Diabetes Management in 2017 · Discuss further updates in diabetes management in 2017 DPP-4...

Diabetes Management in 2017

AliceYYCheng,MD,FRCPC

Twi4er:@AliceYYCheng

Objec;ves

Bytheendofthissession,youwillbeableto:

1.  Describethemajorlandmarkcardiovascularoutcometrialsindiabetesthatshouldchangeprac;ce

2.  U;lizetherecommenda;onsfromrecentupdatestotheDiabetesCanadaclinicalprac;ceguidelines

3.  Discussfurtherupdatesindiabetesmanagementin2017

DPP-4inhibitorGLP-1receptor

agonistInsulin

Insulinsecretatogue

SGLT2inhibitor

MeWormin

Thiazolidinedione

GLP-1receptoragonist

DPP-4inhibitorGLP-1receptor

agonist

MeWormin

Alpha-glucosidaseinhibitor:

carbohydrateabsorp;on

Adapted from: Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009; 58(4):773-95.

Addanotherclassofagentbestsuitedtotheindividual(agentslistedinalphabe.calorder):

Class Rela8veA1CLowering

Hypo-glycemia

Weight EffectinCardiovascularOutcomeTrial

Othertherapeu8cconsidera8ons Cost

α-glucosidaseinhibitor(acarbose)

↓ Rare Neutralto↓

Improvedpostprandialcontrol,GIside-effects $$

DPP-4Inhibitors ↓↓

Neutralto↓

alo,saxa,sita:

Neutral

Cau;onwithsaxaglip;ninheartfailure

GLP-1Ragonists ↓↓to↓↓↓ Rare ↓↓

lira:SuperiorityinT2DMpa;entswithclinicalCVD

lixi:Neutral

GIside-effects

Insulin ↓↓↓ Yes ↑↑ Neutral(glar) Nodoseceiling,flexibleregimens $-$$$$

Insulinsecretagogue:Megli;nideSulfonylurea

↓↓↓↓

YesYes

↑↑

LesshypoglycemiaincontextofmissedmealsbutusuallyrequiresTIDtoQIDdosingGliclazideandglimepirideassociatedwithlesshypoglycemiathanglyburide

SGLT2inhibitors ↓↓to↓↓↓

Rare ↓↓

empa:SuperiorityinT2DMpa;entswithclinicalCVD

Genitalinfec;ons,UTI,hypotension,dose-relatedchangesinLDL-C,cau;onwithrenaldysfunc;onandloopdiure;cs,dapagliflozinnottobeusedifbladdercancer,rarediabe;cketoacidosis(mayoccurwithnohyperglycemia)

Thiazolidinediones ↓↓ Rare ↑↑ Neutral CHF,edema,fractures,rarebladdercancer(pioglitazone),cardiovascularcontroversy(rosiglitazone),6-12weeksrequiredformaximaleffect

Weightlossagent(orlistat)

↓ None ↓ GIsideeffects $$$

alo=aloglip;n;glar=glargine;saxa=saxaglip;n;sita=sitaglip;n;lira=liraglu;de;lixi=lixisena;de;empa=empagliflozin 11/2016

Published online on November 2016

Primary outcome: 3-point MACE: CV death, non-fatal MI or non-fatal stroke

Empagliflozin (pooled) HR 0.86

(95.02% CI 0.74, 0.99) p=0.0382*

Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)

Empagliflozin 25 mg HR 0.86 (95% CI 0.73, 1.02),p=0.0865

Empagliflozin 10 mg

HR 0.85 (95% CI 0.72, 1.01), p=0.0668

Zinman B, Wanner C, Lachin JM, et al. N Engl J Med Sep 17, 2015. 10.1056/NEJMoa1504720

Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value

3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001

Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189

Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638

0.25 0.50 1.00 2.00

CV death, MI and stroke

Favours empagliflozin Favours placebo

Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI

Hospitalisation for heart failure

Empagliflozin (pooled) HR 0.65

(95% CI 0.50, 0.85) p=0.0017

Cumulative incidence function. HR, hazard ratio

Empagliflozin 10 mg HR 0.62 (95% CI 0.45, 0.86), p=0.0044

All-cause mortality

Empagliflozin (pooled HR 0.68

(95% CI 0.57, 0.82) p<0.0001

NNT = 39

For 3 years

Kaplan-Meier estimate. HR, hazard ratio

EMPA-REG OUTCOME: Number needed to treat to prevent one…

CV: cardiovascular; MACE: major adverse cardiovascular event.

Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med Sep 17, 2015. doi: 10.1056/NEJMoa1504720

63 45 39

CV death MACE All-cause death

For 3 years

Primary outcome CV death, non-fatal myocardial infarction, or non-fatal stroke

The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio.

Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

CV Death, Non-fatal MI, Non-fatal stroke

*95.02% CI. CV: cardiovascular; Empa: empaglifloin; Lira: liraglutide; MACE: major adverse cardiovascular event; MI: myocardial infarction; Pbo: placebo.

All-cause death

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; HR: hazard ratio.

LEADER: Number needed to treat to prevent one…

CV: cardiovascular; MACE: major adverse cardiovascular event.

Marso S et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes N Engl J Med June 2016 doi: 10.1056/NEJMoa160382. Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

Start metformin immediately

Consider initial combination with another antihyperglycemic agent

Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin

A1C <8.5% Symptomatic hyperglycemia with metabolic decompensation A1C ≥8.5%

Initiate insulin +/- metformin

If not at glycemic target (2-3 mos)

Start / Increase metformin

If not at glycemic targets

L I F E S T Y L E

Add another agent best suited to the individual by prioritizing patient characteristics:

Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Cardiovascular disease or multiple risk factors Comorbidities (renal, CHF, hepatic) Preferences & access to treatment

See next page…

AT DIAGNOSIS OF TYPE 2 DIABETES

Consider relative A1C lowering Rare hypoglycemia Weight loss or weight neutral Effect on cardiovascular outcome See therapeutic considerations, consider eGFR See cost column; consider access

PATIENT CHARACTERISTIC CHOICE OF AGENT

PRIORITY: Clinical Cardiovascular Disease

Antihyperglycemic agent with demonstrated CV outcome benefit (empagliflozin, liraglutide)

11/2016

Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity CV disease or multiple risk factors Comorbidities (renal, CHF, hepatic) Preferences & access to treatment

Consider relative A1C lowering Rare hypoglycemia Weight loss or weight neutral Effect on cardiovascular outcome See therapeutic considerations See cost column; consider access

If not at glycemic target

From prior page…

•  Add another agent from a different class •  Add/Intensify insulin regimen

Make timely adjustments to attain target A1C within 3-6 months

L I F E S T Y L E

11/2016

Hypo-glycemia

Neutralto↓

alo,saxa,sita:

Neutral

lixi:Neutral

GIside-effects

↓↓↓↓

YesYes

↑↑

Rare ↓↓

Neutral (glar)

alo,saxa,sita:Neutral

Neutral

Empa:SuperiorityinT2DMpa;entswithclinicalCVD

Lira:superiorityinT2DMpa;entswithclinicalCVD

Lixi:neutral

Recommendation 4

4.  In adults with type 2 diabetes with clinical cardiovascular disease in whom glycemic targets are not met, an antihyperglycemic agent with demonstrated cardiovascular outcome benefit should be added to reduce the risk of major cardiovascular events (Grade 1, Level 1A for empagliflozin ; Grade 1, Level 1A for liraglutide if age ≥50 years; Grade D, Consensus for liraglutide if age <50 years).

11/2016

GLP-1 receptor agonist

DAILY AGENTS WEEKLY AGENTS

Parameter Exenatide BID LIxisenatide Liraglutide Albiglutide Dulaglutide Exenatide

Half-life 2.4 hrs ~3 hrs 13 hrs ~5 days ~5 days 7–14 days

Time to steady state

N/D N/D 3–5 days 4–5 weeks 2–4 weeks 6–7 weeks

A1C reduction -0.4 to -1.4% -0.7 to -0.9% -0.8 to -1.5% -0.6 to -0.8% -0.8 to -1.6% -1.3 to -1.9%

FPG reduction + + ++ + ++ ++

PPG excursion reduction

++ ++ + + + +

Gastric emptying

All GLP-1RAs slow gastric emptying, but less tachyphylaxis with EXE BID and LIXI

Body weight change (kg)

-0.9 to -2.8 -0.2 to -2.8

-1.6 to -3.2

+0.3 to -1.2 +0.2 to -3.0 -2.0 to -3.7

Nausea 33–57% 20–40% 10–47% 5–13% 8–28% 9–26%

Vomiting 12–17% 7–18% 4–17% 3–6% 4–17% 4–11%

GLP-1 Receptor Agonists

+ = modest reduction; ++ = strong reduction

GLP-1 receptor agonist CV Safety Trials Currently In Progress

2012 2013 2014 2015 2016 2017 2018 2019 2020

EXSCEL Exenatide QW vs.

Placebo N=14,000

REWIND Dulaglutide vs.

