changing directions in diabetes

CHANGING DIRECTIONS IN DIABETES

Mark Thomas, Dept of Nephrology, RPH

The size of the problem

Micro and macrovascular disease

Oral Rx Insulin Rx

Too tight vs too loose control: oral Rx vs insulin

Currie, Lancet 2010

UK GP database 1986-2008: patients > 50yrs intensified from monotherapy to either oral combination (n= 28,000) or regimen inc insulin (n = 20,000)

Avoiding disaster

Multifactorial Rx in T2DM & legacy effect

Cumulative incidence of

any CV event (%)

STENO 2 TRIAL N Engl J Med 2008;358:580–591.

80

70

60

40

30

10

50

20

0

Conventional therapy

Intensive therapy

Years

0 1 2 3 4 5 6 7 8 9 10 12 1311

Trial: intensive vs conventional Post-trial: all intensive

53% reduction in CVD

N=160 T2DM microalbuminuria

Hazard ratio = 0.47 (95% CI, 0.24–0.73; p = 0.008)

CV events prevented by different interventions per 1000 patient yrs of treatment

Preiss D , and Ray K K BMJ 2011;343:bmj.d4243

Individualise and prioritise therapy targets

Individualise targets

� Tight targets: for young motivated compliant patients, short duration of DM, no micro/macrovascular disease, few co-morbidities

� Gentle targets : treat the elderly with respect

– E.g. Systolic BP 110 vs 140, HbA1c 6 vs 8%

Prioritise targets

1. BP and lipids: easier to achieve, bigger mortality benefit

2. Glucose control and weight loss

Deeper analysis

Worse DM control & complications in ATSI vs non-ATS I despite same Rx: NEPHRON GP study

144 ATSI (53y) vs 449 non-ATSI (64y) at same GP (vs 3893 total)

Similarities:Same obesity 50%, waist 106cm, DM duration 8yrs

Same BP 132/80 & BP Rx, LDL 2.5 & lipid Rx

Differences:More smoking (38 vs 9%), family history DM x2, CVD x3, CKD x5

Worse HbA1c 8.9 vs 7.4%, but same Met/SU/insulin rates

M Thomas & M Thomas BMC Pub Health 2007

CKD

Macrovascular ∆

Hoy e al. Nephrol 2016

ATSI ESKD: esp women in remote Qld

Missing factors in ATSI T2DM: chronic stress

Cause: Chronic stress

• Socio-economic

• Family health

Consequence: Cortisol

• Insomnia

• Constant hunger with central obesity

• Insulin resistance with acanthosis

• Resistant hypertension with relatively low K+

• Muscle weakness and fatigue

• Recurrent infectionsSchmitt & Spargo Bio Soc Sci 1995

Sweeter options

Therapy PRO CON

Metformin Experience / Proven outcomes / Cost

GI symptoms/ CKD

Sulfonylurea Experience / Cost Hypo’s/ Wt. gain / CKD

DPP4-i (gliptin)

Wt. neutral / Low risk of hypo’sCost / CCF (saxa, not sita) / CKD (except lina) / LFT’s (vilda)

TZD (glitazone)

Low risk of hypo’sCost / Fluid retention / Wt. gain / Fracture risk / ?Bladder ca (pio)

SGLT2-i (gliflozin)

Wt. loss / SBP reduction / Low risk of hypo’s

New / Dehydration / DKA$ / UTI & thrush / CKD inefficacy

Acarbose Low risk of hypo’ / Wt. neutral / Cost

Limited efficacy / GI tolerability

GLP-1 (incretin analogue)

Wt. loss / Low risk of hypoglycaemia

Cost / Injection / GI symptoms

Insulin Experience / Effective Injection / Wt. gain / Hypo’ s

16

Pathophysiology of Hyperglycaemia: missing 3?

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

Gut

Pancreas

Hyperglycaemia

Decreased Insulin SecretionIncreased Glucagon Secretion

DecreasedIncretin Effect

Muscle

DecreasedGlucose Uptake

17

Kidney

IncreasedGlucoseReabsorption

Sites/Modes of Action of Pharmacotherapy for T2DM

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

Gut

Pancreas

Hyperglycaemia

Muscle

TZDsMetformin

18

Kidney

SulfonylureasMeglitinidesGLP-1/DPP-4i

α-Glucosidase inhibitorsGLP-1/DPP-4i

SGLT2 inhibitors

Don’t beat up your beta-cells

Maintain beta-cell mass

� Avoid pancreatitis

� Tight BSL control

� Statins: ↓lipotoxicity

� Incretins: ↑proliferation, ↓apoptosis

� Glitazones: ↑proliferation, ↓apoptosis

� ACE-I/ARB: ↓ fibrosis

� ?Immunotherapy for Type I (rituximab 2009; anti IL-1 2013)

