dr brandon orr-walker - gp cme north/sat_plenary_1215_orr... · 2018-06-09 · side effects: glp-1...

Dr Brandon Orr-WalkerEndocrinologist

Clinical Head of Endocrinology and Diabetes

Middlemore

Auckland

12:15 - 12:40 What Can New Agents Offer Us?

Diabetes Management

What do the new agents offer us ?

Brandon Orr-Walker

June 2018

Outline

• Basic Premises and Assumptions

• Identifying the Opportunities

• Current state

• New treatment options, what new treatment options?

Basic Premises and Assumptions• Only worth making the diagnosis if we are going to change the progression of

disease

• Strong evidence base to reduce harm:

• Glycaemia

• BP

• Renal protection

• CVD risk

• Multifactorial management

• Early good control pays long term dividends

• We have people with diabetes at high risk of complications, and disparities exist

• Since 2003 majority of care for people with T2DM is to be in primary care

• Expertise in management is required to manage therapeutic challenge

Adapted from Stratton IM et al. on behalf of the UK Prospective Diabetes Study Group. BMJ 2000; 321:405–412.

Figure 5:DCCT-EDIC: Long-term Risk of Macrovascular

Complications

Years Since Entry*

DCCTEnd of

Randomized Treatment

*Diabetes Control and Complications Trial (DCCT) ended and Epidemiology of Diabetes Interventions and Complications (EDIC) began in year 10 (1993). Mean follow-up: 17 years.

EDICYear 1

EDICYear 7

12%

10%

8%

6%

Hem

oglo

bin

A1C

0.00

0.02

0.04

0.06

0.08

0.10

0.12

Conventional

Cum

ula

tive I

ncid

ence

Any Cardiovascular Outcome

P < 0.001 P < 0.001 P = 0.61

0 2 4 6 8 10

12

14

16

18

20

Conventional

Intensive 42% risk reduction P = 0.02

Intensive

DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569. Copyright © 2002 American Medical Association. All rights reserved. | Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Copyright © 2005 Massachusetts Medical Society. All rights reserved.

IncreasedHepatic Glucose Production

Impaired Insulin Secretion

Hyperglycemia

Decreased GlucoseUptake

TZDsGLP-1 analoguesDPP-4 inhibitorsSulfonylureas Thiazolidinediones

Metformin

MetforminThiazolidinediones

_

Pathophysiologic Approach to Treatment of T2DM

DeFronzo RA. Diabetes. 2009;58:773-795.

Are we at goal?

Currently in CMDHB:

• Approximately 40,000 patients with diabetes

• 20% of patients with diabetes have HBA1c >= 75 mmol/mol

– 8316 patients (CPHAC minutes 20/01/16)

– (nationally 28% >= 64, Australia 22% >= 64)

– Growing faster than the denominator (10% over 2 years)

– Less than ½ as likely to be referred /seen in secondary care diabetes clinics than ADHB/WDHB (only 14%)

• Spending an additional $7 Million on retinal laser and Avastin

– Less than 20% patients commencing laser are referred to specialist diabetes teams in year prior or year after to help with diabetes care.

Clinical Inertia: Failure to advance therapy when recommended

Brown JB et al. Diabetes Care 2004; 27(7): 1535–40.

Treatment Inertia= clinical inertia

Two components:

• Clinician inertia

• Patient inertia– Lack of access– Health literacy– Non-adherence– Competing interests– Refusal of treatment

• Uninformed/misinformed• Well informed

– Lack of acceptable treatment options

– Many of the “patient inertia” factors can be clinician modified, and as healthcare professionals it is our role to do so to the best of our ability.

What does this have to do with diabetes?

Presentation title Date 12

What does this have to do with diabetes? Nothing!


Treatment options in clinical inertia

Two components:

• Clinician inertia • Patient inertia

– Lack of access– Health literacy– Non-adherence– Competing interests– Refusal of treatment

• Uninformed/misinformed• Well informed

– Lack of acceptable treatment options

– Many of the “patient inertia” factors can be clinician modified, and as healthcare professionals it is our role to do so to the best of our ability.

