acute swelling of the feet and legs
    - This is more common in poorly-controlled patients who are started on sudden, intense insulin regimens [5]

  Nerve pain (treatment-induced neuropathy)
    - Long-term, uncontrolled diabetes is associated with the development of nerve pain or nerve loss (neuropathy)
    - Another neuropathy syndrome that is seen less frequently involves the development of neuropathy after
       the initiation of insulin therapy
    - This syndrome is sometimes called "insulin neuritis" or "treatment-induced neuropathy"
    - The syndrome is typically seen when a person with uncontrolled blood sugars is treated with insulin, and their
       blood sugars rapidly come under control
    - Neuropathy typically develops within 6 weeks of rapid control
    - Neuropathy may be associated with signs of autonomic dysfunction including orthostatic hypotension (low blood
       pressure on standing) and diabetic gastroparesis (slow stomach emptying)
    - Diabetic retinopathy may also worsen (see below)
    - The neuropathy typically resolves over a period of months
    - The ideal treatment of "treatment-induced neuropathy" has not been determined
    - Medications used in typical, chronic neuropathy may be helpful [9]
  
StraightHealthcare analysis:
     - A small percentage of patients with chronic, uncontrolled blood sugars who rapidly come under control may
       experience treatment-induced neuropathy
     - The syndrome can take months to resolve, and these patients may benefit from medications used in typical
       diabetic neuropathy

  Eye changes
   
Diabetic eye disease (Retinopathy)
      - Improved blood sugar control over the long run lowers the risk of diabetic eye disease (retinopathy)
     
- However, in some studies, when insulin is initiated and blood sugars are improved rapidly, retinopathy has been
        shown to worsen over the short term (up to 18 months), and then improve [10,11]
     
StraightHealthcare analysis:
       - Some patients appear to experience early worsening of diabetic retinopathy after the initiation of insulin and
         subsequent improvement in blood sugar control
       - In the long-term, diabetic retinopathy is improved by better blood sugar control
       - Previously uncontrolled diabetics who achieve significant blood sugar improvement after starting insulin should
         make sure they get their yearly retinal exam
   
Lens changes
      - For diabetics with uncontrolled blood sugars, treatment changes (ex. starting insulin or other meds) that bring
         blood sugars rapidly under control can cause changes in the lens of the eye
      - These lens changes can cause temporary farsightedness (hyperopia) and blurred vision
         In one review of 14 patients affected by the condition, the following characteristics were seen:
          
▪ Visual changes started 1 - 7 days (average 3.4 days) after new therapy was initiated
           ▪ Maximum visual change occurred at 10 days on average
           ▪ Vision returned to normal at an average of 44.7 days (range 14 - 84 days) after therapy was started [12]
    StraightHealthcare analysis:
      - Diabetics who go from poor blood sugar control to good control quickly should be aware that they may
         experience temporary visual changes
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LANTUS AND CANCER RISK

  Lantus® and cancer
  - In July of 2009, the FDA issued a warning to healthcare providers that three recently published studies had shown
     a possible increase in cancer risk among patients using Lantus
  - Four studies have been published in Diabetologia that have evaluated the association between cancer and various
     diabetes treatments (Diabetologia is the journal of the European equivalent of the ADA)
  
UK study
      - The UK study was a cohort study involving 62,809 diabetics that looked at the risk of cancer among users
        of different diabetes medications
      - Information was derived from a UK medical database
     After an average follow-up of 2.4 years, the following was seen:
      ▪ The risk of cancer for patients taking metformin was not significantly different from diabetics
         taking no medications
      ▪ Patients taking sulfonylureas had a 35% increase in relative risk for cancer compared to
         patients taking metformin
      ▪ Patients using insulin-based therapies had a 42% increase in relative risk for cancer compared to patients
         taking metformin
      ▪ Compared to other insulins, Lantus did not confer a greater risk [13]
    German study
      - The German study was a cohort study involving 127,031 diabetics who had their diabetes treated
        with only one type of insulin (the majority of patients were also taking oral diabetes meds)
      - The information was derived from a large medical database in Germany
      After an average follow-up of 1.63 years, the following was seen:
       ▪ The study found that compared to regular insulin, Lantus was associated with a dose-related increase in
          risk for cancer
       ▪ Patients on Lantus doses of > 40 units a day had a 59% increase in relative risk for cancer compared
          to regular insulin
       ▪ Patients on Lantus dose ≤
40 units a day did not have a significant increase in risk for cancer
       ▪ Novolog and Humalog were not associated with an increase in risk [14]
          NOTE: Cancer rate was 5.26 cancers per 100 people a year in Lantus group compared to 3.1 cancers per 100 people a year
                      in the regular insulin group.
   Scottish study
      - The Scottish study was a cohort study involving 36,254 diabetics who had been treated with insulin
      - The information was derived from a Scottish medical database
       After a follow-up of 26 months, the following was seen:
         ▪ The study found a borderline nonsignificant effect (p=0.057) on overall cancer incidence when Lantus users
           were compared to other insulin users
        
