3/2/2016

Pharmacist Objectives

• Appreciate the pathophysiology of type II Update on Type II Diabetes diabetes Pharmacotherapy • Acknowledge the new treatment options for type II diabetes Christine Ibarra, Pharm.D. • Baptist Hospital PGY-1 Understand the advantages and disadvantages [email protected] of novel therapeutic options March 12, 2016

www.fshp.org

Disclosures Technician Objectives

• I have nothing to disclose • Appreciate the effects of type II diabetes in the body • Identify new used in type II diabetes • Understand how the new medications differ from older diabetes treatment agents

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Diabetes in the U.S. Type II Diabetes Mellitus (T2DM)

• Previously referred to as “non- dependent” or “adult-onset” • Insulin resistance + lack of insulin secretion • Progressively lower insulin secretion over time • Increased risk for macrovascular + microvascular complications

http://www.cdc.gov/features/diabetesfactsheet Diabetes Care. Jan 2016.39(1)S1-39 /DiabetesFactSheet.pdf Endocr Pract. 2016; 22 (No. 1) 84-113

Diabetes Advances in Diabetes

Commercial production of insulin 1923

1st generation (SU) 1955

“Insulin Dependent” vs.“Non-Insulin Dependent” Diabetes 1955 Mellitus A1C becomes preferred method for chronic diabetes 1977 glucose management Diabetes Control and Complications Trial (DCCT) 1993 published , become available Type I Type II Gestational Other 1995 -Like Peptide (GLP)-1 discovered

5-10% 5-10% 1% < 5% Byetta® (exenatide), Januvia® (sitagliptin) approved 2005

ACCORD, ADVANCE and VADT are presented at the 2008 American Diabetes Association (ADA)

Invokana® () is approved 2013

Diabetes Care. Jan 2016.39(1)S1-39 May 2014. History of Diabetes Endocr Pract. 2016; 22 (No. 1) 84-113

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Principles of Care

1. Individualization of glycemic goals 2. Lifestyle optimization 3. Pharmacological therapy Review of the 2016 Guidelines – Patient attributes – Minimizing complications • Hypoglycemia • Weight gain

Diabetes Care. Jan 2016.39(1)S1-39 Endocr Pract. 2016; 22 (No. 1) 84-113

Diagnosis Individualization of Glycemic Goals

• Two blood tests demonstrating • American Diabetes Association (ADA) – Pre-prandial plasma glucose 80-130 mg/dL – Plasma Glucose Criteria – Post-prandial plasma glucose < 180 mg/dL • Fasting Plasma Glucose (FPG) ≥ 126 mg/dL – A < 7% • 2-h Plasma Glucose ≥ 200 mg/dL 1C • American Association of Clinical – A Criteria ≥ 6.5% 1C Endocrinologists (AACE)/ American College • Classic symptoms of hyperglycemia + random of Endocrinology (ACE) plasma glucose > 200 mg/dL – Pre-prandial plasma glucose < 110 mg/dL – 2-hour post-prandial glucose < 140 mg/dL – A1C ≤ 6.5%

Diabetes Care. Jan 2016.39(1)S1-39 Diabetes Care. Jan 2016.39(1)S1-39 Endocr Pract. 2016; 22 (No. 1) 84-113 Endocr Pract. 2016; 22 (No. 1) 84-113

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Lifestyle Optimization: Individualization of Glycemic Goals Obesity Management • Overweight/obese: 5-15% weight loss – Non-pharmacologic: diet, physical activity, behavioral strategies – Pharmacological Optimal A • BMI ≥ 27 kg/m 2: weight loss medications 1C VS. 6.5-7% • Choosing glucose lowering medications that promote weight loss/weight neutral

Diabetes Care. Jan 2016.39(1)S1-39 Diabetes Care. Jan 2016.39(1)S1-39 Endocr Pract. 2016; 22 (No. 1) 84-113 Endocr Pract. 2016; 22 (No. 1) 84-113

