P R E S E N T E D B Y :

L A R I S S A I E N N A F N P - B C

Z A C H M C C A L L , P H A R M D

Insulin Resistance in Type 2 DM

Diabetes by the Numbers

� 2012 Diabetes Statistics� 29.1 million Americans (9.3% of the population) had diabetes.

� 1.7 million people were newly diagnosed

� 86 million Americans age 20 and older had pre-diabetes

� $245 billion of total cost of diagnosed diabetes

� Diabetes is the 6th leading cause of death by disease

� Diabetes is the 7th leading cause of death in the United States

www.diabetes.org/diabetes-basics/statistics/

Complications of Diabetes

� Hyper/hypoglycemia-high cost.

� Hypertension

� Dyslipidemia

� CVD Death Rate (Heart Attack, Stroke…)

� Blindness

� Kidney Disease

� Amputations

� Insulin Resistance

Insulin Resistance by Numbers

� 25% of the world’s adults have metabolic syndrome

� 3% of US population have insulin resistance

� 3-16% of caucasians worldwide have insulin resistance

http://emedicine.medscape.com/article/122501-overviewMoadab, Kelishadi, et. al, 2010Sarti, Gallagher, 2006.

Complications of Insulin Resistance

� Development of Type 2 diabetes mellitus (6th leading cause of death in US)

� Coronary artery disease

� Infertility

� Metabolic syndrome

http://emedicine.medscape.com/article/122501-overview.

So What is Insulin Resistance?

� Broad clinical spectrum:� Obesity� Glucose intolerance� Diabetes� Metabolic syndrome� Extreme insulin state

� When a given concentration of insulin produces a less-than-expected biological effect

www.uptodate.comhttp://emedicine.medscape.com/article/122501-overview

So What is Insulin Resistance?(Continued)

� More than 200 or more units per day of insulin to attain glycemic control and prevent ketosis

� Subnormal glucose response to exogenous and endogenous insulin� Endogenous: Increase serum insulin levels with normal to high blood

glucose levels

� Exogenous: High doses of insulin used to prevent hyperglycemia

www.uptodate.com

http://emedicine.medscape.com/article/122501-overview

Diagnosis of Insulin Resistance (AACE)

� BMI > 25

� Triglyceride level > 150

� HDL-C level < 40 in men or < 50 in women

� Blood pressure >= 130/85

� Glucose level of >140 2 hours after administration of 75 g of glucose

� Fasting glucose level of 110-126

� In clinical practice, no single laboratory test is used to diagnose insulin resistance syndrome

American Association of Clinical Endocrinologists (AACE)

Possible Presenting Symptoms

� Type 2 diabetes

� Acanthosis Nigricans

� Metabolic syndrome

� Polycystic ovarian syndrome

� Muscle cramps

� Obesity

� Large insulin dosing-more than 200 units per day or more

Akanothosis Nigricans

Causes of Insulin Resistance

� Medications

� Infection

� During Pregnancy

� Obesity and Metabolic Syndrome

Causes of Insulin Resistance (Continued)

� High levels of stress

� Hypertension

� Hyperlipidemia

� Uremia

� Glucocorticoid Excess

Insulin Resistance Treatment

� Non-pharmacological approach: Diet, exercise, lifestyle changes

� Can significantly improve survival and quality of life

� Pharmacological approach: Zach will discuss

Obesity

The OBESITY Epidemic

� 33-35% of U.S. adults are obese

� Obesity is nearly 2 x more prevalent in women� 82.1% black women are overweight or obese � 75.7% Hispanic women are overweight or obese

� 168 billion U.S healthcare costs on obesity

� U.S. consumers spent > 50 billion on weight loss products

� 6000 deaths weekly related to obesity

Food Research and Action Center, 2013

What About the Kids?

