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Michigan Association of Osteopathic Family Physicians

Mid-Winter Family Medicine Update

Shanty Creek Resort, MI

January 19-22nd 2017

Michael R. Brennan D.O., M.S., F.A.C.E.

Director Beaumont Endocrine Center

Chief Endocrinology, William Beaumont Hospital Grosse Pointe

Type 2 Diabetes:

A New Approach in a New Era of Therapies

Conflict

• I’m married to a drug representative and she works for Novo Nordisk

• Makers of liraglutide (Victoza), aspart (NovoLog), determir (levemir), 70/30 mix insulin (NovoLog and Novolin 70/30), degludec (Tresiba), repaglinide (Prandin), glucagon (GlucaGen HypoKit), estradiol vaginal tablets (Vagifem), estradiol/norethindrone (Activella), somatropin (Norditropin), coagulation factor VIIIa (NovoSeven)

• I’m a consultant on insulin pumps and lead groups for the Insulet Corporation• They make an insulin delivery system (pod/pump)

called the Omni Pod

Resources

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Resources

Resources -https://www.aace.com/publications/algorithm

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Objectives

• Understand the pathophysiology and prevalence

of type 2 diabetes

• Describe new classes of medication to treat type

2 diabetes

• To learn about concentrated insulins, and a new

form of long acting insulin

• Know the current approach and strategies to

treat type 2 diabetes

2017 ADA Diagnostic Criteria

Diagnostic Studies for Diabetes risk (Pre-Diabetes) or Diabetes

Diagnostic TestIncrease Risk for

Diabetes (Pre-diabetes)Diabetes

Fasting plasma glucose (mg/dL) 100-125 ≥126

Plasma glucose 2hr post 75 gram

oral glucose tolerance test (mg/dL)140-199 ≥200

Hemoglobin A1c (%) 5.7-6.4 ≥ 6.5

Classic symptoms of diabetes or

hyperglycemia crisis random

plasma glucose (mg/dl)≥200

Hemoglobin A1c

• The test measures what percentage of your hemoglobin is coated with sugar (glycated) for the past 2-3 months

• The higher your A1C level, the poorer your blood sugar control and the higher your risk of diabetes complications

• The A1c value is a summation of the fasting and post prandial glucose over the period of months

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Hemoglobin A1c

A1C level (%) Estimated average blood glucose (mg/dl)

5 97

6 128

7 154

8 183

9 212

10 240

11 269

12 298

13 326

14 355

Types of Diabetes

• Type 2 Diabetes

• Type 1 Diabetes and Latent-onset Autoimmune Diabetes of Adulthood

• Gestational Diabetes

• Monogenic DM (formerly Maturity Onset Diabetes of the Young, e.g. MODY)

• Type 3 – A category of diabetes that is a secondary form of diabetes. e.g. pancreatitis, cystic fibrosis, or glucocorticoid induced

Beta Cell Function

• Type 2 diabetes is hallmarked by the body

systemically having insulin resistance, and

therefore at first insulin excess

• Type 1 diabetes is defined by the body having

beta cell destruction, and therefore insulin

deficiency

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Type 2 Diabetes (T2DM)

• The most common form of DM, accounting for more than 90% of cases

• Typically identified in patients older than 30 years who are overweight or obese and/or have a positive family history, but do not have auto antibodies (characteristic of type 1)

• Most persons with T2DM have evidence of insulin resistance (such as high triglycerides or low high-density lipoprotein cholesterol [HDL-C])

The Diabetes Epidemic in the United States

In 2012, 29.1 million Americans or 9.3% of the U.S. population had diabetes (in 2010 it was 25.8 million or 8.3%)

In 2012, among U.S. residents age 65 and older, 25.9% had diabetes

By 2050 it is estimated that 1 in 3 people in the U.S. will have diabetes

–http://www.diabetes.org/diabetes-basics/statistics/

–http://www.cdc.gov/chronicdisease/resources/publications/AAG/ddt.htm

Simple Description of T2DM

Gerich JE. Mayo Clin Proc. 2003;78:447-456

outpatient.aace.com/sites/all/files/T2DM-S2-Clinical-Presentation.pptx

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Transition to T2DM

Figure courtesy of CADRE.