Placebo N=9,622

HARMONY Outcomes Albiglutide vs.

Placebo N=9,400

All are large, non-inferiority,

event driven CV safety studies on individuals with T2DM who are at high baseline CV

EXSCEL, Exenatide Study of Cardiovascular Event Lowering Trial; HARMONY Outcomes, Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus; REWIND, Researching Cardiovascular Events With a Weekly Incretin in Diabetes.

•  Prefilled single-dose pen

•  Does not require reconstitution

•  Injection steps (uncap, unlock, inject)

•  Built-in needle (29g, 5mm)

Data on file. Eli Lilly and Company.

Dulaglutide Pen

•  Prefilled single-dose pen

•  Requires reconstitution

•  Injection steps (attach needle, turn knob to click, tap against palm 80 times or more, turn knob again, inject)

•  Separate needle (23 g, 7 mm)

Bydureon® US Prescribing Information. AstraZeneca. Available at: http://www.bydureonhcp.com Accessed September 16, 2014.

Exenatide QW Pen

Wysham C et al. Diabetes Care 2014;37:2159-67. Dungan KM et al. Lancet 2014;384:1349-1357. Drucker D et al. Lancet 2008;372:1240-50. Buse J et al. Lancet 2013;381:117-24. Pratley R et al. Lancet Diabetes Endocrinol 2014;2:289-97.

BL: baseline; MET: metformin; PIO: pioglitazone; DULA: dulaglutide; LIRA: liraglutide; EXE BID: exenatide twice daily; EXE QW: exenatide once weekly; ALBI: albiglutide

-1.8 -2.0

*Significant difference vs. comparator

Add-on to MET + PIO

AWARD-1** BL~8.1%

Add-on to MET

AWARD-6 BL~8.1%

Noninferior

-1.3 26

-1.5 28

0.04* 16*

-3.6 18

-1.4 LI

-2.9* 20

Add-on to Diet or Orals

DURATION-1 BL~8.3%

Not noninferior

Add-on to MET ± SU or MET + PIO

DURATION-6 BL~8.5%

-3.6 21

-3.6 35

-3.7 26

-1.9* EX

-2.7* 9

Add-on to OADs

HARMONY-7 BL~8.2%

Not noninferior

-2.2 29

-0.6* 10*

I† 50

CAUTION: Cross-trial comparisons cannot be made due to differences in study designs, trial durations and patient populations.

GLP-1RAs: Head-to-Head Trials of Once-Weekly vs. Daily Administration

Wt. Δ (kg): Nausea (%):

** The combination of DULA + MET + PIO is currently not an approved indication in Canada; †Approved but not yet marketed in Canada.

Insulin

3 types of insulin BASAL •  NPH

•  Lantus (glargine 100 u/mL) •  Levemir (detemir)

•  Basaglar (glargine 100 u/mL) •  Toujeo (glargine 300 u/mL)

PRE-MIXED §  30/70

§  Humalog Mix25, Mix50 (insulin lispro/lispro protamine)

§  Novomix 30 (biphasic insulin aspart)

BOLUS •  Regular or Toronto •  Apidra (glulisine) •  Humalog (lispro)

•  Humalog 200 u/mL (lispro) •  Novorapid (aspart)

•  Fiasp (faster aspart)

McMahon GT, Dluhy RG. NEJM 2007;357:1759.

0 12 24

Duration in Hours

Detemir

Glargine

NS=not significant Rosenstock et al. Diab Obes Metab 2015; 17:734-41.

*Gla-100=referenceglargine100u/mLSEBglar=subsequententrybiologicglargine

-1.34 -1.54 -1.01-1.29 -1.48 -1.02

0Total Insulin-naïve PriorIGlar

Gla-100 (N=268) SEB glar (N=267)

∆ = -0.004 95% CI (-0.19, 0.19)

p=NS ∆ = 0.061

95% CI (-0.09, 0.21) p=NS

∆ = 0.052 95% CI (-0.07, 0.18)

ChangeinHbA

Consistent A1C change for SEB glargine vs reference Gla-100 at Month 6 in T2DM

No difference in hypoglycemia since both are Gla-100

http://guidelines.diabetes.ca/browse/appendices/appendix5_2016

Time,h

120100

0 6 12 18 24 30 36

Glargine300U/mL:1/3theVolumeMoreconstantandprolongedPK/PD

U3000.4U/kgU1000.4U/kg

0 6 12 18 24 30 36

Glucoseinfusionrate,mg/kg/min

Bloodglucose,mg/dL

BeckerRHAetal.DiabetesCare.2014;Publishedaheadofprint:doi:10.2337/dc14-0006

Euglycemicclampstudyinpa;entswithT1Daper8days’treatment

PD,pharmacodynamic;PK,pharmacokine;c

Reduc8onofvolumeby2/3

100 U/mL (U100)

300 U/mL (U300)

100 U/mL (U100)

Reduc8onofdepotsurfaceby1/2

McMahon GT, Dluhy RG. NEJM 2007;357:1759.

