!!!!!!!!!DM2$Drug$EXPLOSION$$2015$c.ymcdn.com/sites/npofoklahoma.com/resource/collection/E...CAUTION! Hypoglycemia:!!More!ConservaKve! Mgt.! • Hypoglycemia!unawareness! • Age/funcKonal!status!

!!!!!!!!!DM2$Drug$EXPLOSION$$2015$

Mary!E.!Steward,!APRN2CNP,!MS,!MPH,!CDE!

OU!School!of!Community!Medicine2Tulsa!

Asst.!Professor,!Internal!Medicine!

!

No!

Disclosures!

Alphabet$Soup$for$T2DM$

•  GLP21!!!“Tides”!•  DPPIV!!!“GlipiKns”!•  SGLT22!!“Gliflozins”!•  TZD!!!!!!!“Glitazones”!!

!

!

Victoza,!Bydureon/ByeRa,!Trulicity,!Tanzeum,!Lyxumia!

Januvia,!Janumet!XR,!Tradjenta,!Jentadueto,!Juvisync,!Onglyza,!Kombiglyze,!Nesina,!Kazano,!Oseni!

Farxiga,!Xigduo!XR,!Invokana,!Invokamet,!Jardiance,!Glyxambi!

Pioglitazone/Actos!

!

Toujeo!u2300!insulin!!!!!Humalog!u2200!insulin!!!

Tresiba!(degludec)!and!Ryzodeg!70/30!(degludec/aspart)!

Afrezza!inhaled!insulin!!!

Pathophysiology$

Metabolic$Syndrome$

PreET2$ T2$Onset$

T2$Progression$>10$yrs$

Insulin$resistance$

Insulin$producGon$IncreGn$gut$hormone$

READY$$$TO$$$RX$

•  CauKons!•  Goals!•  PaRerns!•  Potency!

Approach!to!Hyperglycemia!More!Aggressive!!!!!!!!!!!!!!!!!!!!!!!!!!More!ConservaKve!

!!!MoKvaKon!

Adherent!

!!!self2care!

!

Risks!hypo!

!

Disease!

duraKon!

!

Life!

expectancy!

!

ComorbidiKes!

!

Vascular!comp.!

!

Resources,!

support!!

!!!!!!MoKvaKon!

!!!!adherent,!self2care!

!

High!

!

Long2standing!

!

!

Short!

!

!

Severe!

!

Severe!

!

!

Limited!

Few,!mild!

Readily!

Available!

None!

Long!

Newly!

Dx!

Low!

Abtude!&!Expected!Tx!Effort!

Diabetes!Care,!19!April!2012!

CAUTION!

Hypoglycemia:!!More!ConservaKve!Mgt.!

•  Hypoglycemia!unawareness!

•  Age/funcKonal!status!•  Limited!life!expectancy!

•  Cardiovascular!disease!•  Renal!disease!•  Seizure!disorder!•  Work!safety!

•  Live!alone!

ALWAYS$FIX$LOWS$BEFORE$HIGHS$

ADA!Guidelines!2015!Adults!over!65!yrs.!

CharacterisKc!!!!!!!RaKonale!!!!!!!!A1c$!!!!!!!!Meal!!!!!!!!!HS!!!!!!!!!!BP!!!!!!!!Lipids!

Few!illness,!!!!!! !!!!!!!!Long!LE!!!!!!!!!<7.5%$$$$$902130!!!!!902150!!!!<140/90!!!!!staKn!Intact!cogniKon/funcKon!

!

Complex/intermed!!!!!Intermed!LE!!<8%$$$$$$$902150!!!!!1002180!!!!<140/90!!!staKn!Mild/mod!cogniKve/ADL!impairment!

!

Very!complex/poor!!!!!!Limited!LE!!<8.5%*$$$$1002180!!!!1102200!!!!<150/90!!!2nd!prev!health/long!term!care,!end!state!dx,!mod/severe!impairment,!demenKa!

