2013 6-19 DM, Pre-DM & MetS PSEM Weekend course bulacan insulin 101

Insul in 101 : Human vs Analogues:

Which, when, how and to whom?

Jeremy F. Robles, MD, FPCP, FPSEM

5th Diabetes, Prediabetes and Metabolic Syndrome Weekend Course (ENDOCRINE: ENhancing Diabetes Outpatient and

CRitical INitiativEs July 19, 2013 Malolos, Bulacan

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Case

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Case 1:§Age: 52 years§Duration of type 2 diabetes: 7 years§FPG of 180 - 320 mg/dL in last 2 months

§Weight: 209 lbs (95 kg) §BMI: 32 kg/m2

§Blood pressure: 135/85 mmHg§Current treatment:

§Glimepiride 6 mg pre breakfast§Metformin 1000 mg BID

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Lab Results:§FPG: 190 mg/dl, HbA1C 10%§2-hour PPG: 280 mg/dL§Total cholesterol: 200 mg/dl, Triglycerides: 180 mg/dL§AST: 45 IU/L, ALT: 50 IU/L§Urine microalbumin: 18 mg/24 hr

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1.) What would be your next step in managing this patient?

A. Continue meds & monitor HbA1c again in 3 months

B. Add an additional oral agent (ex: TZD, DPP-4 inhib)

C. Add a basal insulin at bedtime

D. Begin a premixed insulin analogue therapy

E. Stop orals and start basal/bolus insulin therapy

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E. Stop orals and start basal/bolus insulin therapy

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2.) What are the primary concerns that you should address in managing this patient?

A. Fear of guilt or failure

B. Fear of weight gain or hypoglycemia

C. Misconception of risks

D. Beliefs on treatment efficacy

E. Psychological barriers to insulin therapy

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2.) What are the primary concerns that you should address in managing this patient?

A. Fear of guilt or failure

B. Fear of weight gain or hypoglycemia

C. Misconception of risks

D. Beliefs on treatment efficacy

E. Psychological barriers to insulin therapy

Friday, July 19, 13

Case 1:§ Patient was started on biphasic human insulin given twice a day 10 U AC breakfast and 5 U AC dinner

§ Metformin 1000mg BID was continued § She was started on rosuvastin 10 mg HS§ She was seen by a dietician § Advised told to eat regularly with adequate servings§ She monitored her blood sugar daily before meals§ Patient came back for follow-up after 2 weeks Succeeding follow-up showed improvement of blood sugars as insulin dose was adjusted

Friday, July 19, 13

FF-up Lab Results after 3 months:§FPG: 120 mg/dl§2-hour PPG: 167 mg/dL§Total cholesterol: 180 mg/dl§Triglycerides: 120 mg/dL§AST: 18 IU/L§ALT: 18 IU/L§HbA1c: 6.5 % §Urine microalbumin: 18 mg/24 hr

Initial Lab Results:§FPG: 190 mg/dl, HbA1C 10%§2-hour PPG: 280 mg/dL§Total cholesterol: 200 mg/dl, Triglycerides: 180 mg/dL§AST: 45 IU/L, ALT: 50 IU/L§Urine microalbumin: 18 mg/24 hr

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Daily Physiologic Insulin Secretion

• Human pancreas secretes about 30 U/day of insulin

• Fasting basal concentration of insulin of 10 U/mL

• Postprandial insulin rise within 8 to 10 minutes, peak by 30 - 45 minutes, then declines to baseline by 90 minutes

• Glucose is the most potent stimulant of insulin release

• Sustained hyperglycemia result in a reversible desensitization of the cell response to glucose

Gardner DG & Shoback D . “Pancreatic Hormones & Diabetes Mellitus” Greenspan’s Basic & Clinical Endocrinology 9th ed.. 2011.

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Physiologic Insulin Production

Basal insulin

• Nearly constant day-long insulin level

• Suppress hepatic glucose production overnight & between meals

• Cover 50% of daily needs

Bolus insulin (mealtime)

• Immediate rise and sharp peak at 1 h

• Limit postmeal hyperglycemia

• Cover 10–20% of total daily insulin at each meal

Rosenstock J & Riddle M . “Insulin therapy in DM type 2”. The CADRE Handbook of Diabetes Management. July 15, 2013. <http://cadre.emsix.com/handbooks/CADRE%20HB%20ch09%20pg145-168.pdf>

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http://cadre.emsix.com/handbooks/CADRE%20HB%20ch09%20pg145-168.pdf




Beaser RS, et. al. “Insulin-Treated Type 2 Diabetes: Balancing Physiologic and Individual Needs” Medscape. 30 June 2013. <http://www.medscape.org/viewarticle/544445>

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http://www.medscape.org/viewarticle/544445


Daily Physiologic Insulin Secretion

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Therapeutic Options for DM type 2

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Houston we have a problem!