Lifestyle Optimization: Pharmacological Therapy Obesity Management Life style modifications • Delay progression pre-diabetes T2DM • Improve glycemic control Initial drug monotherapy: metformin – Two-drug combinations: metformin +  A1C 1-2%, fasting plasma glucose SU TZD DPP-4 GLP-1 Insulin (basal) –  need for glucose lowering medications Three-drug combinations: metformin + • Look AHEAD trial SU + TZD + DPPDPP-4-4 + GLPGLP-1-1 + Insulin (basal) + – TZD or SU or SU or SU or TZD or Equal risk factor control DPP-4 or DPP-4 or TZD or TZD or DPP-4 or – GLP-1 or GLP-1 or Insulin Insulin GLP-1 Fewer glucose, BP, lipid lowering medications Insulin Insulin

More complex insulin strategies: Multiple daily doses

Diabetes Care. Jan 2016.39(1)S1-39 Diabetes Care. Jan 2016.39(1)S1-39 Endocr Pract. 2016; 22 (No. 1) 84-113

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Patient Case 1 Initial Therapy: Metformin

• RD, a 65 y.o. male, is diagnosed with T2DM • , enhances insulin sensitivity – A1C  1.5% • PMH : Obesity (BMI 29.5 kg/m 2), HTN, GERD – Extensive experience • Side effects • Labs – Weight loss, mild hypoglycemia : A 1C 8.5% – GI: diarrhea, nausea, vomiting – Boxed Warning: Lactic acidosis • Low cost

Diabetes Care. Jan 2016.39(1)S1-39 Endocr Pract. 2016; 22 (No. 1) 84-113

Patient Case 1 Anti-Diabetic Medications

• What should we recommend for RD? a) Lifestyle recommendations including 7% weight Dipeptidyl Peptidase- 4 Inhibitor loss and physical activity (SU)* (TZD) (DPP-4) , glyburide, , , , b) Start metformin 500 mg PO BID with morning, , evening meal

c) Start on insulin since it has the highest A 1c Glucagon-Like Sodium GLucose co- Peptide-1 agonist lowering efficacy Transporter-2 (GLP-1) (SGLT-2 Inhibitors) d) Metformin 500 mg PO BID + glyburide extenatide, , , canagloflozin ,,

Others : alpha glucosidase inhibitors, st Diabetes Care. Jan 2016.39(1)S1-39 * AACE does not rec as a 1 line alternative Endocr Pract. 2016; 22 (No. 1) 84-113

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Summary of the Anti-Diabetics Patient Case 2

• RD is back 10 weeks later for a follow up

• Medications : metformin 1000 mg PO BID

• Labs : A 1c 8%

• How can we further optimize his therapy?

http://www.medscape.org/viewarticle/557239

Diabetes Care. Jan 2016.39(1)S1-39 Endocr Pract. 2016; 22 (No. 1) 84-113

Summary of the Anti-Diabetics Patient Case 2

Criteria SU TZD GLP-1 DPP-4 SGLT-2 How can we further optimize his therapy? A1c Lowering 1.5% 1-1.5% 1% 0.5% 0.5% Weight    -  a) Add sitagliptin 100 mg PO daily to his Hypoglycemia Moderate Low Low Low Low regimen CrCl <30 sitagliptin, Renal GFR < 60 GFR <45, None mL/min saxagliptin, mL/min 60 mL/min Considerations () alogliptin b) Increase metformin dose since he is only on Vulvovaginal Fluid GI, 2000 mg daily Nausea, Headache, candidiasis, retention, Injection Side Effects Skin URTI, UTI, Heart Failure reactions, reactions Pancreatitis ? Diabetic c) Add glyburide 2.5 mg PO daily (CHF) Pancreatitis ? Ketoacidosis ? d) Do nothing-it has not been long enough to Boxed Thyroid C-cell None CHF None None Warnings tumor risk see the full effects of his current regimen

Diabetes Care. Jan 2016.39(1)S1-39 Endocr Pract. 2016; 22 (No. 1) 84-113

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Dual Anti-Diabetic Therapy Insulin Management