� 17% of children ages 2-19 are obese (12.5 million adolescents, up from 5% in 1980)

� Overweight adolescents have a 70% chance of becoming overweight adults

� The good news overweight 2-5 year olds is down 43%

Food Research and Action Center, 2013

2014 Medical Nutritional Guidelines

� Achieve and maintain a healthy weight

� Physical activity and behavior modification are important components to weight loss

� Mix of CHO, protein and fat may be applied

2014 Medical Nutritional Guidelines (Cont.)

� CHO counting/monitoring has been shown to work well

� Saturated fat

Does Alcohol Really Matter?

� Alcohol limitations (max drinks/day)

� Women: One

� Men: Two

Rethinking Drinking.

http://rethinkingdrinking.niaaa.nih.gov/toolsresourses/caloriescalculator.asp

Weekly Calorie Count for Daily Drinks

� Beer (12 oz):1070

� Light beer (12 oz): 721

� 80 proof distilled spirits (1.5 oz): 679

� Liquors (1.5 oz): 1155

� Red wine (5 oz): 875

� Martini (2.25 oz): 868

� Mojito (6 oz): 1001

� Margarita (4 oz): 1176

� Pina colada (9 oz): 3430

Rethinking Drinking.

http://rethinkingdrinking.niaaa.nih.gov/toolsresourses/caloriescalculator.asp

Other Drinks….

Calories Converted to Weight Gain

1000-Calories Extra Per Week

Average Weight Gain of 15-lbs in 1-Year

Lots of Diets Out There!

� Atkins

� Low fat vegan

� Mediterranean/DASH

� Weight Watchers

� 5+2

� Portion controlled Approaches� Jenny Craig� Nutrisystem� Slimfast

Setting Up Your Plate

So Which Diet?

� Individualize the eating plan!

� Avoid mindless eating

� Portion control

� Lots of fiber

� Limit eating out

� Eat protein and fat first, then carbs

� Read the labels

� Fitness applications??? Amazing

Physical Exercise (PA)

Physical Exercise (PA) and Diabetes

� Physical exercise (PA) with acute improvements in systemic insulin action lasting from 2 to 72 h. (ACSM evidence category A)

� Both aerobic and resistance training improve insulin action, BG control, and fat oxidation and storage in muscle (ACSM evidence category B. Resistance exercise enhances skeletal muscle mass. ACSM evidence category A)

� INCREASES insulin sensitivity

� Decreases hepatic glucose production

� Decreases HbA1c

� Decreases hyperinsulinemia

Other Benefits

� Controls BP-Aerobic training may slightly reduce systolic blood pressure ACSM evidence category C

� Improves cholesterol-Small reduction in LDL and no change in HDL or triglycerides. Combined weight loss and PA may be more effective than aerobic exercise training alone on lipids. ACSM evidence category C

� Decrease CV Mortality: Observational studies suggest that greater PA and fitness are associated with a lower risk of all-cause and cardiovascular (CV) mortality ACSM evidence category C

http://www.guideline.gov/content.aspx?id=32410

Other Benefits continued

� Weight loss: Requires 60 minutes when relying on exercise alone. ACSM evidence category C

� Increase in lean body mass

� Decreases stress, anxiety, depression and improves self-esteem ACSM evidence category B

Physical Exercise

� 150 minutes of moderate to vigorous aerobic exercise at least 3 days per week

� No more than 2 consecutive days between bouts of aerobic activity (ACSM evidence category B. ADA B level recommendation)

� Resistance training: 2-3 times per week (ACSM evidence category B. ADA B level recommendation)

� Pedometer 10,000 steps per day

� Prescribe exercise!!!!

http://www.guideline.gov/content.aspx?id=32410http://care.diabetesjournals.org/content/33/12/e147.full

Caution:

Before undertaking exercise more intense than brisk walking, sedentary persons with T2DM will likely benefit from an evaluation by a provider. Electrocardiogram (ECG) exercise stress testing for asymptomatic individuals at low risk of coronary artery disease (CAD) is not recommended but may be indicated for higher risk. ACSM evidence category C. ADA C level recommendation.