!

!

*A1c!>8.5%!increases!risk!of!glycosuria,!dehydraKon,!hyperglycemia/hyperosmolar!syndrom,!poor!wound!healing.!!!!

DM#Care#Tab.!10.1!Vol!38,!sup!1,!Jan!2015,!p!S68.!


CharacterisKcs!!!!!!!!

!!!!!Few!illnesses! !!!

Intact!cogniKon/funcKon!

Long!LE!

!A1c! ! ! !<7.5%$$Premeal!Glucose!target !902130!

HS!Glucose!target ! !902150!

BP! ! ! !<140/90!

Lipids! ! !staKn!!




!!!!!Complex,!intermediate !!!

Mild/mod!cogniKon/funcKon!ADL!impairment!

Intermed!LE!

!A1c! ! $ !<8%$$Premeal!Glucose!target !902150!


BP! ! ! !<140/90!

Lipids! ! !staKn!!!


!



!!!!!Very!Complex,!poor!health,!Long!term!care,!End!stage! !!!

Mod/Severe!cogniKon/funcKon!ADL!impairment!

Limited!LE!

!A1c! ! $ !<8.5%$$Premeal!Glucose!target !1002180!


BP! ! ! !<150/90!

Lipids__staKn!only!for!secondary!prevenKon!

*A1c!>8.5%!increases!risk!of!glycosuria,!dehydraKon,!hyperglycemia/hyperosmolar!syndrom,!poor!wound!healing.!!!

!


Enhanced$MeUormin$Use$!

Meqormin!is!“safe”!for!eGFR!>30*!

!

!

!

*Not!FDA!approved!Flory,!JH,!JAMA#Internal#Medicine#2014;!6936.!!ADA!PosiKon!Statement.!

Hypoglycemia$Costs/Risks$

•  Medicare!Hospital!Admissions!for!hypo>hyper!!=!

105/100,000!pt!yrs.!(2011)!

•  Blacks!have!4x!excess!risks>whites!•  Age!>85!yrs.!have!2x!risk!

! ! ! ! ! !ADA!Annual!ScienKfic!Sessions!2013!

Choosing(Wisely(Campaign,!American!Geriatrics!

Society,!cauGons$against$adding$DM$drugs$for$A1c$<7.5%$in$pts$>65$yrs.$(esp.$sulfonylureas$$&$$insulin)$$Recommend$8E8.5%$target$with$serious$comorbidiGes.$

•  Insulin!&!SU!follow!Warfarin!!

#2!for!adverse!drug!events/ER!use!!NEJM!2011;365:2002212.!

!Hypo$CauGons$$ConGnued$Recognize$Dangers$

Hypoglycemia$affects$safety,$adherence,$&$cost$

•  Aver!meqormin,!add!GLP21,!DPPIV,!SGLT22,!TZD!2nd!line!

!

•  AVOID!GLYBURIDE*,!Reconsider!sulfonylurea!use!in!the!elderly.!!!

•  Always!dose!sulfonylureas!before!a!significant!carb!meal.!

•  Don’t!use!sulfonylureas!with!meal!insulin!!

*AGS#Beers#Criteria#

DM!Glucose!Treatment!Goals!

Blood Glucose

ADA <65 yrs.

Conservative >65 yrs

Premeal 80-130 90-150

1-2 hrs. Postprandial or Bedtime

100-180 <200

HbA1c (%) <7% <7.5-8.5% Prescriber’s Letter Vol 20, #6, June 2013 AGS,, ADA 2015

Postprandial Pattern “stairstep”

Fasting Pattern “wave”

PATTERNS!

HIGH!

Baseline!

HIGH!

Excursions!from!

AM,!Lability!

Normal!

122!hrs.!

excursions!

B! L! S!

Recognizing$Paberns$

•  Postprandial$Hyperglycemia$–  (Stair2step!paRern!with!elevaKons!>100!mg/dL!over!fasKng!level,!BS!increase!with!feeding,!no!return!to!baseline!unKl!overnight)!