▪ Patients that used Lantus with other insulins did not have an increased risk [15]
    Swedish study
      - The Swedish study was a cohort study involving 114,841 diabetics who had been prescribed insulin
      - The information was derived from a Swedish medical database
       After a follow-up of 2 years, the following was seen:
        ▪ There was no significant difference in total cancers between users of Lantus and other insulins
        ▪ Lantus users had a significantly higher risk of breast cancer compared to users of other types of
           insulin (relative risk increase 97%)
        ▪ Patients that used Lantus in combination with other types of insulins did not have an increased risk for
           any type of cancer [16]
           NOTE: Cancer rate was 5 breast cancers per 1000 people a year in Lantus group compared to 2.6 breast cancers per 1000 people
                       a year in the other insulin group.
    Professional Guidelines:
      - The FDA states that at this time, they have not determined whether Lantus® increases the risk for cancer
      - They recommend doctors and patients continue to use Lantus® as directed in the product label
      - The FDA's official statement can be read here - CLICK HERE
    StraightHealthcare analysis:
      - The 4 cohort studies in Diabetologia are intriguing, but must be regarded with caution
      - Cohort studies are weaker studies when compared to randomized controlled trials, because there is no way to
        randomize patients and control for all types of confounding (ex. it may be that sicker, less-healthy patients in
        general end up on Lantus
, and therefore Lantus is merely a marker of a sicker, less-healthy patient)
      - Another weakness of these studies is that the data was all derived from medical databases which can have
        many limitations
      - Ongoing studies will hopefully shed some light on a possible association
      - At this time, patients should discuss with their doctors whether the possible risk of cancer with Lantus
        outweighs its benefits
_____________________________________________ 
COMMON AND/OR SIGNIFICANT DRUG INTERACTIONS
 NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to
            encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or
            pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.

  METABOLISM
    - There are no known direct drug interactions with insulin

 
MEDICATIONS THAT EFFECT BLOOD SUGARS

    Drugs that may increase the effect of insulin:
       ▪ Other diabetic medications  - sulfonylureas, GLP-1 analogs, metformin, alpha-glucosidase inhibitors,
                                                   meglitinides, DPP-4 inhibitors, cycloset, glitazones, pramlintide
       ▪ ACE inhibitors - effect not well-defined
       ▪ Beta blockers with alpha-1 blocking activity - carvedilol, labetalol
       ▪ Fluoxetine (Prozac®) - effect not well-defined
       ▪ Sulfa antibiotics - effect not well-defined

    Drugs that may decrease the effect of insulin:
       ▪ Antipsychotics - olanzapine (Zyprexa®), clozapine(Clozaril®), risperidone(Risperdal®), etc.
       ▪ Beta blockers - (excluding carvedilol and labetalol)
       ▪ Corticosteroids  - prednisone, Medrol®, Kenalog®, etc.
       ▪ Danazol
       Niacin 
       ▪ Steroid contraceptives - birth control pills, Depo-Provera®, etc.
       Statins
       Thiazide diuretics
       ▪ Thyroid hormone
_____________________________________________
LONG-TERM SAFETY
 
- Humans cannot live without insulin so it must be replaced when needed
  - A long-term safety concern has arisen with Lantus, the see LANTUS AND CANCER RISK below
_____________________________________________ 
COMMON MEDICAL CONDITION PRECAUTIONS
NOTE: Medical condition precautions presented here are NOT all-inclusive. Other conditions where these medications may be unsafe
            may exist. Always consult your physician or pharmacist before taking any medication.