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Houston we have a problem!

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Absolute Indications for Insulin Therapy

• All patients with type 1 diabetes

• Ketoacidosis or severe hyperglycemia (blood sugars over 500)

• Presence of serious infection (for example, pneumonia)

• Concurrent illness (such as heart attack)

• During and after major surgery

• During pregnancy

• Unable to control glycemic with 2 or 3 oral agents

• A1c over 10%

• A1c over 7.5 % plus fasting glucose over 250

Tanenberg R. “Insulin For Type 2 Diabetes: Who, When, And Why?” Diabetes Health. 30 June 2013. <http://diabeteshealth.com/read/2009/03/20/5564/insulin-for-type-2-diabetes-who-when-and-why/>

Friday, July 19, 13

http://diabeteshealth.com/browse/community/type-1-issues/

http://diabeteshealth.com/browse/community/type-1-issues/





Relative Indications for Insulin Therapy

• Patients who are underweight or losing weight without dieting

• Patients who have symptoms from blood sugars over 200

• Any patient who is hospitalized

• Patients on steroids (such as prednisone) for other disorders

• Onset of diabetes <30 yo, or a duration over fifteen years

• Complications such as painful diabetic neuropathy

Tanenberg R. “Insulin For Type 2 Diabetes: Who, When, And Why?” Diabetes Health. 30 June 2013. <http://diabeteshealth.com/read/2009/03/20/5564/insulin-for-type-2-diabetes-who-when-and-why/>

Friday, July 19, 13

http://diabeteshealth.com/browse/complications-and-care/nerve-care-neuropathy/

http://diabeteshealth.com/browse/complications-and-care/nerve-care-neuropathy/





Barriers to Insulin Initiation

• Misconceptions & stigmas about insulin & complications

• Limitations of insulin formulations

• Complexity of insulin regimens

• Limited time and resources

• Skepticism that patients can reach glycemic targets

• Risk of hypoglycemia & Weight gain

• Misconceptions about insulin with atherogenesis

• Fear of needles


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Overcoming Major Barriers to Insulin Therapy


Barrier Effect of Insulin Therapy

Insulin resistance Improves insulin sensitivity by reducing glucotoxicity

Cardiovascluar risk No evidence of atherosclerotic effectsReduced cardiovascular risk factors

Weight gain Modest & avoidable

Hypoglycemia Rarely causes severe events when used properly

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Insulin preparations


153Insulin Therapy in Type 2 Diabetes

Table Pharmacokinetics of Human Insulinand Analogues

9-3

Onset of Peak Duration of Action (h) Action (h)

Human insulinRegular 0.5–1 h 2–4 6–8NPH 2–4 h 4–10 12–20Lente 2–4 h 4–10 12–20Ultralente 4–6 h Unpredictable 18–20

AnalogueLispro 5–15 min 1–2 4–5Aspart 5–15 min 1–2 4–5Glulisinea 5–15 min 1–2 4–5Glargine 2–4 h Flat ~24Detemira 2–3 h 6–10 16–22

The time course of action of any insulin may vary between individuals, or atdifferent times in the same individual. Consequently, the data presentedshould be considered only as a general guideline.a In development.Source: Refs. 13, 23, 27, 32.

tributing to an increased risk of hypoglycemia, especially at night.Another lente formulation, ultralente, has a more gradual and latepeak with longer duration of action than NPH or lente, but itseffects are similarly erratic and unpredictable.

Long-acting insulin analogues: glargine and detemirInsulin glargine is the first insulin analogue with a prolongedduration of action (Table 9-3, Fig. 9-3, Fig. 9-4). Changes in theamino acid sequence of human insulin produce a shift in the iso-electric point, which results in a clear preparation that is solubleonly at acidic pH 4. In subcutaneous tissues, which have a neutralpH, the reduced solubility of glargine stabilizes the hexamericform of insulin and delays dissociation into dimers and monomersand subsequent absorption into the systemic circulation. Consis-

145-168.CADRE09.QX 4/27/04 5:57 PM Page 153

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Human Classic vs Analog Insulin


Classic Analog

Cheaper better HbA1C control

Readily Available Lesser hypoglycemic risk

Regular

Aspart

Regular GlulisineRegular

Lispro

NPHGlargine

NPHDetemir

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Regular vs Rapid Acting Intermediate vs Long Acting