Acceptability of Treatment Options

Patient (acceptability)• Side effects• Misconceptions• Belief• Experience of success ( especially for uptitration)• Response of health care team

Healthcare team• Resource• Competency• Belief• Promotion

Treatment options per se• Funding• Advantages beyond “targeted indication” (external gains)• Cost

Management of glycaemic control (NZ)

Lifestyle modification

Food, physical activity and behavioural strategies

If measured HbA1c does not meet or closely approach agreed target within 3 months, or if patient is symptomatic, drug therapy should be considered

Gastrointestinal tolerance may be improved by gradual introduction Stop if eGFR <30 ml/min/1.73m2

Metformin

Educate the person on the possibility of hypoglycaemia

Sulphonylurea

First line drug therapy

Review medication adherence and dose optimisation

Acarbose therapy1

If metformin not tolerated or contraindicated

Second line drug therapy

If no congestive heart failureIf at significant risk of hypoglycaemiaConsider increased risk of fracture in women

Thiazolidinedione (pioglitazone)2, 3

If above target (HbA1c 50-55 mmol/mol [6.7 – 7.2%] or as individually agreed)

If above target >3 months

Sulphonylurea

Third line drug therapy

Insulin4

If above target >3 months

Guidance on the Management of Type 2 Diabetes 2011; available online at www.nzgg.org.nz

If above target



ADA 2018 Standards of Care


Psycho-

Bio-

-social

Patient-centred care

Individualising HbA1c goals

Inzucchi et al. Diabetes Care 2012;35:1364–79

CCM: Big Effort, Big Variation

• Incretin Pathway

• SGLT2 inhibitors

Newer agents


No new DKD-specific treatment in the last 15 years

26

1980 1990 2010 20152000


High blood pressure

identified as DKD risk

factor

ß-blockers1

Hydralazine2

Captopril3

T1D

IDNT4, IRMA 25

IrbesartanT2D

RENAAL6

LosartanT2D

RAAS blockade

0

10

20

30

40

50

Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.©2001 Massachusetts Medical Society. All rights reserved.

†In combination with open-label diuretic, calcium channel blocker, beta-blocker, alpha-blocker, and/or centrally acting agent

*doubling of serum creatinine, end stage renal disease, death

RENAAL Patients Reaching the Primary Composite Endpoint*

Cu

mu

lati

ve %

of

pati

en

ts w

ith

even

t

Months

240 12 36 48

554

583

Placebo

Losartan

Risk reduction=16%

P=0.02

762

751

689

692

295

329

36

52

Placebo† (n)

Losartan† (n)

www.hypertensiononline.org

RENAAL

RENAAL First Hospitalization for Heart Failure

0 12 24 36 48

Months

0

5

10

15

20

% o

f p

ati

en

ts

wit

h e

ven

t

32% Risk reductionP=0.005

Placebo* (n)

Losartan* (n)

762 685 616 375 53

751 701 637 388 74

Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.©2001 Massachusetts Medical Society. All rights reserved.

www.hypertensiononline.org

*In combination with open-label diuretic, calcium channel blocker, beta-blocker, alpha-blocker, and/or centrally acting agent

Gila Monster Salivary product is GLP-1 agonist

Incretins Physiologically Regulate Insulin and Glucagon in a Glucose-dependent Manner

Physiologic

glucose

control

Ingestion

of Food

Active

GLP-1 & GIP

Release of

Incretin Gut

Hormones

GI tract

Glucose

uptake and

storage by

muscles and

other tissues

Glucose

output from

the liverGlucagon

from α-cells

(GLP-1)Glucose Dependent

Glucose Dependent

Insulin from β-cells

(GLP-1 and GIP)

Pancreas

α-cells

β-cells

Adapted from Kieffer TJ, Habener JF. Endocrine Reviews. 1999;20:876–913.; Ahrén B. Curr Diabetes Report. 2003;2:365-372. ; Drucker

DJ. Diabetes Care. 2003;26:2929-2940.; Holst JJ. Diabetes Metab Res Rev. 2002;18:430-441.; Drucker DJ. Expert Opin Investig Drugs.

2003;12:87-100.; Ahrén B et al. Horm Metab Res. 2004;36:867-876.

