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11/8/2016Type 2 Diabetes: MedicationManagementElizabeth Stephens, MDProvidence Medical Group- NortheastEndocrinology, Dept. of Medical [email protected] 2016Disclosures None1

11/8/2016Topics to Discuss: Review of pharmacology of medication classes,with updated olidinedioneIncretins DPP-4 GLP-1– SGLT-2 inhibitors– InsulinDrugs for DM Management2

11/8/2016TYPE 2 DIABETES12 Different Classes of TherapyReduce Hepatic GlucoseProduction–Metformin XREnhance Insulin Secretion/Effect–Sulfonylureas Insulin Sensitizers– Thiazolidinediones SGLT 2 Inhibitors Canagliflozin (Invokana),Dapagliflozin (Farxiga),Empagliflozin (Jardiance)glipizide, glyburide, glimepiride–Meglitinides (short acting) Repaglinide (Prandin), nateglinide(Starlix)–Insulin- injectableAttenuate Glucose Absorption–α-glucosidase inhibitors Incretin Therapies– GLP Analogs Acarbose (Precose)Miglitol (Glyset)Other:Pioglitazone (Actos) ,Rosiglitazone(Avandia)Exenatide (Byetta), XR weeklyLiraglutide (Victoza), Albiglutide(Tanzeum), dulaglutide (Trulicity),lixisenatide (Adlyxin)- DPPIV Inhibitors- Bromocriptine- Salsalate- Colesevelam- Amylin Analogs (Symlin) Sitagliptin (Januvia), Saxagliptin(Onglyza), Linagliptin (Tradjenta),Alogliptin (Nesina)Diab Care 2016;39(supp 1):S523

11/8/2016Case: 62 yo with obesity (BMI 34), type 2 diabetesfor 5 yrs, no complications, HTN On metformin, A1c 8.5% Cr 1.6mg/dL(eGFR 45)– Tried glipizide in the past- hypoglycemia Very limited engagement or monitoring Doesn’t want insulin, but willing to considerother injectables Questions:– Is the metformin safe? What to add next?Metformin Mechanism of action (MOA): hepaticglucose production A1c lowering: 1-1.5% Cost: 4/month Pros:long experience, lack of hypoglycemia, CVD (UKPDS), ? cancer protection Cons: Diarrhea/cramping (?less with XR), B12deficiency, ? lactic acidosis (very rare),cautious use with comorbidities (acidosis,hypoxia, CHF, renal insufficiency)4

11/8/2016FDA Revises Metformin WarningsNEW Labeling- 2016 Then: Don’t use in women Cr 1.4mg/dL,Men 1.5mg/dL Now: Before starting metformin, check eGFR– Contraindicated if 30mL/min/1.73m2– Don’t start if between 30-45mL/min/1.73m2 If eGFR falls to 45mL/min/1.73m2, assessrisk/benefits and consider dose Follow annually, or more often if at onylureas MOA: insulin secretion from beta cellsA1c lowering: 1-2%Cost: Low ( 4/month)Pros: effective, long-experience, microvascular risk (UKPDS) Cons: hypoglycemia, weight gain,durability, ? blunts myocardial ischemicpreconditioning5

11/8/2016More on Sulfonylureas Beta cell burnout:– ADOPT: lost glucose control at 45months withmetformin vs 33 months with glyburide– No difference in UKPDS– Over 6 yrs, 34% with SU needed insulin, c/w27% with DPP4 Weight gain: 2-5kg on average Hypoglycemia:– 6x more hypoglycemia c/w other DM medsKahn S, NEJM 2006;355:427; UKPDS 1995;11:1249; Inzucchi S, Diab Obes Metab 2015;Cefalu W, Diab Care 2015Thiazolidinediones: MOA: insulin sensitivityA1c lowering:1-1.5%Cost: low ( 30/month coupon)Pros: no hypoglycemia, durable, HDL, TG’s, CVD events (PROactive),?protective in steatohepatitis Cons: Fluid retention/CHF, weight gain,fractures, LDL, ? MI (rosiglitazone),bladder cancer?6

11/8/2016Pioglitazone in Steatohepatitis 101 pts with pre-DM or dm, biopsy-provennonalcoholic steatohepatitis (NASH)– Randomized to PBO or pioglitazone 45mg/d for 18months 58% achieved score of liver disease– 51% with resolution of NASH Led to reduction in A1c, fasting insulin,AST/ALT, triglycerides Also noted: gain of 2.5 kg, no further benefitwith longer duration of treatment (up to 36 mos)Cusi K, Annals IM 2016Pioglitazone After Stroke/TIA 3876 pts with recent stroke or TIA– Randomized to placebo vs pioglitazone Diagnosed with insulin resistance usingHOMA-IR index 1 outcome: fatal/non-fatal stroke, MI By 4.8 years– 1 outcome: 9% (pio) vs 11.8% (pbo)- HR .76– DM dev: 3.8% (pio) vs 7.7% (pbo)-HR .48– With pio more wt gain, edema and fractureKernan WN, NEJM 20167