Adapted from Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25;

Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med. 2002;347:1342-1349; UKPDS Group. Diabetes. 1995;44:1249-1258

outpatient.aace.com/sites/all/files/T2DM-S2-Clinical-Presentation.pptx

2017 ADA Approach

2016 AACE Approach

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Where is your intervention in the

progression of diabetes?

Spectrum of Diabetes Type of Prevention

No disease

Impaired fasting glucose/impaired glucose tolerance

Primary

Diagnosis of Diabetes Secondary

Complications of Diabetes Tertiary

Death

What’s Your Approach To T2DM Treatment?

• Pathophysiologic approach to correct the core defects with T2DM? -Preferred!!!!!

• Treat with an agent until failure by A1C readings?

What approach you chose is based on several variables, i.e. your familiarity with the medicine, patient age and comorbidities, insurance, formulary, cost, medication side effects, patient adherence, etc…

Ideal Treatment

• Try to select complimentary anti-diabetes agents that correct specific pathophysiologic disturbances present in T2DM

• Treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing HbA1c

• Early treatments can prevent/slow progressive beta cell failure/T2DM

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Declining to Diabetes

• Diabetes occurs partially because of beta cell failure

• It appears that with beta cell decline, multiple pathophysologic events happen simultaneously

• In 2008, Dr. DeFronzo of University of Texas coined the term the “ominous octet” to describe the eight major known players thought to exacerbate diabetes

“Ominous Octet”• Beta cell failure

• Insulin resistance in

muscle

• Adipocyte resistance to

insulin’s antilipolytic

effect

• Decreased incretin effect

• Insulin resistance in liver

• Increased glucagon secretion by

Alpha cells & enhanced hepatic

sensitivity to glucagon

• Enhanced glucose renal

reabsorption

• Central nervous system Insulin

resistance

Defranzo RA, Diabetes. 2009;58, 773-95

Further Pathways of Beta Cell Decline

• 8 years to think about it, and several studies

later the ominous octet becomes named the

“egregious eleven” by the work of Dr. Stanley

Schwartz of University of Pennsylvania

Diabetes Care 2016 Feb; 39(2): 179-186. http://dx.doi.org/10.2337/dc15-1585

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“Egregious Eleven”

• Beta cell failure

• Insulin resistance in

muscle

• Adipocyte resistance to

insulin’s antilipolytic

effect

• Decreased incretin

effect

• Insulin resistance in liver

• Increased glucagon

secretion by Alpha cells &

enhanced hepatic

sensitivity to glucagon

• Enhanced glucose renal

reabsorption

• Central nervous system

Insulin resistance

• Increased

inflammation and

immune dysregulation

• Colon/Microbiom

dysregulation

• Stomach and small

intestine increased

absorption of glucose

Diabetes Care 2016 Feb; 39(2): 179-186. http://dx.doi.org/10.2337/dc15-1585

T2DM Treatment

• If no intervention occurs and beta cells are

destroyed, then all roads lead to insulin

• Insulin is a miracle medicine and will arguably

always work, but some caveats exist

The Medications for T2DM Treatment

• ALL approaches begin with metformin, if

possible

• ALL approaches end with insulin, if possible

• What pharmacological agents are used between

metformin and insulin is your clinical decision

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All T2DM Treatment Drug Classes (13)

• Metformin (MET)

• Alpha-Glucosidase Inhibitors (AGI)

• Amylin Mimetic (AM)

• Bile Acid Sequestrants (BAS)

• Dipeptidyl peptidase-4 inhibitor

(DPP-4i)

• Dopamine-2 Agonist (D2A

• Glucagon-like peptide-1 (GLP-1)