Insulin secretion

β-cell neogenesis

β-cell apoptosis

Glucagon secretionGlucose production

Heart

GI Tract

Liver

MuscleDrucker DJ. Cell Metab. 2006;3:153-165.

BrainAppetite

Cardioprotection

Cardiac output

StomachGastric emptying

Neuroprotection

Glucose Uptake

_

+

Stomach

GLP-1

GLP-1 Actions in Peripheral Tissue

Levels of Active Incretins GLP-1 and GIP Are Increased by DPP-4 Inhibition

*Refers to amino acid number. Deacon CF et al. Diabetes. 1995;44:1126–1131.

Meal

Intestinal

GIP and

GLP-1

release

GIP and GLP-1

Actions

DPP-4

Enzyme

GIP-(1-42*)

GLP-1(7-36)*

Active

GIP-(3-42)*

GLP-1(9-36)*

Inactive

Rapid

InactivationX

DPP-4

Inhibitor

Side Effects: GLP-1 Receptor Agonists and DPP-4 Inhibitors

GLP-1 Receptor Agonists DPP-4 Inhibitors

Side effects Gastrointestinal Well tolerated

Weight> 85% patients

lose weightWeight neutral

AdministrationTwice-daily

injectionOral, once daily

Other cardiac risk factors

↓ Triglycerides

↑ HDL

↓ Blood pressure

Unknown

Davidson JA. Cleve Clin J Med. 2009;76(suppl5):S28-S38.

Schnabel CA, et al. Vasc Health Risk Manag. 2006;2:69-77.

GLP-1 Receptor Agonists

• First-in-class (exenatide) approved in 2005

• Augment insulin secretion

• Inhibit glucagon secretion

• Lower fasting glucose and improve postprandial glucose profile

Exenatide Sustained A1c Reductions Over 82 Weeks

82-wk completer, N = 314; 82-wk ITT, N = 551; Mean ±SE.

Time (week)

Placebo-controlled Open-label extension

0 10 20 30 40 50 60 70 80 90-1.5

-1.0

-0.5

0.0

-1.1% ± 0.1%

-0.8% ± 0.1%

Ch

an

ge i

n A

1c (

%)

(All patients 10 mg BID)

8.3%8.4%

Mean Baseline A1c

82-Week ITT82-Week Completer

Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447.



Durability of Exenatide: Weight

Exenatide vs Insulin Glargine as Add-on Therapy in T2DM

A1

c Le

vel (

%)

**

**

**

0 2 4 8 12 18 26

Ch

ange

in B

od

y W

eig

ht

(kg)

Heine RJ, et al. Ann Intern Med. 2005;143:559-569.

Exenatide group (n = 275)

Insulin glargine group (n = 260)

Effects of GLP-1 Agonists on Cardiovascular Risk Factors

• A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n = 151)

• Triglycerides decreased 12% (P = .0003)

• Total cholesterol decreased 5% (P = .0007)

• LDL-C decreased 6% (P < .0001)

• HDL-C increased 24% (P < .0001)

Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.

LEADER trial: Primary Outcome

15

10

20

5

0

0 6 12 18 24 30 36 42 48 54

Placebo

Liraglutide

Patients

with a

n e

vent

(%)

Months since randomisation

Hazard ratio, 0.87 (95% CI, 0.78–0.97)P<0.001 for noninferiorityP=0.01 for superiority

First occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke in the time-to-event analysis in patients with type 2 diabetes and high CV risk.

Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial

Adapted from: Marso SP et al., NEJM 2016

LEADER trial:

Death from Cardiovascular Causes

15

10

20

5

0

0 6 12 18 24 30 36 42 48 54

Placebo

Liraglutide

Patients

with a

n e

vent

(%)

Months since randomisation

Hazard ratio, 0.78 (95% CI, 0.66–0.93)P=0.007

Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial

Adapted from: Marso SP et al., NEJM 2016

Presentation titleSlide no

43Date

No new DKD-specific treatment in the last 15 years: SGLT2 inhibition

44

IDNT, Irbesartan Type 2 Diabetic Nephropathy Trial; RAAS, renin–angiotensin-aldosterone system; RENAAL, Reduction of