– Fix!the!meal!coverage!before!highest!BS!

•  FasGng$Hyperglycemia$–  (Start!high—stay!high,!<100!mg/dL!variance!through!day!from!fasKng!level,!return!basically!to!fasKng!level!later!through!the!day,!covering!meals)!

– Fix!the!fasKng!BS!

Sample$Paberns$

AM Noon PM Bedtime 185 224 279 312 215 290 343 298 147 218 325 360 AM Noon PM Bedtime 220 243 278 251 195 222 244 260 247 239 250 301

Factors$affecGng$Rxn$Choice$

•  Risk!of!inducing!Hypoglycemia!

•  Risk!of!Wt!Gain!

•  Ease!of!use!•  Cost!•  Safety!for!heart/kidney/liver!disease!•  Strength!in!A1c!lowering!

Potency$A1c$ReducGon$

•  GLP!1!“Tides” ! !~1.5% !Inject!q!day/wk!

!“biggest!bang!for!the!buck”!

•  SGLT22!“Gliflozins”! !~1.5% !oral!AM!

!“formulary,!prior!auth!issues!for!now”!

•  DPPIV!“GlipKns” !~1.0% !oral!

!“easy”!

•  TZD!“Glitazone” !~1.5% !oral!

!“4!Fs!–!fluid,!faRer,!failure!(HF),!fracture!(women)”!

What!next?!

•  45!yrs.!CF,!T2DM!x!6!mos,!on!meqormin!1000!

BID.!!!

•  BMI!37,!A1c!8.2%!

•  SoonerCare!insurance!•  Asks!about!diet!pills!

GLP21!Pens!

GLPE1$RecommendaGons$Add2on!GLP21!(approved!as!monotx):!

•  Want!weight$loss/maintenance$–  CombinaKon!with!meqormin!(Rx!met!1000!BID!#60!Tab;!have!

pt!break!in!½!to!start,!take!½!met!aver!eaKng,!!!!!!increase!dose!as!GI!tolerance).!!OR!Met!XR!500mg!4!daily!#120!

•  A1c!>7%,!rarely!>10%!–  3rd!party!insurance!coverage,!Tier!2!or!3,!PA!–  Copay!reducKon!cards/website!for!commercial!insur.!

•  Document!Tg,!pancreaKKs!hx/discussion!

•  Can!add!SGLT22!as!3rd!line.!•  Can!add!basal!insulin!(fasKng!paRern)!3rd!line;!off!

label!with!bolus!insulin!(postprandial!paRern)!

!

!

IncreGn$Concerns$!!

•  July!2013,!FDA!&!European!Medicines!Agency!(EMA)!agree!that!available!data!!

DO!NOT!confirm!concerns!over!pancreaKc!side!effects!!

with!GLP21!based!therapies.!

!

!!CONTRAINDICATIONS:((Gastroparesis,(use(of(Reglan(Thyroid(cancer,(or(MulBple(Endocrine(Neoplasia(2((

(•  Nausea!most!common#

!•  Medscape!Medical!News!!Aug!1,!2013!

•  DigesKve!Disease!Week!2013;!May!18221.!!Chao!DT.!!

•  Internal!Medicine!News!8/22/13!Consensus!Statement:!!Data!on!cancer,!pancreaKKs!do!not!warrant!change!in!prescribing!of!anKhyperglycemics.!!AACE.!!Endocrine!PracKce!2013;19:675293.!

SGLT2EI$Sodium$Glucose$CoETransporter$2$

•  Oral!drug!once!daily!in!AM.!!

•  Facilitates!excreKon!of!glucose!(70280!g/daily!excreKon)!and!related!calories!(22502350!kcal)!in!urine.!!

•  Requires!adeq!eGFR!to!work!!(>45),!may!need!to!dose!adjust.!

•  Monotx!0.521.5%!reducKon!A1c,!dec!FPG!30md/dL!