Human Classic vs Analog Insulin

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Insulin Pharmacodynamics

Tanyolac S. “Insulin - Pharmacology, Types of Regimens, and Adjustments” Endotext. 30 June 2013. <http://www.endotext.org/diabetes/diabetes14/diabetesframe14.html>

Insulin Onset Peak Duration Appearance

Regular 0.5 - 1 hr 2 - 4 hrs 5 - 8 hrs Clear

Lispro 0.25 hr 0.5 - 1.5 hrs 3 - 5 hrs Clear

Aspart 0.25 hr 1 - 3 hrs 3 - 5 hrs Clear

Glulisine 0.25 - 0.5 hrs 0.5 - 1 hr 4 hrs Clear

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Regular vs Rapid Acting Insulin

• Regular Acting Insulin

• appears 30 after injection, regular schedule

• used when the insulin requirement is changing rapidly

• action prolonged with larger doses

• immediate effect if given IV

• Rapid Acting Insulin

• duration of action remains at 4 hrs irrespective of dosage

• quickly dissociate into monomers & absorbed rapidly

• superior control over post-prandial hyperglycemiaGardner DG & Shoback D . “Pancreatic Hormones & Diabetes Mellitus” Greenspan’s Basic & Clinical Endocrinology 9th ed.. 2011.

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7:00am 7:00pmnoon midnight 7:00am

Breakfast Lunch Supper

Physiologic insulin secretion

Classic Insulin

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Classic Insulin

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Analog Insulin / Rapid Acting

Classic Insulin

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Analog Insulin / Rapid Acting

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NPH 1 - 2 hr 4 - 10 hrs 14 hrs Cloudy

Detemir 3 - 4 hrs 6 - 8 hrs 20 - 24 hrs Clear

Glargine 1.5 hrs flat 24 hrs Clear

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Intermediate vs Long Acting Insulin

• Intermediate Acting Insulin

• delayed onset of action, requires 2 injections daily

• Long Acting Insulin

• no pronounced peak, less nocturnal hypoglycemia

• given once or twice a day

• glargine (acidic) cannot be mixed with other insulins

• detemir lower within-subject pharmacodynamic variability compared to NPH insulin and insulin glargine


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Classic Insulin (NPH)

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Analog Insulin (Detemir, Glargine)


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Analog Insulin (Detemir, Glargine)

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Split Mixed vs Premixed

• Split Mixed Insulin

• Given before breakfast and dinner

• Intermediate + regular/rapid

• Can adjust each component (Flexible)

• Premixed Insulin



• Fixed dose, cannot adjust components


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Classic 70/30 0.5 - 1 hr 3 - 6 hrs 14 hrs Cloudy

Aspart Mix (70/30)

0.1 - 0.2 hr 1 - 4 hrs 18 - 24 hrs Cloudy

Lispro Mix(75/25)

0.25 - 0.5 hr 0.5 - 2.5 hrs 14 - 24 hrs Cloudy

Lispro Mix(50/50)

0.25 - 0.5 hr 0.5 - 3 hrs 14 - 24 hrs Cloudy

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Classic Insulin

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Classic Insulin

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Analog Insulin

Classic Insulin

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Analog Insulin

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Beaser RS, et. al. “Insulin-Treated Type 2 Diabetes: Balancing Physiologic and Individual Needs” Medscape. 30 June 2013. <http://www.medscape.org/viewarticle/544445>

Friday, July 19, 13



Split Mixed vs Premixed

• Split Mixed Insulin



• Can adjust each component (Flexible)

• Premixed Insulin



• Fixed dose, cannot adjust components


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Basal - Bolus Insulin Strategy




Prandial Insulin

Basal Insulin

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Insulin Regimens for Diabetes Mellitus Type 2

McGill JB. “Diabetes Mellitus Type 2”. Endocrinology Subspecialty Consult 2nd ed. 2009.