Endpoints in NIDDM with the Angiotensin II Antagonist Losartan.1. Mogensen CE et al. Br Med J (Clin Res Ed)1982;285:685; 2. Parving HH

et al. Lancet 1983;1:1175 3. Lewis EJ et al. N Engl J Med 1993;329:1456; 4. Lewis EJ et al. N Engl J

Med 2001;345:851; 5. Brenner BM et al. N Engl J Med 2001;345:861

1980 1990 2010 20152000


High blood pressure

identified as DKD risk

factor

ß-blockers1

Hydralazine2

Captopril3

T1D

IDNT4, IRMA 25

IrbesartanT2D

RENAAL6

LosartanT2D

RAAS blockade

Renal glucose reabsorption in patients with hyperglycaemia

45SGLT, sodium glucose cotransporter.Gerich JE. Diabet Med 2010;27:136

Filtered glucose load >180 g/day

SGLT1

SGLT2 When blood

glucose increases above the

renal threshold

(>~10 mmol/L or

>180 mg/dL), the capacity of

SGLTs is exceeded,

resulting in urinary glucose

excretion

Empagliflozin increases urinary glucose excretion via SGLT2 inhibition

46

SGLT, sodium glucose cotransporter.*Loss of ~ 80 g of glucose per day = 240 cal/day.

Bakris GL et al. Kidney Int 2009;75;1272

Filtered glucose load >180 g/day

SGLT1

compensate

SGLT2

~90%SGLT2

inhibitors reduce glucose

reabsorption in the

proximal tubule,

leading to urinary glucose

excretion*and osmotic

diuresis

SGLT2inhibit

or

~ 80 g

Renal anatomy and physiology

GFR, glomerular filtration rateCherney D et al. Circulation 2014;129:587

47

KeyFlow of bloodFlow of filtrate

Afferent arteriole

Vasoconstriction decreases GFR

Efferent arteriole

Vasoconstriction increases GFR

Bowman’s capsule

Proximal convoluted tubule

The kidney auto-regulates glomerular filtration by moderating afferent and efferent arteriole tone

NO, nitric oxide; RAAS, renin–angiotensin-aldosterone systemBurke M et al. Current Vascular Pharmacology 2014;12:845

48

Prostaglandins

NORAAS

Afferent arteriole

Efferent arteriole

Flow of filtrateIncreased filtration

Empagliflozin exerts a hemodynamic effect within the kidney

• By restoring the Tubulo-Glomerular Feedback (TGF), empagliflozin increases the afferent arteriole tone, thereby lowering glomerular hypertension

SGLT, sodium glucose cotransporter; GFR, glomerular filtration rate.Adapted from: Cherney D et al. Circulation 2014;129:587

Skrtic M et al. Diabetologia 2014;57:259949

Action: Clinical implications:

SGLT2 inhibition

Afferent arteriole narrowing

• Glomerular pressure decreases

• Early clinical marker:

– Initial dip in GFR

– Reduction of albuminuria

narrowing

Empagliflozin effect on glomerular hyperfiltrationshows similar magnitude as ACE inhibitor

177.7 172.0

142.8 139.0

0

20

40

60

80

100

120

140

160

180

200

ACEi Empagliflozin

Mean

GFR

(m

l/m

in/

1.7

3 m

2)

Note: Data from two different studies. ACEi, angiotensin-converting enzyme inhibitor; GFR, glomerular filtration rate.

1. Sochett E et al. J Am Soc Nephrol 2006;17:1703; 2. Cherney D et al. Circulation 2014;129:587

50

-33 ml/min-35 ml/min

Baseline ACEi Empagliflozin

Patients received JARDIANCE® or placebo on top of standard of care for CV and T2D management1

†Standard of care included antihypertensives, lipid-lowering agents, anticoagulants and glucose-lowering therapies.1

‡Data from both doses of JARDIANCE® were pooled for statistical analysis versus placebo. # JARDIANCE® can be used be used down to an eGFR of 45 mL/min/1.73m2.