• Recommended for Basal Lantus® (glargine) – 10 U/day, Levemir® (detemir) A1C ≥ 7.5% or 9% at baseline 0.1-0.2 U/kg/day Not controlled after – Target A not achieved after 3 months (+) (+) 1C FPG at goal? • Adding non-insulin therapy  A 0.9-1.1% Rapid Humalog® (lispro) 1C Rapid > Short acting 4 U, 0.1 U/kg, 10% of Novolog® (aspart) A1C 8% ? basal dose Glulisine® (apidra)

SU TZD DPP-4

Basal-Bolus ≥ 2 rapid insulin injections SGLT-2 GLP-1 Inhibitors Diabetes Care. Jan 2016.39(1)S1-39 Diabetes Care. Jan 2016.39(1)S1-39 Endocr Pract. 2016; 22 (No. 1) 84-113

Initiation of Insulin Therapy AACE vs ADA

• Recommended for Criteria AACE/ ACE ADA – A1C ≥ 10% or plasma glucose ≥ 300 mg/dL Diagnosis Plasma Glucose Criteria A1c , Plasma Glucose Criteria – Unlikely to reach target A Preference 1C A Goal ≤ 6.5% < 7% • 1c 2 anti-diabetic agents + A 1C > 8% Lifestyle Strongly encouraged • Longstanding T2DM Modifications Preferred Initial Metformin Therapy Metformin • Start : basal insulin ± metformin ± anti-diabetic GLP-1, SGLT-2, DPP-4,TZD SU, GLP-1, SGLT-2, DPP-4,TZD Alternative BP Goal < 130/80 mmHg < 140/90 mmHg Cholesterol Goal LDL < 100 mg/dL, < 70 mg/dL Refer to ATP-4

Diabetes Care. Jan 2016.39(1)S1-39 Diabetes Care. Jan 2016.39(1)S1-39 Endocr Pract. 2016; 22 (No. 1) 84-113 Endocr Pract. 2016; 22 (No. 1) 84-113

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SGLT-2 Inhibitors

Invokana® Farxiga® Jardiance® Criteria (canagliflozin) () (empagliflozin) Jardiance— New Treatment Options Manufacturer Janssen AstraZeneca Boehringer Ingelheim Dosing 100-300 mg daily 5-10 mg daily 10-25 mg daily GFR Cut-Off 45 mL/min 60 mL/min 45 mL/min Class Side Effects Vulvovaginal candidiasis, UTI, diabetic ketoacidosis (?) Hyperkalemia Bladder cancer  All cause + CV Comments  fractures  fractures death

Invokana (canagliflozin) [package insert]. Farxiga (dapagliflozin) [package insert] JARDIANCE® (empagliflozin) [package insert]

SGLT-2 Inhibitors Afrezza® (Insulin Human)

• Glucosuric- action is independent of insulin • Rapid-acting, inhaled before meal – –  A1c 0.7% Shorter duration vs injectable – Limited efficacy in GFR < 45-60 mL/min – Supplied as 4, 8, or 12 units • Side Effects • Boxed warning: Risk of acute bronchospasm –  weight, systolic BP has been observed in asthmatics + COPD – Dehydration, hypotension – Slight increases in LDL, HDL • Post-marketing reports of diabetic ketoacidosis (?)

Diabetes Care. Jan 2016.39(1)S1-39 Diabetes Care. Jan 2016.39(1)S1-39 Endocr Pract. 2016; 22 (No. 1) 84-113 http://www4.dresskibc.tk/wall/sodium-glucose-cotransporter-2-inhibitor/ AFREZZA® (insulin human). [package insert]

8 3/2/2016

New Long Acting Clinical Trials in Progress..

