Let s not sugarcoat it! Update on Pharmacologic Management of Type II DM

Let s not sugarcoat it! Update on Pharmacologic Management of Type II DM Gregory Castelli, PharmD, BCPS, BC-ADM Clinical Pharmacist UPMC St. Margaret

Objectives By the end of this presentation, participants should be able to: Describe literature updates for common oral DM medications Recall new formulations and combinations of injectable DM medications Review practical information for two newer classes of DM medications-glp 1 agonists and SGLT2 inhibitors

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Timeline Literature Updates GLP1 Agonists Summary New Products, Same Med SGLT2 Inhibitors

Timeline Literature Updates GLP1 Agonists Summary New Products, Same Med SGLT2 Inhibitors

Patient Case: AZ AZ is a 45 yo obese male. PMH significant for T2DM diagnosed 4 years ago. FX includes MIs, CAD, HLD, HTN. He is an accountant and his exercise and eating habits are poor. Currently, he takes MTF 1000 mg BID. His last A1C is 9.5%. What do you start for better glycemic control? A. Diet and exercise only B. Glipizide C. Sitagliptin (Januvia ) D. Liraglutide (Victoza ) E. Pioglitazone (Actos ) F. Canagliflozin (Invokana ) G. Basal insulin H. Bromocriptine (Cycloset )

http://www.fda.gov/drugs/drugsafety/ucm493244.htm Metformin and Renal Dysfunction Previously SCr 1.5 mg/dl in men and 1.4 mg/dl in women New recommendations: GFR Start MTF? Continue MTF? 30 ml/min No No, discontinue 30-45 ml/min No Yes, dose, monitor GFR 3 months 45-60 ml/min Yes Yes, monitor GFR 3-6months >60 ml/min Yes Yes, monitor GFR annually

Gold Standard: Metformin Retrospective cohort of 15,516 patients 57.8% started on MTF Starting anything else: Increased risk of second oral medication Increased risk of starting insulin Similar for all individual meds Berkowitz SA et al. JAMA Intern Med. 2014 Dec;174(12).

Gold Standard: Metformin Berkowitz SA et al. JAMA Intern Med. 2014 Dec;174(12).

News Flash: Metformin and Cancer

After metformin, ask yourself: What medications reduce cardiovascular risk? What is the potential A1C reduction potential of medication classes? What medications are costly? What are my patient s preferences?

Sulfonylureas Do Not Increase Mortality Major guidelines advise no use or use with caution Meta-analysis of 47 trials including 38,000 pts Sulfonylureas not associated with: Increase in all-cause mortality Cardiovascular mortality Myocardial infarction Stroke Rados D et al. PLOS Medicine 2016;13(4):e1001992.

Sitagliptin and CV outcomes Designed after others show to HF Noninferiority trial design of 14,735 pts No difference in primary composite outcome Green JB et al. N Engl J Med 2015;373(3):232-242.

Timeline Literature Updates GLP1 Agonists Summary New Products, Same Med SGLT2 Inhibitors

Insulin Lispro (Humalog ) Twice as much insulin per ml Same 5 pen box Inject up to 60 units at once Humalog (insulin lispro injection) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; Aug 2016.

Insulin Glargine (Toujeo ) Delivers 3 times as much as Lantus in same volume 3 pen box Inject up to 80 units at once Toujeo (insulin glargine) [prescribing information]. Bridgewater, NJ: Sanofi-Aventis; September 2015.

Insulin Glargine (Basaglar ) Same as Lantus Pens 5 pen box Inject up to 80 units at once Basaglar (insulin glargine) [prescribing information]. Indianapolis, IN: Lilly USA, LLC; December 2015.

Insulin Regular (Humulin ) U-500 Delivers 5 units per click 2 pen box Inject up to 300 units at once Humulin R (human insulin) [prescribing information]. Indianapolis, IN: Eli Lilly; July 2016.

Insulin Degludec (Tresiba ) Ultra-long acting insulin 24-42 hours Same dosing as insulin glargine 10 units daily 0.2 units/kg daily Available as pen only 100 units/ml and 200 units/ml Insulin Degludec (Lexi-Drugs ). Lexi-Comp, Inc.; Aug 29, 2016.