Results

� Insulin resistance improved by 25% going from no exercise to 60 minutes per day

� Insulin resistance improved by 50% from no exercise to 120 minutes per day

http://www.ijbnpa.org/content/10/1/10

Nelson et al, 2014.

Take Home Message?

� Lifestyle changes can help treat and prevent diabetes and insulin resistance

� Exercise and eat a healthy diet!

� Now for pharmacological interventions…

Pharmacotherapy for Insulin Resistance

� Options we’ll discuss today

� Oral Medications

� Injectable Medications

� Supplements

Oral Medications

� Insulin sensitizers

� DPP4 inhibitors

� SGLT2

� Immunomodulators

Insulin sensitizers

� Best evidence for use of metformin

� Increases uptake of peripheral glucose, decreases gluconeogenesis and decreases intestinal absorption of glucose

� Making metformin tolerable…

� TZD’s associated with weight gain, edema, fractures, MI risk (rosi), Bladder cancer (pio),

Dipeptidyl Peptidase-4 Inhibitors

•Alogliptin (Nesina)•Linagliptin (Tradjenta)

•Saxagliptin (Onglyza)•Sitagliptin (Januvia)

Dipeptidyl Peptidase-4 Inhibitors

http://en.wikipedia.org/wiki/Dipeptidyl_peptidase-4_inhibitor#mediaviewer/File:Incretins_and_DPP_4_inhibitors.svg

Dipeptidyl Peptidase-4 Inhibitors

� Not much data for insulin resistance specifically but practice experiences suggest they may be helpful

� Pancreatitis

� Hepatic injury (alogliptin)

� Renal failure (sitagliptin)

Sodium-glucose co-transporter 2 inhibitor

� Canagliflozin (Invokana)

� Dapagliflozin (Farxiga)

� Empagliflozin (Jardiance)

Sodium-glucose co-transporter 2 inhibitor

http://www.nature.com/nrendo/journal/v8/n8/fig_tab/nrendo.2011.243_F1.html

Sodium-glucose co-transporter 2 inhibitor

� No specific studies on insulin resistance but…

� Novel mechanism = novel side-effects

� Mycotic infection

� UTI

� Hypotension

� Hyperkalemia

� Increased LDL

� Bladder cancer?

� Careful with renal dysfunction

Immunomodulators

� Used for Type B Insulin Resistance- caused by an autoantibody to cell surface insulin receptor

� Cyclosporin

� Cyclophosphamide

� Azathioprine

� Mycophenolate

� IVIG

� Rituximab

� Glucocorticoids

Injectable Medications

� GLP-1

� Symlin

� U-500

Glucagon-like Peptide-1

� Exenatide (Byetta, Bydureon)

� Liraglutide (Victoza)

� Albiglutide (Tanzeum)

� Dulaglutide (Trulicity)

http://en.wikipedia.org/wiki/Gila_monster#mediaviewer/File:Gila_monster2.JPG

Glucagon-like Peptide-1

� Increases insulin secretion in a glucose-dependent manner

� Decreases glucagon secretion

� Increases insulin-sensitivity

� Inhibits gastric emptying

� Increases satiety

� Pancreatitis warning

� Caution with gastroparesis

� Thyroid C-cell tumors

Amylin Analog

� Pramlintide (Symlin)

� Amylin is co-secreted with insulin� Inhibitory effect on meal-related glucagon secretion� Slows gastric emptying � Improves satiety

� Risk Evaluation and Mitigation Strategy Program� Poor compliance� A1c >9%� Gastroparesis� Hypoglycemia requiring assistance in the past 6 months

� Reduce insulin by 50% when starting pramlintide� For DM2- start at 60 micrograms before meals, increase to target of

120micrograms.

