Updates in Diabetes Managment Tiffany Soper NP CDE MGH Diabetes Center

Conflicts of Interest No relevant conflict of interest to disclose.

Objectives Review goals and individualization of type 2 diabetes treatment Learn about updates in treatment options for type 2 diabetes

Treatment goals for type 2 Diabetes Avoid acute complications of diabetes Prevent micro- and macrovascular complications Minimize hypoglycemia Minimize weight gain Improve/maintain quality of life

2012 ADA/EASD Position Statement Individualize treatment targets Diet, exercise, education = foundation Metformin = 1st line drug Combination therapy with 1-2 oral or injectable agents is reasonable Ultimately, many patients will require insulin therapy Focus on comprehensive CV risk reduction Adapted from slide from E. Cagliero MD

Modulation of the intensiveness of glucose lowering in type 2 diabetes Depiction of the elements of decision-making used to determine appropriate efforts to achieve glycaemic targets. Greater concerns about a particular domain are represented by increasing height of the ramp. Thus, characteristics/predicaments towards the left justify more stringent efforts to lower HbA1c, whereas those towards the right are compatible with less stringent efforts. Where possible, such decisions should be made in conjunction with the patient, reflecting his or her preferences, needs and values. This ‘scale’ is not designed to be applied rigidly but to be used as a broad construct to help guide clinical decisions. Adapted with permission from Ismail-Beigi et al [ref 20] Inzucchi S E et al. Dia Care 2015;38:140-149 Copyright © 2014 American Diabetes Association, Inc. 6

Individualized A1c Targets <6.5-7% If this can be achieved with diet, exercise, metformin, minimal poly-pharmacy and few adverse effects 7-7.9% For older or complicated patients who have adverse effects or require poly-pharmacy 8-9% End-of-life, dementia Avoid >9%: Associated with catabolism, increased infection, metabolic disarray

Type 2 Diabetes Therapies Adapted from a slide by N. Wei MD

Case 1 74 year old male with 10 year history of type 2 diabetes mellitus complicated by worsening renal function with most recent EGFR 38. Patient has had acceptable control with A1c from 6.8 - 7.4% since treatment with metformin 1000 mg BID.

Type 2 Diabetes is a Progressive Disease Secondary Failure of Metformin Monotherapy Diabetes Care 2010; 33:501-506

Case 1: Treatment considerations Renal function fluctuating from eGFR 30s-45 Is it okay to continue Metformin? Diabetes Care 2011 Jun; 34(6): 1431-1437 Diabetes Care 2011 Jun; 34(6): 1431-1437

Insulin Secretagogues Sulfonlyureas – Glipizide, Glyburide, glimepiride Meglitinides – Repaglinide (Prandin) Tablet, generic HbA1c decrease of 1-2% Associated with weight gain and hypoglycemia

Insulin Secretagogues Drug Dose range Time to peak Duration excretion Repaglinide 0.25-4mg 1 4-5 Liver metabolism; 80% Bile Glyburide 1.25-20mg ~4 10 50% bile 50% urine Micronized glyburide 1.5-12 mg 2-3 4 glimeperide 1-8 mg 9 60% urine Glipizide 2.5 - 40 mg 1-3 2-4 Urine excretion Glipizide XL 5-20 mg Steady https://www.micromedexsolutions.com/micromedex2/librarian/CS/AF6079/PFActionId/pf.

DPP4’s role on incretins GLP-1 70-80% of the incretin effect in non-diabetics Half-life ~ 4-11 minutes, inactivated by DPP-4 GLP-1 actions Stimulates insulin secretion when glucose is elevated Inhibits gastric emptying, appetite, glucagon secretion Has proliferative and anti-apoptotic effects on b-cells Slide adapted from D. Wexler MD To understand DPP4 inhibitors, first we need to understand the role of incretins in glycemic control. Incretins are hormones made by the GI system that have an impact on glycemic control. DPP = dipeptidyl peptidase Produced in enteroendocrine L cells in ileum and colon

DPP4 inhibitors Usual dose Renal dose adjustment Hepatic monitoring Change in HbA1c* Sitagliptin 100 mg daily Yes No -0.7 Saxagliptin 5 mg daily Vildagliptin** 50 mg twice a day -0.6 Linaglptin -0.5 Alogliptin 25 mg daily *in combination with metformin vs. metformin + placebo **not available in US https://www.micromedexsolutions.com/micromedex2/librarian/CS/AF6079/PFActionId/pf

Case 2 49 year old female with 4 year duration of suboptimally controlled type 2 DM complicated by depression and obesity BMI 38. She has been maintained on metformin 1000 mg twice a day. Most recent A1c has crept up to 7.6%. Patient is frustrated with progressive weight gain since menopause.