• Inhaled insulin (II)

• Meglitinides (GLN)

• Thiazolidinedione(TZD)

• Sodium-glucose transporter-2 inhibitor (SGLT-2i)

• Sulfonylurea (SU)

• Subcutaneous Insulin (SI)

T2DM Treatment Drug Classes To Know

Metformin (MET)

Dipeptidyl peptidase-4 inhibitor (DPP-4i)

Glucagon-like peptide-1 (GLP-1)

Sodium-glucose transporter 2 inhibitor (SGLT-2i)

Subcutaneous Insulin (SI) – This lecture focusing on concentrated insulin

ADA Approach 2017

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Metformin

• Always first line therapy

• Rarely controls HbA1c over time by itself

• Contraindicated: Renal disease or renal dysfunction with GFR < 30 or Creatinine >1.4-1.5

• Lactic acidosis potential concern with kidney injury

• Provides a weight neutral/loss benefit

• Does help correct the pathophysiologic components of the ominous octet

• HbA1c drop approximately 0.5-1%.

Beta Cell Function – the “incretin effect”

Nauck et al. Diabetologia. 1986;29:46–52.

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The Incretin Effect

• The hormone Glucagon Like Peptide-1(GLP-1)

is currently the best know agent responsible for the

incretin effect

• It is the understanding of the GLP-1 hormone

receptors and its metabolism/breakdown by which

the GLP-1RA and DPP-4i drug classes work

Glucagon Like Peptide-1 Receptor Agonist

(GLP-1 RA)

• Albiglutide (Tanzeum)

• Dulaglutide (Trulicity)

• Exenatide (Byetta)

• Exenatide Extended release (Bydureon)

• Liraglutide (Victoza)

• Lixisenatide (Adlyxn) – Use in U.S.A 2017/18

GLP-1 Receptor Agonist

Disadvantages:

• Requires an injection

• Used to have limited formulary coverage

(Greatly improved recently)

• Can have GI difficulty

• Black box warning for medullary thyroid

carcinoma in rats

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GLP-1 Receptor Agonist

Advantages:

• Restore beta cell glucose sensitivity

• May replenish beta cell insulin stores, and may cause beta cell proliferation

• Appears to slow gastric empting and cause satiety

• Inhibit glucagon secretion

• Cause weight loss

• Minimal to no hypoglycemia

• Estimated A1c decline 0.5 to 1.5%

Dipeptidyl peptidase- 4 inhibitor (DPP- 4i)

• Aloglipitin (Nesina)

• Linagliptin (Trajenta)

• Saxaglipitin (Onglyza)

• Sitagliptin (Januvia)

DPP- 4 Inhibitor

Disadvantage:

• The effect of the drug depends on endogenous

GLP-1 quantity

• Used to have limited formulary coverage

(Greatly improved recently)

• Every formulation, except linagliptin, requires

adjustment based on renal function

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DPP- 4 Inhibitor

Advantages:

• Restores Beta cell glucose sensitivity

• Appears to slow gastric emptying

• Inhibit glucagon secretion

• Weight neutral

• Minimal to no hypoglycemia

• Estimate A1c decline 0.5-1.0%

GLP-1 Receptor Agonists vs. DPP-4 Inhibitors

GLP-1 RA DPP-4i

Injection Oral

SupraphysiologicLimited by endogenous GLP-1

level

Large A1c decline Moderate A1c decline

Weight Loss Weight Neutral

GI upset, Black box warningSome renal adjustment, well

tolerated

Sodium Glucose Transporter 2 Inhibitors (SGLT2-i)

• Canagliflozin (Invokana)

• Dapagliflozin (Farxiga)

• Empagliflozin (Jardiance)

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SGLT-2 Inhibitor

Disadvantages:

• Not recommended for prescribing to people with kidney disease as kidney disease prevents the drug from working

• Increase urinary tract yeast infection

• Clinical trials display possible liver damage as well as breast and bladder cancers (not high enough degree to indicate a clear increase in risk)