Reduce insulin demand

� Small meals with low glycaemic index

� Tight control

� Avoid high-dose SU’s

� Early insulin

Increase insulin sensitivity

� Increase exercise & muscle

� Reduce body fat mass & stress

� Use metformin +/- ?glitazones

50% of Australian Type 2 diabetics have CKD

10% GFR < 60 & normal uACR

25% ↑↑↑↑uACR & normal GFR

50% Either or both

NEPHRON study

MJA 2006; 185 (3): 140-144

uACR = spot urine albumin: creatinine ratio

Metformin in CKD

Dose-related GI side-effects

Renal excretion:

� Dose-adjust to GFR

Idiosyncratic lactic acidosis

Blocks liver glucose release & lactic acid uptake:

� Stop if unwell

Rates of lactic acidosis/10^5 patient-years:

� 57 (12-168) on metformin (n = 3)

� 28 (3-100) off metformin (n = 2), p = nsKamber, Davis et al. MJA 2008;188:446

Incretin Effect: normal vs T2DM

IR=Immune Reactive.Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag. 9

Time, minIR

Insu

lin, m

U/L nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

Control Subjects(n=8)

Patients With Type 2 Diabetes(n=14)

Time, min

IR In

sulin

, mU

/L nmol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

Oral glucose load Intravenous (IV) glucose infusion

Incretin Effect

The incretin effect is diminished

in type 2 diabetes.

Effects of incretins and incretin-based therapy1

Adapted from DeFronzo RA, 20091

Reference 1. DeFronzo RA, Diabetes 2009; 58: 773-95.

Incretin effects are

enhanced by GLP-1

agonists and DPP-4

inhibitorsAlpha cells:

Reduction ofpostprandialglucagon secretion

Beta cells: Increase of glucose-dependent insulinsecretion

Liver: GlucagonReduceshepatic glucoseproduction

Stomach:Slowing of gastricemptying

GLP-1 secretion occurs after food intake

1yr Gliptin vs SU in CKD & ESKD

CKD ESKD

Number 426 129

HbA1c ∆ -0.8 v -0.6 -0.7 v -0.9

Hypo’s 6 v 17% 6 v 11%

Wt ∆ -0.6 v +1.2 -0.2 v +0.8

Other All equivCellulitis/headache

Ferreira et al Diabetes Care 2012 Am J Kidney Dis 2013

DPP4i safety – watch the BNP , not the lipase

BYDUREON Pen: Microsphere technology enables once-

weekly dosing1,2

Proven microsphere technology provides a continuous level of exenatide

� Biodegradable polymer that dissipates into CO2 and water

� Technology used in extended-release products, e.g. risperidone & naltrexone

Adapted from 1. DeYoung MB et al. 20111

Reference 1. DeYoung MB et al. Diabetes Technol Ther 2011;13:1145–54. 2. BYDUREON Approved Product Information.

Subcutaneous

injection of

microsphere

suspension of

exenatide

Individual

microspheres

aggregate and

initial release of

exenatide

Microsphere

degradation and

continued release of

exenatide

Further degradation

and metabolism of

microsphere polymer

provide sustained

level of exenatide

Exenatide QW Pharmacokinetics*

Pla

sma

Exe

natid

e C

once

ntra

tion

1 Steady state maintainedwith subsequent doses

• 2 mg single dose releases exenatide over 9-11 weeks 1

• Steady state concentrations reached by week 6-7 2

• Exenatide not detectable approximately10 weeks after last dose 1,2

0 2 4 6 8 10 12 14 16 18 20 22 24Weeks

PK/PD data does not necessarily predict clinical effect* Graphical representation of ExQW pharmacokinetics.Reference 1. Fineman, M et al. Clin Pharmacokinet. 2011;50(1):65-74; 2. BYDUREON Approved Product Information.

Effective FPG and PPG reduction1

Exenatide BID Week 14

Exenatide BID Baseline

Exenatide QW Week 14

Exenatide QW Baseline

-1 0 1 2 3 4 5

100

150

200

250

300

Time (h)

Glu

cose

(mg/

dL)

-1 0 1 2 3 4 5

100

150

200

250

300

Time (h)

Glu

cose

(mg/

dL)

Exenatide QW 2 mg1 Exenatide BID 10 µg1

*

Mean data;

*P = 0.0124 vs. exenatide QW

Reference 1. Drucker DJ, et al. Lancet 2008;372:1240-1250;

17

14

11

8

5

DURATION-2: BYDUREON vs sitagliptin or pioglitazone, on background metforminBYDUREON effective as first medication added to metformin1,2

Graph adapted from Wysham C, et al. 2011, showing data for the evaluable population as least squares mean ±

standard error.2

BL=baseline; CI=confidence interval.