RegimenOral

AgentsInsulin Type

StartingDose

Basal + Oral(starting regimens)

continue all oral agents, TZD submaximal

Intermediate /Long acting

0.1 - 0.2 U/kg at bedtime till FBS at

target

Premixed (Patients with regular meal schedule)

continue insulin sensitizers

70/30 NPH/regular; Humalog mix 75/25;

Novomix 70/30

0.1 U/kg am & pm, increase until glucose

nears target

Multiple Daily(Irregular meal schedule/

needs tighter control)

continue insulin sensitizers, discontinue

secretagogues

Basal: glargine or detemir/NPH OD or BID

Premeal: rapid or regular

0.5 - 2 U/kg/day, 50% basal, 50% divided

pre-meals

Continuous Infusion

sensitizers may still be useful

Lispro, Aspart, Glulisine 0.5 - 2 U/kg/day

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Basal - Oral Strategy




Basal Insulin

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Goals of Insulin Therapy

ADA Standards of Care 2013

Blood Glucose Level

Preprandial Plasma Glucose 70 - 130 mg/dl

Postprandial Plasma Glucose < 180 mg/dl

HbA1c < 7 %

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Factors Affecting Insulin Absorption

• Exercise of injected area

• Local massage

• Temperature

• Site of injection

• Lipohypertrophy

• Jet injectors

• Insulin mixtures

• Insulin dose

• Physical status

(soluble vs. suspension)

* The abdomen is the preferred site of injection because it is the least susceptible to factors affecting insulin absorption. Variability is correlated to blood flow at the injection sites.


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Insulin Administration

• Syringes • Available in 1-mL, 0.5-mL, and 0.3-mL sizes• 30- to 31-gauge needles reduced the pain • Needle length short (8 mm) and long (12.7 mm)• Long needles for obese reduce absorption variability

• Insulin Pens• Eliminate the need to carry vials and syringes• Cartridges are available for reusable pens• 31 gauge needles (4, 5, 8 and 12 mm long) painless• angle of entry (subcutaneous)


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Insulin Storage

• All insulins have an expiration date which is labeled on directly on the product applies when they are unopened and refrigerated.

• Insulin should not be frozen or stored in a temp > 30°C.

• Insulin vial in use may be kept at room temperature, below 30°C for a month.

• Insulin cartridges, disposable pens & other delivery devices can have different storage recommendations for room temperature. Once opened, insulin cartridges and pens should not be refrigerated.


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Adverse Effects

• Most significant adverse effect of insulin is hypoglycemia• Patients should be aware of hypoglycemia & its treatment

• Weight gain is another significant side effect of insulin therapy.

• Less weight gain is encountered with long-acting insulin

• True allergic reactions and cutaneous reactions are rare.• Avoid lipohypertrophy by rotating injection sights


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Case

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Case 2:§Age: 40 years§Duration of type 2 diabetes: 3 years§FPG of 230 mg/dL over the past mo.§Weight: 200 lbs (92 kg) §BMI: 30 kg/m2

§Blood pressure: 140/80 mmHg§Current treatment:

Intermediate insulin N BID 15 units sc before BF 5 units sc before dinner

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Lab Results:§FPG: 162 mg/dl§2-hour PPG: 190 mg/dL§Total cholesterol: 245 mg/dl§Triglycerides: 320 mg/dL§AST: 90 IU/L§ALT: 50 IU/L§HbA1c: >12 %

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E. Start basal/bolus insulin therapy

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E. Start basal/bolus insulin therapy

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Case 2:§Patient was started on Basal-Bolus regimen

§Glargine 20 units sc before breakfast§Glulisine 4 units before meals (skip am if no BF)

§Started on metformin 500 TID PC & Fenofibrate 160 mg §He was asked to control his diet and refrain from drinking softdrinks

§He borrowed his neighbors glucometer to monitor his sugar at pre breakfast and 2 hours after lunch every other day

§Patient came back for follow-up after 2 weeks Succeeding ff -up showed improvement of blood sugars as insulin dose was adjusted

Friday, July 19, 13

FF-up Lab Results after 3 months:§FPG: 101 mg/dl§2-hour PPG: 142 mg/dL§Total cholesterol: 190 mg/dl§Triglycerides: 120 mg/dL§AST: 15 IU/L§ALT: 18 IU/L§HbA1c: 6.2 %

Initial Lab Results:§FPG: 162 mg/dl§2-hour PPG: 190 mg/dL§Total cholesterol: 245 mg/dl§Triglycerides: 320 mg/dL§AST: 90 IU/L§ALT: 50 IU/L§HbA1c: >12 %

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2013 AACE Guidelines for Diabetes Management

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Sumary

• Good glycemic control decreases risk of microvascular disease

• Oral agents less effective as beta cell function further decline, consider insulin therapy in patients with uncontrolled hyperglycemia especially with mutilple oral medications

• Choosing the appropriate insulin regimen for your patient

• Less aggressive control for older patients

• Monitor the blood sugar closely & follow up patients regularly

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Magandang umaga po sa inyong lahat . . .

Huwag po tayo matakot sa insulin.

Friday, July 19, 13

Health & Medicine

2013 6-19 DM, Pre-DM & MetS PSEM Weekend course bulacan insulin 101