  Kidney disease
    - In some patients, worsening kidney function can increase the levels and subsequent effects
      of insulin (hypoglycemia)
    - This is typically seen at the very end stage of kidney disease
    - Patients with significant kidney disease should monitor blood sugars closely and be aware that dose
      adjustments may be necessary

  Liver disease
    - In some patients, worsening liver function can increase the levels and subsequent effects of
       insulin (hypoglycemia)
    - This is typically seen at the very end stage of liver disease
    - Patients with significant liver disease should monitor blood sugars closely and be aware that dose
      adjustments may be necessary
_____________________________________________ 
DOSING
  - There are many different ways to dose insulin
  - Full review of insulin dosing
_____________________________________________ 
PROPERTIES OF DIFFERENT INSULINS

  Insulin chart
    - We have created the StraightHealthcare insulin chart that includes all the available insulins
     The chart has the following information:
     ▪ Onset of Action
     ▪ Duration of action
     ▪ Peak effect
     ▪ Availability (vials, pens, etc)
     ▪ Mixing guidelines
     ▪ Storage guidelines

  Insulin synthesis
   
Apidra® (Insulin glulisine)
      ▪ Synthesized from genetically-altered E. Coli bacteria
     
▪ Apidra is identical to human insulin except that 2 amino acids have been altered
   
Humalog® (Insulin lispro)
      ▪ Synthesized from genetically-altered E. Coli bacteria
     
▪ Humalog is identical to human insulin except that 2 amino acids have been reversed
     
▪ Insulin lispro protamine is a combination of insulin lispro with protamine
     
▪ Insulin lispro protamine is absorbed more slowly and acts longer
   
Humulin N® (NPH)
      ▪ Synthesized from genetically-altered E Coli bacteria
     
▪ Humulin N is identical to human insulin
     
▪ Humulin N is combined with protamine and zinc so that it is absorbed more slowly and acts longer
   
Humulin R® (Regular)
      ▪ Synthesized from genetically-altered E Coli bacteria
     
▪ Humulin R is identical to human insulin
   
Novolog® (Insulin aspart)
      ▪ Synthesized from genetically-altered Saccharomyces cerevisiae (baker's yeast)
     
▪ Novolog is identical to human insulin except that 1 amino acid has been changed
     
▪ Insulin aspart protamine is a combination of insulin aspart with protamine
     
▪ Insulin aspart protamine is absorbed more slowly and acts longer
   
Lantus®  (Insulin glargine)
      ▪ Synthesized from genetically-altered E. Coli bacteria
     
▪ Lantus is identical to human insulin except that 1 amino acid has been changed and 2 have been added
   
Levemir®  (Insulin detemir)
      ▪ Synthesized from genetically-altered Saccharomyces cerevisiae (baker's yeast)
     
▪ Levemir is identical to human insulin except that 1 amino acid has been omitted and a fatty acid chain
        has been attached
   
Novolin N® (NPH)
      ▪ Synthesized from genetically-altered Saccharomyces cerevisiae (baker's yeast)
     
▪ Novolin N is identical to human insulin
     
▪ Novolin N is combined with isophane so that it is absorbed more slowly and acts longer
   
Novolin R® (Regular)
      ▪ Synthesized from genetically-altered Saccharomyces cerevisiae (baker's yeast)
     
▪ Novolin R is identical to human insulin
                        [Reference: Manufacture's Package Inserts]
_____________________________________________
INSULIN MIXES

  Insulin mixes
    - Insulin mixes contain two different types of insulin
    - One of the insulins is a short or rapid-acting insulin, and the other insulin is an intermediate-acting insulin
    - Insulin mixes are typically injected before meals
     The two types of insulins work together in the following way:
     
▪ The rapid- or short-acting insulin is active during and immediately after the meal
      ▪ The intermediate-acting insulin acts later to keep blood sugars down between meals