•  Cost!$300+/mos.!!Tier!3!SoonerCare.!

•  Sustained!wt!loss!up!to!90!wks;!3!kg/24!wks.!

!! ! ! ! !!

Medscape!May!7,!2013;!ADA!ScienKfic!Sessions!2013;!

!

$SGLTE2$Inhibitors$

•  EffecKve!Glycemic!Control.!!No!hypoglycemia!(unless!combined!with!

Insulin!or!!Secretagogue!Therapy).!!!!Durable!effect2!(2!yr!data)!

•  Reduces!A1c,!FasKng!and!Postprandial!Hyperglycemia1,!!

•  Decreases!variability,!(related!to!increased!risk!of!DM!complicaKons)!

•  AddiKve!benefits!with!increKns,!esp.!GLP21’s!•  Delay,!prevent!need!for!insulin;!esp.!fast2analog!(meal)!insulin!in!T2DM!22thus!decrease!potenKal!hypo2with!insulin!Rx!!!(85%!reducKon!if!avoid!fast2analogs)!

•  Works!with!FIRST!DOSE2!paKents!love!to!see!QUICK!benefit!Slide!by!Stan Schwartz MD, FACP

!!

1.  Blonde!L.!Am#J#Manag#Care.!2007;13(suppl!2):S362S40.!2.Blonde!L,!et!al.!J#Manag#Care#Pharm.!2006;12(7!suppl!A):S22S12.!

Jardiance!1st!to!show!CAD!benefit!•  Empagliflozin:!“the!benefit!was!driven!by!significant!reducKon!in!cardiovascular!mortality,!overall!mortality,!and!heart!failure!hospitalizaKons!as!there!were!no!differences!between!the!group!on!the!drug,!a!once2daily!sodium2glucose!cotransporter!2!(SGLT2)!inhibitor!used!to!treat!type!2!diabetes,!and!the!control!group!in!terms!of!rates!of!myocardial!infarcKon!or!stroke!over!the!3!years!of!the!study.”!

•  TreaKng!39!paKents!with!empagliflozin!for!3!years!would!prevent!one!cardiovascular!death!

•  SitaglipKn!(Januvia)!&!lixisenaKde!(Lyxumia)neutral!!!2015!

•  JAMA!Sept!2015:!EASD!MeeKng!presentaKon!9/2015;!MedPage!Today!9/18/2015!

SGLTE2$Concerns$

•  Women!more!likely!to!have!genital!tract!

infecKons!(10%!vs!3%!placebo!w/!yeast),!men!

balaniKs!(8%!vs!2%),!esp!in!first!6!mos!tx.!&!

uncircum!males.!!If!yeast!/!UTI!–!not!a!reason!to!stop!agent,!repeat!infecKon!rate!low.!!May!need!to!treat!with!fluconazole!2!doses!approx.!223!days!apart.!!

•  Drop!in!DBP.!!!CauKon!hypotension,!hypovolemia.!

•  !!!!K+,!LDL!cholesterol!

What!next?!

•  58!yrs.!AAM!with!T2DM!x!5!yrs.!on!meqormin!

1000!mg!BID.!

•  A1c!8.4%;!eGFR!>60;!BMI!34.!

•  BP!poorly!controlled!(160/96)!on!Lisinopril!40!and!amlodipine!5.!!!

•  AtorvastaKn!80!mg!daily.!!LDL!115.!

•  Strong!FH!CAD!father!&!brother!before!age!60.!

SGLTE2$

•  Farxiga!–!free!copay!with!commercial!

insurance,!even!if!not!covered!on!formulary!

(no!govt!plans).!!!

•  Xigduo!XR!–!(combo!with!meqormin!XR)/free!

•  Class!recommendaKon:!!Stop!if!nausea,!

vomiKng,!dehydraKon!concerns!(DKA!

potenKal!with!lower!glucose!than!normal)!or!