Basaglar ® () Tresiba ® () • Glycemia Reduction Approaches in Diabetes: • 1st insulin approved through • Ultra long acting basal A Comparative Effectiveness Study (GRADE) abbreviated pathway insulin, “peakless” – Glimepiride • Expected cost savings – Duration beyond 42 hours – Sitagliptin – Greater dosing flexibility plus metformin – Liraglutide • Available as U-100, U-200 – Insulin glargine • Less hypoglycemia vs insulin glargine • Vitamin D and (D2d)

• Restoring Insulin Secretion Study (RISE) BASAGLAR ® (insulin glargine injection). [package insert] TRESIBA ® (insulin degludecinjection).[package insert] Aug 2015. Clinical Trials Diabetes Care. 2012 Dec;35(12):2464-71

In the Pipeline Conclusion

• Novel combinations • T2DM is a multifaceted disease state requiring – Xultophy®: insulin degludec + liraglutide coordination of care – LixiLan®: insulin glargine + lixisenatide • Treatment and assessment of goals should be • Novel dosing schedules individualized – Marizev®: omarigliptin • Lifestyle optimization and metformin continue – to be the cornerstones of therapy • Novel mechanisms • New and innovative treatment options are – Emapticap pegol: diabetic nephropathy underway – Human proIslet Peptide: HIP2B

ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [Feb 2016]. NCT01085292

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References

• ADA. Standards of Medical Care in Diabetes-2016.Diabetes Care. Jan 2016.39(1)S1- 39. DOI: 10.2337/dc16-S001 • AACE/ ACE Task Force. consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type Update on Type II Diabetes 2 diabetes management algorithm – 2016 executive summary. 2016. Endocr Pract. 2016; 22 (No. 1) 84-113. Pharmacotherapy • Metformin: Drug Information. In: Lexicomp®, Online Database. Post, TW (Ed), UpToDate, Waltham, MA. 2016. • McCulloch DK. Sulfonylureas and in the treatment of diabetes mellitus. In: UpToDate®, Online Database. Post, TW (Ed), UpToDate, Waltham, MA. 2016. Christine Ibarra, Pharm.D. • McCulloch DK. in the treatment of diabetes mellitus. In: Baptist Hospital PGY-1 UpToDate®, Online Database. Post, TW (Ed), UpToDate, Waltham, MA. 2016. • Invokana (canagliflozin)[package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc; [email protected] 2015. March 12, 2016 • Farxiga (dapagliflozin) [package insert]. Princeton, NJ: Bristol-Myers Squibb Pharmaceuticals Inc; 2014. • Jardiance® (empagliflozin). [package insert]. Ridgefield, CT : Boehringer Ingelheim Pharmaceuticals, Inc. 2016. • Afrezza® (insulin human). [package insert]. Danbury, CT : MannKind Corporation. 2014. www.fshp.org

References

• Food and Drug Administration. (2015). FDA approves Basaglar, the first “follow-on” insulin glargine product to treat diabetes[Press Release]. Retrieved from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm477734.htm. • http://www.cdc.gov/features/diabetesfactsheet/DiabetesFactSheet.pdf • American Diabetes Association. May 2014. History of Diabetes. Retreived from http://www.diabetes.org/research-and-practice/student-resources/history-of- diabetes.html. • Basaglar ® (insulin glargine injection). [package insert]. Indianapolis, IN. Eli Lilly and Company. Dec 2016. • Tresiba ® (insulin degludec injection).[package insert]. Bagsvaerd, Denmark . Novo Nordisk A/S. Sept. 2015. • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Targeting INflammation Using SALsalate in Type 2 Diabetes (TINSAL-T2D) In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [Feb 2016].Available from: https://clinicaltrials.gov/ct2/show/results/NCT00392678?sect=X70156&term=type+2+d iabetes&rank=7#outcome1. NLM Identifier: NCT00392678. • American Diabetes Association. Aug 2015. Clinical Trials. Retrieved from http://www.diabetes.org/living-with-diabetes/treatment-and-care/clinical-trials.html • NOXXON Pharma AG. NOX-E36 Multiple Ascending Dose Study in Healthy Volunteers and Patients With Type 2 Diabetes Mellitus. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [Feb 2016].Available from: https://www.clinicaltrials.gov/ct2/show/NCT01085292.

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