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!!!!!!!!!DM2$Drug$EXPLOSION$$2015$
Mary!E.!Steward,!APRN2CNP,!MS,!MPH,!CDE!
OU!School!of!Community!Medicine2Tulsa!
Asst.!Professor,!Internal!Medicine!
!
No!
Disclosures!
Alphabet$Soup$for$T2DM$
• GLP21!!!“Tides”!• DPPIV!!!“GlipiKns”!• SGLT22!!“Gliflozins”!• TZD!!!!!!!“Glitazones”!!
!
!
Victoza,!Bydureon/ByeRa,!Trulicity,!Tanzeum,!Lyxumia!
Januvia,!Janumet!XR,!Tradjenta,!Jentadueto,!Juvisync,!Onglyza,!Kombiglyze,!Nesina,!Kazano,!Oseni!
Farxiga,!Xigduo!XR,!Invokana,!Invokamet,!Jardiance,!Glyxambi!
Pioglitazone/Actos!
!
Toujeo!u2300!insulin!!!!!Humalog!u2200!insulin!!!
Tresiba!(degludec)!and!Ryzodeg!70/30!(degludec/aspart)!
Afrezza!inhaled!insulin!!!
Metabolic$Syndrome$
PreET2$ T2$Onset$
T2$Progression$>10$yrs$
Insulin$resistance$
Insulin$producGon$IncreGn$gut$hormone$
Approach!to!Hyperglycemia!More!Aggressive!!!!!!!!!!!!!!!!!!!!!!!!!!More!ConservaKve!
!!!MoKvaKon!
Adherent!
!!!self2care!
!
Risks!hypo!
!
Disease!
duraKon!
!
Life!
expectancy!
!
ComorbidiKes!
!
Vascular!comp.!
!
Resources,!
support!!
!!!!!!MoKvaKon!
!!!!adherent,!self2care!
!
High!
!
Long2standing!
!
!
Short!
!
!
Severe!
!
Severe!
!
!
Limited!
Few,!mild!
Readily!
Available!
None!
Long!
Newly!
Dx!
Low!
Abtude!&!Expected!Tx!Effort!
Diabetes!Care,!19!April!2012!
CAUTION!
Hypoglycemia:!!More!ConservaKve!Mgt.!
• Hypoglycemia!unawareness!
• Age/funcKonal!status!• Limited!life!expectancy!
• Cardiovascular!disease!• Renal!disease!• Seizure!disorder!• Work!safety!
• Live!alone!
ALWAYS$FIX$LOWS$BEFORE$HIGHS$
ADA!Guidelines!2015!Adults!over!65!yrs.!
CharacterisKc!!!!!!!RaKonale!!!!!!!!A1c$!!!!!!!!Meal!!!!!!!!!HS!!!!!!!!!!BP!!!!!!!!Lipids!
Few!illness,!!!!!! !!!!!!!!Long!LE!!!!!!!!!<7.5%$$$$$902130!!!!!902150!!!!<140/90!!!!!staKn!Intact!cogniKon/funcKon!
!
Complex/intermed!!!!!Intermed!LE!!<8%$$$$$$$902150!!!!!1002180!!!!<140/90!!!staKn!Mild/mod!cogniKve/ADL!impairment!
!
Very!complex/poor!!!!!!Limited!LE!!<8.5%*$$$$1002180!!!!1102200!!!!<150/90!!!2nd!prev!health/long!term!care,!end!state!dx,!mod/severe!impairment,!demenKa!
!
!
*A1c!>8.5%!increases!risk!of!glycosuria,!dehydraKon,!hyperglycemia/hyperosmolar!syndrom,!poor!wound!healing.!!!!
DM#Care#Tab.!10.1!Vol!38,!sup!1,!Jan!2015,!p!S68.!
ADA!Guidelines!2015!Adults!over!65!yrs.!
CharacterisKcs!!!!!!!!
!!!!!Few!illnesses! !!!
Intact!cogniKon/funcKon!
Long!LE!
!A1c! ! ! !<7.5%$$Premeal!Glucose!target !902130!
HS!Glucose!target ! !902150!
BP! ! ! !<140/90!
Lipids! ! !staKn!!
DM#Care#Tab.!10.1!Vol!38,!sup!1,!Jan!2015,!p!S68.!
ADA!Guidelines!2015!Adults!over!65!yrs.!
CharacterisKcs!!!!!!!!
!!!!!Complex,!intermediate !!!
Mild/mod!cogniKon/funcKon!ADL!impairment!
Intermed!LE!
!A1c! ! $ !<8%$$Premeal!Glucose!target !902150!
HS!Glucose!target ! !1002180!
BP! ! ! !<140/90!
Lipids! ! !staKn!!!
DM#Care#Tab.!10.1!Vol!38,!sup!1,!Jan!2015,!p!S68.!
!
ADA!Guidelines!2015!Adults!over!65!yrs.!
CharacterisKcs!!!!!!!!
!!!!!Very!Complex,!poor!health,!Long!term!care,!End!stage! !!!
Mod/Severe!cogniKon/funcKon!ADL!impairment!
Limited!LE!
!A1c! ! $ !<8.5%$$Premeal!Glucose!target !1002180!
HS!Glucose!target ! !1102200!
BP! ! ! !<150/90!
Lipids__staKn!only!for!secondary!prevenKon!
*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.!
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!
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)!
Recommended