Timeline Literature Updates GLP1 Agonists Summary New Products, Same Med SGLT2 Inhibitors

Glucagon-like peptide-1 Agonists GLPs (incretin hormone) Increases glucose-dependent insulin secretion Decreases inappropriate glucagon secretion Increases B-cell growth/replication Slows gastric emptying Decreases food intake Trujillo J, et al. Ther Adv Endocrinol Metab. 2015 Feb; 6(1): 19 28.

GLPs Considerations Safety Thyroid C-cell tumor risk Contraindicated in medullary thyroid carcinoma and multiple endocrine neoplasia syndrome Pancreatitis? Adjustments No renal adjustment Caution in liver impairment Many GI symptoms Trujillo J, et al. Ther Adv Endocrinol Metab. 2015 Feb; 6(1): 19 28.

GLPs Comparison GLP1 Product Dosing *Ease of Use Liraglutide (Victoza ) 0.6-1.8 mg daily +++ Exenatide (Byetta ) 5-10 mcg twice daily + Lixisenatide (Lyxumia ) 10-20 mcg daily + Exenatide (Bydureon ) 2 mg weekly + Dulaglutide (Trulicity ) 0.75-1.5 mg weekly +++ Albiglutide (Tanzeum ) 30-50 mg weekly ++ Daily and weekly injections tend to have better A1C reduction. Semaglutide weekly injection pending FDA approval. *Highly subjective Trujillo Green J, et al. JB Ther et al. Adv N Engl Endocrinol J Med 2015;373(3):232-242. Metab. Feb; 6(1): 19 28.

GLPs Administration Exenatide (Byetta ) Administer 60 minutes prior to meal Main meals must be 6 hours apart New pen set up requires 4 specific actions prior to use Exenatide (Bydureon ) Let pen reach RT Attach needle Twist pen until green area disappears Firmly tap the pen at least 80 times Rotate your pen ¼ turn every 10 taps Verify mixing Twist pen until orange area disappears Press injection button Liraglutide (Victoza ) Like most insulin pens Attach needle Dial to desired dose Press injection button

GLPs Administration Dulaglutide (Trulicity ) Uncap pen Twist pen to unlock position Press injection button Albiglutide (Tanzeum ) Twist pen to mix medication Rock pen 5 times Let pen reach RT 15 min for 30 mg 30 min for 50 mg Verify mixing Attach needle Twist pen to prime Press injection button Lixisenatide (Lyxumia ) Prime pen Attach needle Pull back to draw dose Press injection button

GLPs A1C Reduction Trujillo J, et al. Ther Adv Endocrinol Metab. 2015 Feb; 6(1): 19 28.

GLPs Weight Loss Potential Trujillo J, et al. Ther Adv Endocrinol Metab. 2015 Feb; 6(1): 19 28.

Liraglutide and CV Outcomes Included 9340 patients 50 yoa patients with diabetes High CV risk Randomized to liraglutide at highest tolerated dose or placebo Median follow-up 3.8 years Primary composite outcome First occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke Marso SP, et al. N Engl J Med 2016 Jul 28;375(4):311.

Effect Assessment Liraglutide and CV Outcomes Outcomes Placebo Lira NNT/H Safety Any serious ADE Severe hypoglycemia Acute gallstone disease 32.8 3.3 1.9 32.2 2.4 3.1 NS 112 83 Tolerability Effectiveness Any adverse event Nausea (leading to d/c) Vomiting (leading to d/c) Diarrhea (leading to d/c) Primary endpoint CV death All-cause mortality Nephropathy 62.3 0.6 0.1 0.1 14.9 6 9.6 7.2 60.8 1.7 0.7 0.6 13 4.7 8.2 5.7 NS 91 167 200 53 77 72 67 Marso SP, et al. N Engl J Med 2016 Jul 28;375(4):311.

GLP-Insulin Combinations Insulin degludec/liraglutide (IDegLira ) 100 units/3.6 mg per 1 ml (1 unit/0.036 mg) Already approved in Europe as Xultophy Current max dose is 50 units/1.8 mg Insulin glargine/lixisenatide (Soliqua ) Available 100/33 combination Current max dose is 60 units/ 22 mcg Novo Nordisk NDA Briefing Document. May 2016.