Role of GLP-1 analogs Jump start weight loss Injection (pen), Tier 2-3 On average loss of 2.3-3.2 kg HbA1c improvement of 0.5-1.5% Injection (pen), Tier 2-3 Side effects – nausea, vomiting Black box warning: thyroid c-cell tumors for exenatide LAR and liraglutide (seen in rats) Slide adapted by D. Wexler

GLP-1 Receptor Agonists Exenatide (Byetta®) Twice/day sc. Injections Start with 5 mcg bid within 60 minutes of a meal and after 1 month increase the dose to 10 mcg bid if eGFR > 30 ml/min Liraglutide (Victoza®) Once day sc injection, “use with caution in renal impairment” Start with 0.6 mg qd for 1 week, then increase to 1.2 mg qd; may go to 1.8 mg qd Exenatide ER (Bydureon®) Once per week injection 2 mg, do not use if eGFR < 30 ml/min Albiglutide (Tanzeum®) Once per week injection, 30 mg, can increase to 50 mg if eGFR> 15 ml/min Dulaglutide (Trulicity®) Once per week, start 0.75 mg, can increase to 1.5 mg. No renal dose adjustment needed Lixisenatide (Adlyxin®) 10 mcg daily, can increase to 20 mcg daily. No dose adjustments for patient with moderate renal impairment (eGFR >30 ml/min) https://www.micromedexsolutions.com/micromedex2/librarian/CS/AF6079/PFActionId/pf

Other GLP-1 analogs Semaglutide (weekly) CVD Benefit in SUSTAIN-6 (NEJM 2016) Awaiting FDA approval Dulaglutide / Trulicity (weekly) Albiglutide / Tanzeum (weekly) Exenatide LAR / Bydureon (weekly) Lixisenatide / Lyxumia (daily) Combo with glargine: Soliqua 100/33 30 units insulin/10 mcg lixisenatide Start at ½ dose insulin Adapted from D. Wexler https://www.micromedexsolutions.com/micromedex2/librarian/CS/AF6079/PFActionId/pf

Adverse Events and Incretin-based Therapy 2008 – FDA warned of a strong temporal association between exenatide and pancreatitis (30 reported pancreatitis AE) 2009 – prescribing info for sitagliptin changed (88 reported pancreatitis AE) 2014 meta-analysis of 55 RCT and 5 observational studies of incretin treatment – no association of incretin treatment and pancreatitis All patients should be counseled to stop therapy if they develop persistent severe abdominal pain FDA and EMA – insufficient evidence to confirm an increased risk for pancreatic cancer or pancreatitis N Engl J Med 2014;370:794-797

Bariatric surgery 20-30% sustained weight loss after 1-2 years Schauer, P. R., et al. "Bariatric Surgery versus Intensive Medical Therapy for Diabetes — 3-Year Outcomes." NEJM May 2014

Sodium-Glucose Co-Transporter 2 SGLT2 inhibitors “Glucoretic” Inhibits glucose reabsorption in proximal tubule of the kidney, inducing glucosuria Effects HbA1c change: ~0.6-0.9% Weight change: ~2.5 kg US Approved agents Canaglifozin Dapagliflozin Empagliflozin Slide adapted from D. Wexler

SGLT2 inhibitors Canagliflozin (Invokana®) Dapagliflozin (Farxiga®) 100 mg qd, if eGFR> 60 mg/min can increase to 300 mg qd Dapagliflozin (Farxiga®) 5 or 10 mg qd, do not use if eGFR< 60 mg/min Empagliflozin (Jardiance®) 10 to 25 mg qd, do initiate if GFR is below 45 https://www.micromedexsolutions.com/micromedex2/librarian/CS/AF6079/PFActionId/pf

We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. Median duration of treatment 2.6, median observational time 3.1 years 7020 randomized, placebo, 10 mg, 25 mg.

acarbose α-glucosidase inhibitor – delays digestion of complex carbs and disaccharides, thus decreased glucose absorption Generic, Tier 1 HbA1c decrease 0.5-0.8% BID-TID dosing Flatulence and GI distress Popular in Asia

Updates on Insulin Generics Concentrated insulins

Basaglar Bioequivalent to glargine Can be considered interchangeable

Case 3 45 year old male with longstanding poorly controlled type 2 diabetes complicated by obesity with BMI 42 and retinopathy. Patient currently is using glargine 75 units twice a day and humalog 30-50 units before meals. He reports that he is experiencing pain when injecting the glargine doses.

Insulin absorption Rate of insulin absorption is inversely proportional to dose volume At high doses, volume injected can be large Slower Faster Adapted from D. Wexler

Glargine - dose-dependent peak and duration of action 10 men and 10 women with T2DM and obesity (BMI 36 kg/m2, HbA1c 8.3%) Studied with 24 hour euglycemic clamp Vast majority of T2D on <1.5 units/kg (0.7-1.0) Doses 2.0 units/kg 1.5 units/kg 1.0 units/kg 0.5 units/kg Placebo Figure 2—Effects of single injections of insulin glargine (0.0.5, 1.0, 1.5, and 2.0 units/kg) on endogenous glucose production, glucose rate of disappearance, and glucose infusion rates in overnight fasted type 2 diabetic individuals. Rates of endogenous glucose production are significantly suppressed by a greater amount (P 0.05) after 1.0, 1.5, and 2.0 units/kg compared with that for placebo. Rates of glucose disposal are similar after placebo and all doses of glargine. Glucose infusion rates are significantly increased (P 0.05) after all doses of glargine compared with that for placebo. Incremental AUC values for 1.0, 1.5, and 2.0 units/kg doses were also significantly increased compared with that for 0.5 units/kg dose. Lower doses do not last 24 hours Wang Z. Diabetes Care 2010; 33:1555 Adapted from D. Wexler