U-500

� Regular insulin that is 5 times the concentration of standard insulin

� 0.2mL = 100 units = 20 unit-marks on an insulin syringe

� Consider if using more than 200-300 units daily

U-500

� Possible benefits of U-500

� Potentially improves absorption and compliance

� Cost savings

� Daily study found a sustained drop in A1c by 1.4%

� Initial weight gain and insulin need stabilize after 1 year

� Possible risks of U-500

� Easily confused with regular insulin

� Miscommunication about dosing leads to potentially fatal errors

U-500 Kinetics

� Regular insulin, but….

� Concentration means delayed peak and longer duration of action- looks closer to NPH� Peak in 1-3 hours, duration of 8 hours or longer, onset in 30min.

Converting to U

Cochran E, Gorden P. Use of U-500 insulin in the treatment of severe insulin resistance. Insulin. 2008;3:211-218.

Writing the script for U-500

� Insulin regular U-500

� Sig: Inject 0.3mL (150 units) subcutaneously 3 times daily. (Concentrated insulin. Do not adjust dose.)

Or…

� Sig: Inject 150 units (30 unit-marks on an insulin syringe) subcutaneously 3 times daily. (Concentrated insulin. Do not adjust dose.)

U-500 Key Points

� Patients must be clearly instructed that they are using a higher-strength insulin- 5 times more concentrated that U-100 insulin

� Patients should never allow others to use their vial of U-500 insulin

� U-500 should be defined in terms of volume, marks or “lines” on the syringe, and actual total units to avoid dosing errors

� U-500 comes in a 20mL vial and while initial cost per vial is more than U-100 regular insulin. Because of the reduced injected volume, however, cost per unit of U-500 is less than U-100.

� U-500 in hospitalized patients should be restricted to facilities with protocols for its inclusion in the formulary and clear, well-documented instructions for the nursing staff.

Wait for it….

� Currently in the pipeline

� U-200

� U-300

Supplements

� Acetyl-L-Carnitine

� Chromium

� Magnesium

� Vanadium

� Studied but insufficient and inconsistent data to support.� Vitamin C, D, E

� Alpha Lipoic Acid

� Coenzyme Q10

� Ginseng

Acetyl-L-Carnitine

� Acetyl-L-carnitine-

� Thought to prevent mitochondrial dysfunction associated with incomplete beta-oxidation and accumulation of intramyocellular lipids (contributor to insulin resistance)

� Several mice/rat studies. One study in humans showing improved glucose disposal rate.

� Optimal dose is 2000mg daily

Chromium

� Thought to up-regulate insulin receptors, thus improving insulin sensitivity.

� Mixed studies on effect

� Potentially useful to increase insulin sensitivity, decrease A1c

� Seems to work best if Chromium picolinate 200-500µg bid

Magnesium and Vanadium

� Magnesium

� Conflicting, but one large trial did find that increased magnesium intake in the diet was associated with decreased insulin resistance.

� Potentially even more true for overweight and obese individuals.

� Best study used 3 grams per day

� Vanadium

� Conflicting results, no longer term studies.

� Concerns about toxicity over time.

� 50mg daily

Drug causes

� Glucocorticoids

� Niacin

� Terbutaline

� HIV-1 protease inhibitors

� Nucleoside reverse transcriptase inhibitors

� Interferon-alpha

� Atypical antipsychotics

� Progestogens

Case Study 1

� 40 yo M, high-functioning developmentally delayed, smoker, obese, HTN, familial hypercholesterolemia, insulin resistant.

� 30 units bid Lantus; 10-24 units Novolog

� 2000mg metformin

� Pt is resistant to lifestyle changes…

� What other medication options do we have?

Case Study 2

� 55 yo F, BMI 27, maxed on oral agents and recently prescribed insulin. When she got home with the insulin, she decided that she is not going to take it-and wants to know what changes she can make to her lifestyle to avoid needing to use insulin.

� What advice do you have for her diet and activity?