0 12 24

Duration in Hours

Human Regular

Aspart Glulisine Lispro

Faster aspart vs insulin aspart: Faster onset of exposure and faster absorption

Faster aspart

Heise T et al. Diabetes, Obesity and Metabolism 2015; 17:682–688.

Thr Lys

Thr Tyr Phe Phe

Gly Arg

Glu Gly Cys Val Leu Tyr Leu Ala Glu Val

Leu His

Ser Gly

Cys Leu His Gln Asn Val Phe

Gly Ile Val Glu

Gln Cys Thr Ser Ile Cys Ser

Leu Tyr Gln Leu Glu

Asn Tyr

Cys Asn

Nicotinamide

O NH2 N L-arginine

•  Inject up to 2 minutes before the meal OR up to 20 minutes after the meal

Hotoffthepress!

FDADrugSafetyCommunica;onsMay16,2017

NNH = 323 in 1yr

NNH = 270 in 1yr

What should we do?

•  Do NOT use in type 1 diabetes

•  Remember EUGLYCEMIC diabetic ketoacidosis is a rare possibility

•  Be cautious with insulin dose reductions in “insulin deficient” pt

•  Be cautious in acute illness / surgery

•  Do not routinely check for ketonuria

S - sulfonylurea

A – ACE-inhibitor

D – diuretic, DRI

M - metformin

A - ARB

N - NSAIDs

S – SGLT2 inhibitors

Keeping it simple …

Insulin All options available

COULD THE PATIENT BE INSULIN DEFICIENT?

•  Lower BMI •  Lack of glycemic

lowering with other meds •  Duration of T2DM

(sometimes)

•  Higher BMI •  Shorter duration of

T2DM (sometimes)

Boiling it down …

1.  Does this patient have clinical cardiovascular disease? à empa or lira

2.  How high are the sugars? 3.  Is he/she at risk of hypoglycemia? 4.  What is the eGFR? 5.  Is there a drug plan?

Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity CV disease or multiple risk factors Comorbidities (renal, CHF, hepatic) Preferences & access to treatment

Consider relative A1C lowering Rare hypoglycemia Weight loss or weight neutral Effect on cardiovascular outcome See therapeutic considerations See cost column; consider access

Hypo-glycemia

Neutralto↓

alo,saxa,sita:

Neutral

lixi:Neutral

GIside-effects

↓↓↓↓

YesYes

↑↑

Rare ↓↓

Antihyperglycemic Agents and Renal Function

* do not initiate if eGFR <60 ml/min ** Davies ML et al. Diabetes Care 2016;DOI:10.2337/dc14-2883. Adapted from: Product Monographs as of March 2016. Harper W et al. Can J Diabetes 2015;39:440

eGFR(mL/min/1.73m2): <15 15–29 30–59 60–89 ≥90CKDStage: 5 4 3 2 1

Acarbose Notrecommended 25

Dapagliflozin 60Empagliflozin 45

Thiazolidinediones 30Contraindicated SafeCau8onand/ordose

reduc8on

Canagliflozin 25 60*100mg45

60*10or25mg

Nodoseadjustmentbutclosemonitoringofrenalfunc8on

Notrecommended

MeWormin 30 60

15Linaglip;n

Sitaglip;n 5030 50mg25mg

Saxaglip;n 5015 2.5mg

Aloglip;n Notrecommended 506.25mg 12.5mg30

Exena;de(BID/QW) 30 50Liraglu;de** 50

Albiglu;de 50

Repaglinide

Gliclazide/Glimepiride 15 30Glyburide 30 50

Insulin Secreta-gogues

SGLT2 inhibitors

GLP-1R agonists

Alpha-glucosidase

Inh. Biguanide

DPP-4 inhibitors

Dulaglu;de 50

Guidelines.diabetes.ca

Summary

•  Remember pathophysiology •  Metformin still top dog •  Cardiovascular disease priority

individualization – empa or lira •  Use the tools available to you:

www.guidelines.diabetes.ca

Twitter: @AliceYYCheng

Diabetes Management in 2017 · Discuss further updates in diabetes management in 2017 DPP-4...

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