1. Zinman B et al. N Engl J Med 2015;373:2117–28.

Standard of care + JARDIANCE®

10 mg (n=2345)


25 mg (n=2342)

Standard of care† + Placebo(n=2333)

Randomised and treated(n=7020) Pooled‡

• Adults with T2D• Established CV disease (CAD,

PAD, MI or stroke)• HbA1c 7-10%• eGFR >30 mL/min/1.73m2#

• Glucose-lowering therapy was to remain unchanged for the first 12

weeks

• The trial was to continue until at least 691 patients experienced an

adjudicated primary outcome event

Slide 3 of 20

CV risk factor profile at study entry1

Data are mean or %. BMI, body mass index.


Patient characteristics

57%Pt with T2Dduration >10 years

30.6BMI (kg/m2)

105Waist circumference (cm)

Previous CV events

76%Coronary artery disease

21%Peripheral artery disease

47%History of MI

23%History of stroke

10%Heart failure

63Age (years)

Slide 4 of 20

Glycaemicmanagement

Mean HbA1c 8.1%

Metformin use 74%

Insulin use 48%

Patients treated appropriately for their CV risk1

In 7020 patients treated with ≥1 dose of study drug.

SBP, systolic blood pressure; DBP, diastolic blood pressure.


Blood pressure management

SBP/DBP, mmHg 136/77

Any BP-lowering drug 95%

ACEi/ARB 81%

Lipid managementAny lipid lowering drug 81%

Statins 77%

Anti-platelet and anti-coagulant therapies

Any anti-platelet / anti-coagulant drug

89%

Acetylsalicylic acid 83%

Slide 5 of 20

0

1

2

3

4

5

6

7

8

9

0 6 12 18 24 30 36 42 48Pati

en

ts w

ith

even

t

(%

)

Months

HR 0.62p<0.001

Adapted from Zinman B et al. 2015.1

*Within 6 months from start. #Up to 48 months from start.CV death was a pre-specified secondary endpoint. Cumulative incidence function. HR, hazard ratioThe absolute risk for CV death was 5.9% in patients receiving standard of care plus placebo and was reduced to 3.7% in patients receiving standard of care plus JARDIANCE® (p<0.001).1

1. Zinman B et al. N Engl J Med 2015;373:2117-28.

Standard of care +Placebo


Early* and sustained# response

Results achieved on top of standard of care• Antihypertensives• Lipid lowering

agents• Anticoagulants• Glucose lowering

agents

CV deathJARDIANCE® reduced the relative risk of CV death by

38% vs placebo on top of standard of care in patients with T2D and established CV disease (CAD, PAD, MI or stroke)1

.

Slide 8 of 20

Standard of care +Placebo

Standard of care +JARDIANCE®

*Within 6 months from start. #Up to 48 months from start.

All cause mortality was a pre-specified secondary endpoint. Kaplan-Meier estimate. HR, hazard ratio

The absolute risk for all-cause mortality was 8.3% in patients receiving standard of care plus placebo and was reduced to 5.7% in patients receiving standard of care plus JARDIANCE® (p<0.001).1

1. Zinman B et al. N Engl J Med 2015;373:2117-28.


0

2

4

6

8

10

12

14

0 6 12 18 24 30 36 42 48Pati

en

ts w

ith

even

t

(%

)

Months

HR 0.68p<0.001

Early* and sustained# responseJARDIANCE® is not indicated to reduce all-cause mortality

All-cause mortalityJARDIANCE® reduced the relative risk of all-cause mortality by 32% vs placebo on top of standard of care in patients with T2D and established CV disease (CAD, PAD, MI or stroke)1



agents

Slide 10 of 20

0

1

2

3

4

5

6

7

0 6 12 18 24 30 36 42 48Pati

en

ts w

ith

even

t (%

)

Months

Standard of care + Placebo


Hospitalisation for heart failureJARDIANCE® reduced the relative risk of hospitalisation for heart

failure by 35% vs placebo on top of standard of care in patients with T2D and established CV disease (CAD, PAD, MI or stroke)1

*Within 6 months from start. #Up to 48 months from start.