    Available insulin mixes include:
     • Novolin
® 70/30 - 70% Novolin N and 30% Novolin R
     • Humulin® 70/30 - 70% Humulin N and 30% Humulin R
     • Humalog Mix® 75/25 - 75% Insulin lispro protamine and 25% insulin lispro
     • Humalog Mix® 50/50 - 50% Insulin lispro protamine and 50% insulin lispro
     • Novolog Mix® 70/30 - 70% Insulin aspart protamine and 30% insulin aspart

  Calculating insulin amount
      - To calculate the amount of each insulin in a dose, take the total dose and multiply by the percentage of each
         insulin in the product.
                         Example:
                                 60 units of Novolin 70/30 contains:
                                 Novolin 70/30 has 70% NPH therefore 60 units X 0.70 = 42 units of NPH
                                 Novolin 70/30 has 30% Regular therefore 60 units X 0.30 = 18 units of Regular
_____________________________________________
INSULIN PUMP
  - An insulin pump is a device that attaches to a patient's abdomen
  - It has a needle that is inserted into the subcutaneous space under the skin (the same space an insulin injection is
     given)
  - The pump delivers a continuous flow of insulin to the patient at a rate that is adjustable
  - The pump can also be instructed to give larger, one-time doses of insulin if needed (a bolus)
  - Insulin pumps require a high degree of maintenance and attention, and thus are typically reserved for very
     motivated patients
  - They are mostly used in Type 1 diabetics, and less often in Type 2 diabetics
  - They are filled with either rapid or short-acting insulin
_____________________________________________
GENERICS

  Generic insulin
    - Insulins are caught in the FDA's Neverland of "biologic drugs" meaning they do not fall under the Hatch-Waxman
       Act (like most drugs)
    - The FDA has yet to clarify how generic drug companies can make and submit generic insulins for approval
    - Patents have expired on a number of insulins, but until the FDA issues guidance for generic drug makers, no
       generics can be approved.

   
Expired patents: Humulin N and R, Novolin N and R

   
Future patent expirations:
                                                        DRUG         PATENT EXPIRES
                                                       Lantus
®             Feb 2015
                                                       Levemir
®          Feb 2014
                                                       Apidra
®             Jun 2018
                                                       Novolog
®          Dec 2014
                                                       Humalog
®        May 2013

  Note: Drug companies typically file multiple patents on their drugs in order to protect them from competition. The patent expiration
           listed here is the date that the earliest patent on the drug expires (accounting for pediatric exclusivity). Because drug companies
           use numerous techniques to extend  the life of their patents, it does not necessarily mean a generic will become available
           around this date.
_____________________________________________
COST SAVING OPPORTUNITIES

  - Walmart® and Elly Lilly® have teamed up to offer Humulin R
®, Humulin N®, and Humulin® 70/30
     afor about $25 a vial
  - They are marketed under the name ReliOn
®
  - They are exactly the same as the Humulin® products
  - To visit their website -  CLICK HERE
  - Switching to one of these cheaper insulins may be an option for some people
  - Dosing and effect can vary greatly between insulin products, so you should consult your physician before making
     any changes to your insulin regimen
_____________________________________________
OVER-THE-COUNTER INSULIN
 
- In many U.S. states, insulin can be bought over-the-counter (without a prescription) at pharmacies
 
- Over-the-counter insulin is typically limited to Regular, NPH, and the NPH/Regular 70/30 mixes
 
- The availability of over-the-counter insulin is intended to help diabetics in a bind or emergency
  - A simple way to find out if a state allows over-the-counter insulin is to call a pharmacy in that state
_____________________________________________
RECENT STUDIES INVOLVING INSULINS
 
• None
_____________________________________________
BIBLIOGRAPHY

  Bibliography        What is [PMID?]    PI = Manufacturer's Package Insert

#    PMID
1 -  20821847
2 -  14507228
3 -  17303282
4 -  11874968
5 -  Lantus PI
6 -  Novolog PI
7 -  17785428
8 -  18945920
9 -  20437589
10 - 15309288
11 - 7826293
12 - 11004091
13 - 19572116
14 - 19565214
15 - 19603149
16 - 19588120
17 - 16847295
18 - 15855574
19 - Humalog PI


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