• Questionable induction of DKA

SGLT-2 Inhibitor

Advantages:

• Work by preventing the kidneys from reabsorbing glucose back into the blood stream

• Increase insulin sensitivity in muscle and in liver tissue

• Decrease gluconeogenesis

• Weight neutral or loss

• Estimate A1c decline 0.5-1.0%

Insulin Injections

General clinical classes of insulin:

• Rapid

• Regular

• Mix

• NPH

• Basal

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Insulin Injections

Disadvantages:

• Possible weight gain

• In type 2 diabetes, treating a hyper insulinemic state with more insulin may beget macrovascular disease

• Hypoglycemia

• Injections are considered by some patients and physicians to require more maintenance

Insulin Injections

Advantages:

• All roads lead to insulin once all other methods have failed

• Improved glucose storage

• Decreased glucagon production

• Decreased hepatic glucose production

• Universally effective

• Estimate A1c decline = can always get to goal

Introduction To Concentrated Insulin

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A Unit Of Insulin

• 1 unit of insulin is approximately 50 micrograms of

crystalline insulin

• This “unit” was termed by Dr. Fredrick Banting (One of

two people who won the Nobel Prize for the discovery of

insulin)

• This unit of insulin would lower a fasting rabbit’s blood

sugar approximately 50 mg/dL

The term U

• The “U” represents the amount of a particular enzyme

(e.g. U/ml). Written on an insulin vial, it describes the

number of insulin units (or concentration) in one 1ml or

1cc of fluid

Therefore:

• U-100 is 100 units of insulin per 1 ml or cc

• U-200 is 200 units of insulin per 1 ml or cc

• U-300 is 300 units of insulin per 1 ml or cc

• U-500 is 500 units of insulin per 1 ml or cc

1 Unit of Insulin

• 1 unit of insulin in the United States comes in a variety of

fluid concentrations (U-40, U-80, U-100, U-200, U-300

and U-500)

• The most commonly used concentration of insulin in

clinical medicine today is the U-100 insulin concentration

• U-500 first entered the U.S. market in 1952 to address

patients with diabetes requiring high dose insulin therapy

• In 1952 patients with diabetes requiring high insulin

doses were those with antibodies to pork insulin

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Which Has More Insulin?

1 Unit Of U-100 Insulin Or 1 Unit Of U-500

Insulin?

Answer: They are the same!

Akin to the following:

Which weighs more?

A pound of feathers or a pound of

bricks?

Both are a pound

Point of Confusion – U-100 syringe

Point of Confusion

In the US, insulin syringes were designed for U-100 insulin. If any concentration of insulin other than U-100 is drawn into an insulin syringe, then it WOULD NOT correlate with the demarcated dose

A thought experiment for example: Draw the insulin up in the syringe to the 10 unit line…

• If drawn up with U-100 then the dose is 10 units

• If drawn up with U-200 then the dose is 20 units

• If drawn up with U-300 then the dose is 30 units

• If drawn up with U-500 then the dose is 50 units

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Points of Clarity – U-100 and U-500 syringe

No Longer A Point Of Confusion

To stop this confusion of dosing concentrated insulins, the pharmaceutical industry created pens to help the patient, the pharmacist, the nurse, and the prescriber

When administering with a concentrated insulin pen, the dose on the pen is the amount of insulin the patient will receive

Example: Take 50 units of U-200 insulin in the pen. The patient simply places the pen to 50 unit mark and administers dose (the proper volume is administered by the pen)

Concentrated Insulin Today

Concentrated Insulin – Insulin resistance can be

so severe that the volume of the insulin injection

can be overwhelming. Therefore, the units of

insulin can be manufactured and delivered in a

smaller volume.