Case Study 3

� 59-year-old female with hba1c 13%. Daily sugars are 200-500. States she gives insulin regularly. Cannot tolerate Metformin secondary to GI side effects. Rx Lantus 70 units bid, Novolog 30 units before meals. Morbidly obese. Husband just passed away. What are other medication options?

References

� Moadab MH, Kelishadi R, Hashemipour M, Amini M, Poursafa P. The prevelence of impaired fasting glucose and type 2 diabetes in a population-based sample of overweight/obese children in the Middle East. PediatrDiabetes. March 2010, 11)2):101-6.

� Sarti C, Gallagher J. The metabolic syndrome: prevelence, CHD risk and treatment. J Diabetes Complications. Mar-Apr 2006;20(2): 121-32.

� http://emedicine.medscape.com� Food Research and Action Center, 2013� http://rethinkingdrinking.niaaa.nih.gov/toolsresourses/caloriescalculator.asp� http://www.guideline.gov� Neson R, Horowitz J, Holleman R, Swartz A, Strath, S, Kriska A, Richardon C.

Daily phsyical activity predicts degree of insulin resistance: a cross-sectional observational study using the 2003-2004 National Health and Nutrition Examination Survey. International Journal of Behavioral Nutrition and Physical Activity 2013, 10:10.

� Barnard N, Cohen J, Jenkins D et al. Risk factors in a Randomized Clinical Trial in Individuals with Type 2 Diabetes Care, 2006.

References Continued

� Wiegand S. et al. Metformin and placebo therapy both improve wieght management and fasting insulin in obese insulin-resistant adolescents: a prospective, placebo-controlled, randomized study. European Journal of Endocrinology. 2010. 163; 585-92.

� Malek R et al. Treatment of Type B Insulin Resistance: A Novel Approach to Reduce Insulin Receptor Autoantibodies. J Clinical Endocrinology and Metabolism. 2010. 95(8): 3651-7

� Oriet P et.al. Exenatide improves Weight Loss Insulin Sensitivity and Beta-cell function following Administration to a type 2 diabetic HIV patient on antiretroviral Therapy. Annals of Endocrinology. 2011. 72: 244-6.

� Daily AM, Gibert JA, Tannock LR. Durability of Glycemic Control Using U-500 Insulin. Diabetes Research and Clinical Practice. 2012. 95. 340-4.

� Segal AR, Brunner JE, Taylor-Burch F, Jackson JA. Use of Concentrated insulin Human Regular (U-500) for Patients with Diabetes. American Journal of Health-System Pharmacists. 2010. 67;1526-35.

� Cochran E, Gorden P. Use of U-500 insulin in the treatment of severe insulin resistance. Insulin. 2008;3:211-218.

� Taylor S. U-500 concentrated regular insulin: Practical application in the outpatient setting. The Nurse Practitioner. Sept 2012. 37(9): 47-52.

� Brown A, Desai M, Taneja D, Tannock L. Managing Highly Insulin-resistance Diabetes Mellitus: Weight Loss Approaches and Medical Management. Postgraduate Medicine. Jan 2010. 122(1): 163-71.

� Ruggenenti P et al. Ameliorating hypertension and insulin resistance in subjects at increased cardiovascular risk: effects of acetyl-L-carnitine therapy. Hypertension. 2009; 54:567-74.

� Anderson RA, Cheng N, Bryden NA, Polansky MM, Chi J &Feng J (1997b) Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes 46, 1786–1791

� Anderson RA. Chromium and Insulin Resistance. Nutrition Research Reviews. 2003. 16:267-75. � Cahill F et al. High Dietary Magnesium Intake is Associated with Low Insulin Resistance in the Newfoundland

Population. PLoS One. 2013; 8(3): e58278. doi:10.1371/journal.pone.0068278� Bradley R, Oberg E, Calabrese C, Standish LJ. Algorithm for Complementary and Alternative Medicine

Practice and Research in Type 2 Diabetes. The Journal of Alternative and Complimentary Medicine. 2007. 13(1); 159-75.