Hospitalisation for heart failure was a pre-specified secondary endpoint. Cumulative incidence function. HR, hazard ratioThe absolute risk for hospitalisation for heart failure was 4.1% in patients receiving standard of care plus placebo and was reduced to 2.7%in patients receiving standard of care plus JARDIANCE® (p<0.002).1


HR 0.65p=0.002


Early* and sustained# responseJARDIANCE® is not indicated to reduce hospitalisation for heart failure



agents

Slide 12 of 20

Pre-statin era <29% statin

Pre-ACEi/ARB era

Number needed to treat (NNT) to save 1 life

4S1 HOPE2

Standard of care included antihypertensives, lipid-lowering agents, anticoagulants and glucose-lowering therapies.3

ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blockers,1. 4S investigators. Lancet 1994;344:1383-89. 2. HOPE investigators, N Engl J Med 2000;342:145-53. 3. Zinman B et al. N Engl J Med 2015;373:2117-28.

Simvastatin1

for 5.4 years

30In high CV risk5% diabetes,

26% hypertension

Ramipril2

for 5 years

56

JARDIANCE®3

for 3.1 years

39

> 75% statin

> 80% ACEi/ARB

EMPA-REG OUTCOME®3

1994

2000 Now

In high CV risk38% diabetes,

46% hypertension

T2D with established CV disease (CAD, PAD, MI or stroke)

on top of standard of care

92% hypertension

Slide 14 of 20

*Incident or worsening nephropathy analysed in patients who did not have macroalbuminuria at baseline. Modified intention to treat analyses in patients who received ≥1 study drug.Defined as progression to macroalbuminuria (urinary albumin to-creatinine ratio, >300mg of albumin per gram of creatinine); a doubling of the serum creatinine level, accompanied by an eGFR of ≤45 ml/min/1.73m2,

as calculated by the Modification of Diet in Renal Disease (MDRD) formula; the initiation of renal-replacement therapy; or death from renal disease. Death due to renal disease: 3 events on JARDIANCE® and 0 on placebo.Standard of care included antihypertensives, lipid-lowering agents, anticoagulants and glucose-lowering agents.2

1. Wanner C et al. N Engl J Med 2016. 2. Zinman B et al. N Engl J Med 2015;373:2117–28.

JARDIANCE® slowed the progression of renal indicators in the EMPA-REG OUTCOME® study in patients with T2D and established CV disease (PAD, CAD, MI or stroke) on top of standard of care1*#

#JARDIANCE® is not indicated to prevent decline in renal function

Slide 15 of 20

SGLT2 inhibition and RAAS blockade

Afferent narrowing andEfferent widening

• Potential for normalisation of intraglomerular pressure

• Potential additive intraglomerularpressure reduction

• Potential for long-term renal protection

Future outlook – Dual SGLT2 and RAAS inhibition

Empagliflozin is not indicated for CV risk reduction or kidney diseaseAdapted from: Cherney D et al. Circulation 2014;129:587; Lewis et al. N

Engl J Med 2001;345:851; Kon V et al. Kidney Int 1993;44:545

59

Actions:SGLT2 inhibition

Afferent arteriole narrowing

Clinical implications:

• Decreased glomerular pressure

• Reduction in albuminuria

• Renal protection suggested

RAAS blockade

Efferent arteriole widening

• Decreased glomerular pressure

• Reduction in albuminuria

• Renal protection proven in clinical trials

CO

NCEPT

• Diabetes prevalence is growing

• Strong evidence base or reduced complications with optimal management

• There remain substantive numbers of people not at/near target for management

• Therapy needs to multifactorial and introduced progressively and incrementally to manage diabetes over time reflecting the progressive pathogenesis

• Newer therapies offer several advantages including convenience, side effect profile and are showing superiority in studied populations for renal and CVD endpoints above standard care

• Maori and Pacifica are at particularly high risk for CVD and renal harm from diabetes

• Cost is an issue, but largely because of the high numbers with diabetes with suboptimal control currently, thus cost is likely to come with substantive benefit.

Summary


dr brandon orr-walker - gp cme north/sat_plenary_1215_orr... · 2018-06-09 · side effects: glp-1...

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