11/8/2016DPP 4’s MOA: Inhibitors of metabolism ofGLP1/GIP to enhance incretin effect A1C lowering: .5-1% Cost: high ( 370/month coupon) Pros: less hypoglycemia unless used withSU/insulin, oral, option with renalinsufficiency (linagliptin) Cons: angioedema/urticaria, ?pancreatitis,? CHFGLP-1 Medications MOA: insulin secretion, glucagon, slowsgastric emptying, satiety A1C lowering: 1-1.5% Cost: high ( 580-650/month coupon) Pros: no hypoglycemia, weight loss, CVbenefit Cons: injectable, pancreatitis, GI sideeffects, medullary thyroid cancer inanimals, renal issues (exenatide)8

11/8/2016GLP-1 Weekly Useful to consider inreluctant injectors Equivalent benefit todaily dosing– Wt loss, A1c lowering,hypoglycemia, SE– Review showed betterA1c/wt loss withdulaglutide/weeklyexenatide, but databiased (Zaccardi F, Ann IM 2015) Pick the one toleratedand affordableSGLT2 Inhibitors: MOA: blocks glucose reabsorption bythe kidney- glucosuria A1c lowering: .5-1% Cost: high ( 400/month coupon) Pros: no hypoglycemia, weight, BP,durable, CV benefit, renal protection Cons: GU infections, polyuria, volumedepletion/hypotension, LDL/creatinine9

11/8/2016CV Outcomes in DM Medications Motivated by high prevalence of CV indiabetes concerns raised by rosiglitazone FDA Guidance to Industry, 2008– Sponsors should demonstrate that new type 2DM drugs should not result in unacceptable CVrisk– Require inclusion of higher risk CV patients, belong enough to detect adverse CV effects,include in protocol and committees to evaluateSmith RJ, Diabetes Care 2016Completed CV Outcome TrialsTrial, n ofsubjectsMACE*Hosp for CHFAll-causemortalitySAVOR-TIMI(saxagliptin), n 16,4921.00 (.89-1.12)1.27 (1.07-1.51)1.11 (.96-1.27)EXAMINE (alogliptin),n 5,380.96 (.8-1.16)1.19 (.9-1.58).88 (.71-1.09)TECOS (sitagliptin),N 14,671.98 (.88-1.09)1.0 (.83-1.2)1.01 (.9-1.14)EMPA-REG(empagliflozin), n 7020.86 (.74-.99).65 (.5-.8).68 (.57-.82)ELIXA (lixisenatide),n 6,0681.02 (.89-1.17).96 (.82-1.16).94 (.78-1.13)LEADER (liraglutide)n 9340.87 (.78-.97).87 (.73-1.05).85 (.74-.97)Sustain 6 (semaglutide)n 3,297.74 (.58-.95)1.11 (.77-1.61)1.05 (.74-1.5)10

11/8/2016DPP4’s and CHF? No increase noted in retrospective cohort of376,677 pts comparing risks for CHF withsaxagliptin/sitagliptin (Toh et al, Annals IM 2016) Explanations:– Chance finding, differences in studies/patientsenrolled, background care provided,differences in drugsFilion KB, Diab Care 2016EMPA-REG OUTCOME Trial 7028 patients, type 2 DM CVD– Followed 3.1 years– Empagliflozin 10mg vs 25mg vs PBO Primary outcome:Composite CVD death,non-fatal MI, non-fatal stroke– 97% completed study With empagliflozin:– rates of CV death from CV causes, CHFadmits, death from any cause– A1c : 12 wks: -.54-.6%, 206 wks: -.24-.36%Zinman B et al, NEJM 2015;373:211711

11/8/2016Results from EMPA-REGACP JC 1-19-16SGLT-2’s Cardioprotective?EffectLikelihoodReasonMetabolic actions- BGUnlikelyBG a weak CV risk factor, benefit ofA1c on CVD takes 10 yrs- fat oxidation or ketoneconcentrationUnlikely O2 demand per ATP generated- Weight lossUnlikelyModest changesHemodynamic actions- BPLikelyProven CV protection in prior studies- Diuretic effectLikelyProven against CHF in prior trials- Impaired arterial elasticityPossible? Some effect of empagliflozin- Direct effect on myocardiumUnlikelyNo evidence-Decreased sympathetic tonePossibleNo in HR with in BP and volumeAbdul-Ghani M, Diab Care 201612