Lispro kinetics are also dose-dependent Subjects: 6 healthy (age 23, BMI 22 kg/m2) and 7 with obesity and T2DM (age 60, BMI 38 kg/m2, studied with euglycemic clamp Lispro injection Δ 50 units, obese T2DM □ 30 units, obese T2DM • 10 units, healthy subject ○ 10 units, obese T2DM Conclusion: lispro absorption and glucose lowering action are delayed with higher doses and in obesity/T2DM ….but worth noting: these higher doses are unusual, even in obese patients Gagnon-Auger, Diabetes Care 2010; 33:2502-2507

Concentrated insulins Nomenclature and general principles U-100 = 100 units in 1 ml NPH, R, lispro, aspart, glulisine ,glargine, detemir, degludec U-100 U-200 = 200 units in 1 ml Lispro U-200 (Humalog), degludec (Tresiba) U-200 U-300 = 300 units in 1 ml Glargine U-300 (Toujeo) U-500 = 500 units in 1 ml R U500 Same potency may be delivered in smaller volume, leading to improved absorption Slide adapted from D. Wexler

U-500 R: the original concentrated insulin At high doses - U-500 compared to U-100 Onset time similar (~30 min) Blunted peak Longer duration of action U-500 Peak 4-6 hours Duration of action 10-16 hours BID or TID dosing depending on dose Similar to NPH (blue line) de la Pena, Diabetes Care. 2011 Adapted from D. Wexler

Dosing U-500 R Error-prone Expensive Dosed in a U-100 syringe Ideally, instructions should be written in volume and equivalent U-100 units 0.15 ml on U-100 syringe, equivalent to 75 units Stable up to 28 days in pre- filled syringes New U-500 pen Expensive But costs less per unit than high-dose U-100 May be more effective due to improved absorption Use in pumps? Slide adapted from D. Wexler

New concentrated insulin formulations approved in 2015 All are dosed in pre-filled pens in which one unit dispenses a proportionately smaller volume May be safer All are more concentrated than U-100… …. but less concentrated than U-500 New concentrated insulins Glargine U-300 (Toujeo) Degludec U-200 (Tresiba) Lispro U-200 (Humalog U-200 Kwikpen) Studied in open-label randomized controlled trials designed and conducted by pharmaceutical sponsors Slide adapted by D. Wexler

Toujeo (glargine U-300) 1.5 ml prefilled Solostar pen (450 units) Maximum dose = 80 units Flatter peak Half-life 18-19 hours Duration >30 hours Less hypoglycemia Steinstraesser, A et al. Diabetes Obes Metab. 2014; 16:873-6 http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206538lbl.pdf

Tresiba (Degludec U-100 AND U-200) 3 ml prefilled Flextouch pen U-200: Max dose 160 units U-100: Max dose 80 units BEGIN clinical trial program Peak 6-10 hrs Half-life 24 hours Duration ~42 hours

Humalog (Lispro) U-200 3 mL prefilled Pen Max dose 60 units Bioequivalent to lispro U-100 May be useful for people on high doses of prandial insulin Not available in vials (cannot use in pumps) http://www.humalog.com/humalog-u200-hcp.aspx

New Combinations of basal insulin plus GLP-1 agonist Xultophy Dosing: Recommended starting dose is 16 units of degludec (and 0.58 mg of liraglutide) Maximum daily dosage 50 units of degludec and 1.8 mg liraglutide https://www.soliqua100-33.com/

GoodRx.com searches 11/8/2016 Insulin Cost Total Units Cost per unit Humulin R U-500, 20 mL vial $1655 10,000 $0.17 Humulin R U-500, 2 x 3 mL pen $684 3,000 $0.23 Toujeo (glargine U-300), 3 x 1.5 mL pen $403 1,350 $0.29 Lantus (glargine U-100), 5 x 3 mL pen $447 1,500 $0.30 Lantus (glargine U-100), 10 mL vial $298 1,000 Tresiba (Degludec) U-200, 3 x 3 mL pen $639 1,800 $0.36 Tresiba (Degludec) U-100, 5 x 3 mL pen $535 Humulin N Kwikpen, 5 x 3 mL pen $444 Humulin N, 10 mL vial $144 $0.14 Humulin R U-100, 10 mL vial Novolin N, ReliOn (Walmart), 10 mL vial $145, $26 $0.15, $0.03 Novolin R, ReliOn (Walmart), 10 mL vial Humalog U-200, 5 x 3 mL pen $1335 $0.45 200 units a day = $60/day of glargine 200 units a day = $6/day of Relion GoodRx.com searches 11/8/2016

Medtronic Minimed 670 insulin pump https://www.medtronicdiabetes.com/blog/introducing-the-minimed-670g-system/

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