• U-500 Regular (Humulin R)

• U-300 Glargine (Toujeo)

• U-200 Lispro (Humalog)

• U-200 Degludec (Tresiba)

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Regular U-500 also known as Humulin R U-500

Used for meals and/or basal insulin

Recent FDA approval now available in a prefilled pen

Each pen contains 3mL of fluid and 1,500 units

Warning! This insulin is available in both pens and vials

Regular U-500 also known as Humulin R U-500

Lispro U-200 also known as Humalog U-200

• Concentrated version of rapid mealtime insulin

• Each pen contains 3mL of fluid and 600 units

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Lispro U-200 also known as Humalog U-200

Glargine U-300 also known as Toujeo

Concentrated version of a basal insulin

Each pen contains 1.5 mL of fluid and 450 units

Glargine U-300 also known as Toujeo

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Degludec U-100 and U-200 also known as

Tresiba U-100 and U-200

• New class of basal insulin (1st one in a decade)

• Half life is 25 hours, with 42+ hours of clinical

duration of action

• U-100 pen holds 3mL of fluid and 300 units

• U-200 pen holds 3mL of fluid and 600 units

Degludec U-100 and U-200 also known as

Tresiba U-100 and U-200

Advantages:

• Has a better clinical effect by having less

variability, less hypoglycemia, and less stringent

dosing time

• Because of the afore mentioned effects, it

appears that it is a more clinically appropriate

basal insulin

Degludec U-100 and U-200 also known as

Tresiba U-100 and U-200

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Degludec (Treisba) U-100 and U-200

So Why Use Concentrated Insulin?

This is generally for patients receiving greater than 60 units of U-100 insulin per injection

• There may be better absorption and physiologic effect

• Potentially, less pain with injection

• Likely, less loss of insulin with injection

• Patient may get more insulin for the same price

New Mix! Long acting insulin plus GLP-1

Insulin Glargine plus Lixisenatide (Soliqua 100/33)

• Both are once a day injection formats to manage Type 2 diabetes

• One drug takes care of lack of Basal glucose control

• Glargine

• One drug takes care of lack of post prandial control• Lixisenatide

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New Mix! Long acting insulin plus GLP-1

Insulin Glargine plus Lixisenatide (Soliqua 100/33)

Clinical Application

Current Applications For T2DM

(After METFORMIN)

• Use a weight neutral, and beta cell preservation

strategy

• Be familiar with at least one agent of the

following classes:

• DPP-4i

• SGLT-2i

• GLP-1RA

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Not a Good Combination

(After METFORMIN)

• GPL-1RA and DPP-4i are NOT given together

• Both work in the incretin pathway

Theoretical Combinations (AFTER

METFORMIN)

• Add one of the following either a GLP-1 RA,

SGLT-2i, or DPP-4i

• If still not to goal

• Try combination either GLP-1 RA and SGLT-2i,

or DPP-4i and SGLT-2i

• If still not to goal, consider

thiazolidinedione(TZD), alpha-glucosidase

inhibitors(AGI) or insulin

Best Approach

• Great T2DM therapeutic approaches improve the following:

• Long lasting tolerability

• Glucose lowering efficacy

• Have a weight loss effect

• Improve blood pressure

• Decrease lipid profile

• Provide cardiovascular protection

• Decrease side effects (e.g. particularly hypoglycemia)

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In Conclusion

• Once T2DM is diagnosed, use a pathophysiologic approach, not a treat until failure (A1c rises) approach

• Be familiar with at least one drug from the following class: DPP-4i, GLP-1RA, and SGLT-2i

• Use concentrated insulin PENS, so the dosing is simplified

• The science and art of medicine are both very important in the management of diabetes

• Giving great care to your patients, can result in long and healthy lives without complications

Thank you!

• Questions?

• To Contact Dr. Michael R. Brennan

• Contact the Beaumont Endocrine Center• 25631 Little Mack, Suite 204

• St. Clair Shores, MI 48084

• Phone: 586-443-2380

• Fax: 586-443-2381

• Call Beaumont Health system and ask to have him paged• 248-898-5000

Inhaled Insulin