11/8/2016Liraglutide and CV OutcomesLEADER Trial: 9340 pts, followed for 3.8 yrs, randomized to liraglutide or placeboNNT to prevent one event in 3 yrs was 66 (primary outcome), 98 (death)Marso SP et al, NEJM 2016In-Progress CVD TrialsTrialMedPlanned #Planned dateSUSTAIN-6Semaglutide3297Jan 2016CANVASCanagliflozin4407June 2017CARMELINALinagliptin8300Jan 2018EXSCELExenatide14000Jan 2018ITCA 650Exenatide4000July 2018CAROLINALinagliptin6000Sept 2018DECLARE-TIMI58Dapagliflozin17150April 2019REWINDDulaglutide9622April 2019HARMONYAlbiglutide9400May 2019CV OUTCOMESERTUGLIFLOZINErtugliflozin3900Oct 2020CV OUTCOMESOMARIGLIPTINOmarigliptin4202Dec 2020Smith RJ, Diab Care 201613

11/8/2016Summary of CVD Data Studies note benefit/harm with particularmedications– Unclear if class effect Many payors are responding to this datato make certain brands “preferred” Plenty of ongoing trials, so more to come!Case: 62 yo with obesity (BMI 34), type 2 diabetesfor 5 yrs, no complications, HTN On metformin, A1c 8.5% Cr 1.6mg/dL(eGFR 45)– Tried glipizide in the past- hypoglycemia Very limited engagement or monitoring Recs: continue metformin, consider addingGLP1 or sulphonylurea14

11/8/2016Next Case: 68yo with type 2 dm, chronic LBP, GERD,obesity, HTN, on statin Meds include: glargine 75units qd– Intolerant of metformin, dapagliflozin causedrecurrent yeast infections A1c now 8.7%, nl renal and liver function Wants better control without weight gain.How about the one on TV?New insulin Options Degludec (Tresiba ):– Comes as U100 or U200– Transition 1:1 (consider 20% decrease withBID or lower A1c)– Dosing flexibility (not given every 8 hours) U300 Glargine(Toujeo ):– Transition 1:1 from long-acting Often requires dose 10-15% c/w regular glargine– Once daily, same time15

11/8/2016Clinical ProfilesU300LantusDurationof ActionHalf-life SteadyStateMaxDoseUnits/penPens/boxCost 30hours18-19hrs80 U4503 (1350) 3505 daysU10042 hrsDegludec25 hrs 2-3days80 U300(1U adj)5 (1500) 450U20042 hrsDegludec25 hrs 2-3days160 U600(2U adj)3 (1800) 560When to consider new insulins?My opinion Degludec: shift workers, higher dosingrequirements, forgetting insulin doses,long-acting twice/day, variability thoughtdue to long-acting U300 glargine: long-acting twice/day,forgetting insulin doses, variabilitythought due to long-acting16

11/8/2016Don’t Overlook NPH andRegular Insulin Among privately insured adults DM2– 19% using analogs in 2000, c/w 96% in 2010– From 2001 2015, lispro vials increased from 35 234, human insulin 20 131 LOTS of marketing with insulin analogs– Emphasizing more physiologic, lesshypoglycemia No difference in A1c, no data on outcomesor complicationsTylee T, Hirsch I, JAMA 2015Combinations instead ofbolus? GLP-1 or SGLT2 inhibitors– Effective to control BG weight loss hypoglycemia TZD also an option– fluid retention, weight gain when used with insulinACP JC 1-20-1617

11/8/2016Cost DataMean all-cause costsDM Health-related costsDalal MR, Endo Prac 2015Total health costs for 18,413 (GLP1) vs 20,821 (RAI),but diabetes costs were similar.Returning to Case 68yo with type 2 dm, chronic LBP, GERD,obesity, HTN, on statin Meds include: glargine 75units qd– Intolerant of metformin, dapagliflozin causedrecurrent yeast infections A1c now 8.7%, nl renal and liver function Recs: consider GLP118

11/8/2016Conclusions DM is complicated, on so many levels Many new medications to choose from– Newer isn’t necessarily better But lots of direct-to-consumer marketing, sogood to have some familiarity Cost an ongoing challenge More people have diabetes but:– Management is improving– Fewer complicationsTHE END19