UTI,!Candida.!!Can!retry!if!GU!complicaKon.!

Maximize$Benefits$and$Minimize$Risks$SGLT2s$

– Teach!Volume!Issues!

•  Keep!Urine!Dilute!(let!kidney!tell!paKent!!!!!if!they’re!drinking!‘enough’)!

!

– UTI/!Yeast!InfecKon!Issues!• Make!sure!ho!history!frequent!issues!in!past2!if!so,!don’t!use!

•  Female2!careful!bathroom!habits,!urinate!aver!intercourse!!and!before!sleep!

• Male2!especially!uncircumsized2!get!Kp!of!penis!dry!before!leave!bathroom!

!Slide!by!Stan Schwartz MD, FACP

!

Euglycemic$DKA$in$SGLTE2$use$•  "PaKents!with!type!1!(off2label)!or!type!2!(FDA2approved!use)!diabetes!who!

experience!nausea,$vomiGng,$or$malaise$or!develop!a!metabolic!acidosis!in!the!sebng!of!SGLT2!inhibitor!therapy!should!be!promptly$evaluated$for$the$presence$of$[ketones$in]$urine$and/or!serum."!And!SGLT2!inhibitors!"should!only!be!used!with!great!cauKon,!extensive!counseling,!and!close!monitoring!in!the!sebng!of!type!1!diabetes,"!they!cauKon.!

•  SGLT2!inhibitors!increase$glucose$loss$through!the!urine!and!have!also!been!linked!to!increased!glucagon!levels,!which!could!cause!gluconeogenesis,!free2faRy2acid!release,!and!increased!serum2ketone!levels.!Volume$depleGon$associated!with!SGLT22inhibitor!use!could!exacerbate!the!problem!by!further!increasing!glucagon,!corKsol,!and!epinephrine,!the!case!report!authors!suggest.!

•  The!Diabetes!Care!paper!describes!nine!paKents!with!13!episodes!of!euglycemic!DKA,!some!of!whom!had!repeat!episodes!of!ketosis!on!rechallenge!with!SGLT2!inhibitors.!In!the!two!paKents!with!type!2!diabetes,!euglycemic!DKA!developed!postoperaKvely.!And!in!most!of!the!seven!paKents!with!type!1!diabetes,!euglycemic!DKA!developed!in!the!sebng!of!reduced!insulin!dose.!

DPPIVs!

•  Januvia,!Janumet!XR,!Tradjenta,!Jentadueto,!

Juvisync,!Onglyza,!Kombiglyze,!Nesina,!

Kazano,!Oseni!

FDA$Safety$Announcement$DPPIVs$

•  FDA$Drug$Safety$CommunicaGon:$FDA$warns$that$DPPE4$inhibitors$for$type$2$diabetes$may$cause$severe$joint$pain$

•  !822822015!!•  “The!U.S.!Food!and!Drug!AdministraKon!(FDA)!is!warning!that!the!type!2!diabetes!medicines!sitaglipKn,!saxaglipKn,!linaglipKn,!and!aloglipKn!may!cause!joint!pain!that!can!be!severe!and!disabling.!We!have!added!a!new!Warning!and!PrecauKon!about!this!risk!to!the!labels!of!all!medicines!in!this!drug!class,!called!dipepKdyl!pepKdase24!(DPP24)!inhibitors.”!

•  Typical!adverse!reacKons!are!URI!sx.!

TZD$“Glitazones”$

•  Pioglitazone/Actos!!!!!!15,!30,!45!mg.!

– Limit!to!low!or!mid!dose!range!if!use!insulin!

•  Insulin!SENSITIZER!at!muscle/fat/periphery!

–  Postprandial!glucose!effect!70%/fasKng!30%!•  Once!daily!oral,!generic,!Tier!1!•  4!F’s:!!Fluid!(edema),!FaRer!(wt!gain),!Failure!

(HF),!Fracture!(women);!bladder!cancer!assoc!very!limited/unlikely;!?!Macular!edema!