Timeline Literature Updates GLP1 Agonists Summary New Products, Same Med SGLT2 Inhibitors

SGLT2 Inhibitors Work by blocking sodium-glucose cotransporter 2 in proximal tubules Result is reduced reabsorption of glucose, decreased plasma glucose levels Diuretic effect potentially decreasing blood pressure Burke, et al. Pharmacotherpy 2017 Jan; 37(2):187 194.

SGLT2 Inhibitors Considerations Safety Dehydration, hyperkalemia DKA Amputations UTIs Bone fractures Adjustments Renal adjustments Burke, et al. Pharmacotherpy 2017 Jan; 37(2):187 194.

FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate 7 out of every 1,000 patients treated with 100 mg daily of canagliflozin 5 out of every 1,000 patients treated with 300 mg daily of canagliflozin 3 out of every 1,000 patients treated with placebo http://www.fda.gov/safety/medwatch/safetyinformation/saf etyalertsforhumanmedicalproducts/ucm501565.htm

SGLT2s Comparison GLP1 Product Dosing Combo with MTF? Canagliflozin (Invokana ) 100-300 mg daily Yes Dapagliflozin (Farxiga ) 5-10 mg daily Yes Empagliflozin (Jardiance ) 10-25 mg daily Yes

Empagliflozin and CV Outcomes Included 7020 patients Average age 63, 71% white, 72% male Mostly on MTF, ACEI, Statins Randomized to empagliflozin 10 mg or 25 mg 25% drop out rate Primary composite outcome Death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke Zinman, et al. N Engl J Med 2015 Nov 28;373:2117-2128.

Effect Assessment Empagliflozin and CV Outcomes Outcomes Placebo Empa NNT/H Safety Confirmed hypoglycemia Urosepsis Acute Renal Failure DKA 27.9 0.1 6.6 0.1 27.8 0.4 5.2 0.1 NS NS NS NS Tolerability Effectiveness Any adverse event ADE leading to d/c UTI Genital infection Primary endpoint CV death All-cause mortality HF hospitalization 91.7 19.4 18.1 1.8 12.1 5.9 8.3 4.1 90.2 17.3 18.0 6.4 10.5 3.7 5.7 2.7 NS NS NS 21 63 46 39 72 Primary Outcome Hazard ratio, 0.86 (95.02% CI, 0.74 0.99) Zinman, et al. N Engl J Med 2015 Nov 28;373:2117-2128.

Timeline Literature Updates GLP1 Agonists Summary New Products, Same Med SGLT2 Inhibitors

Medication Comparison Class of medications A1C Reduction CV Benefit Cost Biguanides (metformin) ~2% $ Sulfonylureas (glipizide) 1-2% $ DPP4 Inhibitors (sitagliptin) 0.5-1% $$$ GLP1 Agonists (liraglutide) 1-1.5% $$$ SGLT2 Inhibitors (empagliflozin) 0.5-1% $$$ Thiazolidinediones (pioglitazone) ~1% $$ Insulin (4%) $$$ CV Benefit: Beneficial= Harm= Unknown= $= inexpensive generic $$= expensive generic $$$= brand

Return to AZ AZ is a 45 yo obese male. PMH significant for T2DM diagnosed 4 years ago. FX includes MIs, CAD, HLD, HTN. He is an accountant and exercise and eating habits are poor. Currently he takes MTF 1000 mg BID. His last A1C is 9.5%. What do you start for better glycemic control? A. Diet and exercise only B. Glipizide C. Sitagliptin (Januvia ) D. Liraglutide (Victoza ) E. Pioglitazone (Actos ) F. Canagliflozin (Invokana ) G. Basal insulin H. Bromocriptine (Cycloset )

Summary Metformin forever remains the gold standard Many other options exist and selection should be patient specific Look for products with good evidence of reducing CV events/mortality

Let s not sugarcoat it! Update on Pharmacologic Management of Type II DM Gregory Castelli, PharmD, BCPS, BC-ADM Clinical Pharmacist UPMC St. Margaret