Case!1:!37!yrs.!HISP!F!with!T2DM!x!1!yrs.!

•  GI!side!effects!with!meqormin!IR,!able!to!

tolerate!met!XR!500!2!tabs!BID!x!5!mos.!!!

•  A1c!is!7.9%,!BMI!35.!!Joining!the!gym.!

•  Does!not!want!to!take!shots.!•  Normal!blood!pressure,!ASCVD!10!yrs!risk!<7.5%!

•  Good!commercial!insurance!

•  Goal!A1c?!!!!!!!!!Med!opKons?!

– What!if2222Loss!job222no!coverage!!??!

Case!2:!!72!yrs.!AAM!with!T2DM!x!5!yrs.!

•  CKD4!with!eGFR!26230,!meqormin!stopped.!

•  A1c!is!7.4%!prior!to!meqormin!stop.!

•  Goal!A1c?!•  Replacement!med!opKons?!

Case!3!:!!56!yrs.!CM!with!T2DM!x!3!yrs.!

•  BMI!29.3.!!Bydureon!weekly,!meqormin!1000!BID!with!good!GI!tolerance,!A1c!remains!mid!8%!range.!

! !Tests!sugar!once!daily!2002220!range!fasKng.!!!Lost!wt!over!the!past!1.5!yrs.!purposeful.!!!

!FH!posiKve!in!father!dx!at!age!52!yrs.! !!!!!!!!!!!!!!!Numbness!&!Kngling!stocking/glove.!!!

•  HYPERTENSION!2!lisinopril!20!&!lisin!20/12.5!mg!daily!with!poor!control;!BP!162/98;!!

!!!!microalbumin!+!157!mcg.!in!Jan!2015!

•  DYSLIPIDEMIA!2!simvastaKn!40!in!AM!

!

Case!4:!!63!yrs.!Asian!F!w/T2DM!x!21!yrs.!!!

•  BMI!29,!apple2shaped.!!Prior!good!response!to!meqormin,!but!stopped!2!yrs.!ago!for!CKD.!

•  Taking!Apidra!33!TID,!Lantus!80,!Tradjenta!5,!!!!!Actos!15!added!in!past!4!wks.!!

•  A1c!9%!2!12%!past!few!years.!Lately!BS!“high!no!maRer!what,”!gained!weight!from!127!to!148#!over!past!18!Mos.!!

•  Intolerance!to!SGLT2!drugs!(Invokana!Oct!2014)!•  Very!careful!eaKng,!mostly!carbs,!small!porKon!sizes,!liRle!protein,!uses!Splenda,!no!sugared!drinks.!!

•  Bad!neurop,!poor!balance,!limited!walking.!

•  Recent!eGFR!!40.!!

More$New$Insulins$

Concentrated!Insulins!=!Same!dose,!less!volume!

•  Toujeo!SoloStar!(glargine)!!!u2300!

!

•  Humalog!(lispro)!u2200!

!

!

•  Tresiba!(degludec)/Ryzodeg!70/30!!

•  Afrezza!inhaled!insulin!

??$$SGll$to$Come$for$DM2$??$

•  More!drugs!in!the!GLP21,!DPPIV,!SGLT22!

classes!

•  Combo!injectables!of!GLP21!&!basal!insulin!

•  Glitazar!orals!(new!class)!

!!!!!!!!!DM2$Drug$EXPLOSION$$2015$

Mary!E.!Steward,!APRN2CNP,!MS,!MPH,!CDE!

OU!School!of!Community!Medicine2Tulsa!

Asst.!Professor,!Internal!Medicine!

!

Documents

!!!!!!!!!DM2$Drug$EXPLOSION$$2015$c.ymcdn.com/sites/npofoklahoma.com/resource/collection/E...CAUTION! Hypoglycemia:!!More!ConservaKve! Mgt.! • Hypoglycemia!unawareness! • Age/funcKonal!status!