Reference 1. Bergenstal RM, et al. Lancet 2010;376:431–9; 2. Wysham C, et al. Diabet Med 2011;28:705–14.

At the primary endpoint of 26 weeks, HbA1c changes from baseline were –1.5% with BYDUREON, –0.9%

with sitagliptin and –1.2% with pioglitazone (p<0.05 for BYDUREON vs both comparators)1

HbA1c reductions were sustained to week 52 throughout continued treatment with BYDUREON, or after

switching from sitagliptin or pioglitazone to BYDUREON at week 262

HbA1c Change from Week 26 to Week 52:Sitagliptin ��BYDUREON –0.31% (95 % CI, –0.50 to –0.13), P<0.05BYDUREON�� BYDUREON 0.06% (95 % CI, –0.13 to 0.25), P value not reportedPioglitazone �� BYDUREON –0.10% (95 % CI, –0.29 to 0.09), P value not reported

Ch

an

ge

in

Hb

A1

c(%

)

Ch

an

ge

in H

bA

1c

from

ba

selin

e (m

mo

l/mo

l)

-0.5

-1.0

-1.5

-2.0

0

-5

-10

-15

-20

0.0

0 4 6 1

0

1

4

1

8

2

2

2

6

3

0

3

4

4

0

4

6

5

2Time (weeks) BYDUREON, BL=8.6% (70.5 mmol/mol)

Sitagliptin �� BYDUREON, BL=8.5% (69.4 mmol/mol)

Pioglitazone �� BYDUREON, BL=8.5% (69.4 mmol/mol)

DURATION-3: BYDUREON vs insulin glargine

HbA1c improvement with BYDUREON vs insulin sustained for 3 years1

Modified from Diamant M, et al. 2014.1

*The daily dose of insulin glargine was based on the INITIATE algorithm (Initiate Insulin by Aggressive Titration and Education) and was individually

adjusted to achieve fasting glucose values of 4.0–5.5 mmol/l.

In the Insulin glargine arm, from a starting daily insulin dose of 10IU/day, mean dose increased to approximately 31 IU/day at 26 weeks.

Background therapy: Metformin with or without sulfonylurea.

Reference 1. Diamant M, et al. Lancet Diabetes Endocrinol 2014; 2:464-73.

8.5

8.0

7.5

7.0

6.5

Hb

A1

c(%

)

Insulin glargine (n=220)Once daily, variable dose based on treat-to-target algorithm*

Exenatide QW (n=228)2 mg once weekly

Time (weeks)

0 3

6

8 13

2

1

8

2

6

4

8

6

0

7

2

8

4

9

6

1

0

8

12

0

14

4

15

6

Δ -0.20 %

p=0.03

Weight in DURATION studies: Overview*1–5

Modified from Bergenstal RM, et al 20101.

Reference 1. Bergenstal RM, et al. Lancet 2010; 376:431-9; 2. Drucker DJ, et al. Lancet 2008; 372:1240-50; 3. Blevins T, et al. J Clin Endocrinol Metab 2011; 96:1301-10;

4. Buse JB, et al. Lancet 2013; 381:117-24; 5. Diamant M, et al. Lancet 2010; 375:2234-43.

††BYDUREON did not meet primary endpoint of non-inf eriority vs 1.8mg liraglutide (upper limit of CI <0.25%) in DURATION-6. 4

æBYDUREON is not indicated for use in combination wi th TZDs

*BYDUREON is not indicated for weight loss.

DURATION-3: BYDUREON vs insulin glargine

Weight change over 3 years1,2

Graph adapted from Diamant M, et al. 2014, showing data for the modified intent-to-treat population as least squares mean ± standard

error.1 *p<0.001.

BL=baseline.

Reference 1. Diamant M, et al. Lancet Diabetes Endocrinol 2014;2:464–73; 2. BYDUREON Approved Product Information.

Treatment with Bydureon resulted in significant weight reduction compared to

weight gain with insulin glargine over 3 years1*

4

2

0

-2

-4

Ch

an

ge

in

bo

dy

we

igh

t (k

g)

Insulin glargine, BL=90.6 kg (n=222)

Bydureon, BL=91.2 kg (n=233)

Time (weeks)

0 3

6

8 13

2

1

8

2

6

4

8

6

0

7

2

8

4

9

6

1

0

8

12

0

14

4

15

6

Change from BL:+2.01 ± 0.28 kg

–2.49 ± 0.28 kg*

*BYDUREON is not indicated for weight loss. 2

DURATION-2: individual efficacy vs weight change

Bergenstal et al. Lancet 2010 376; 431-439

HbA1c HbA1c

7 v 6.5

WeightfBSL

HbA1c

vs

Weight

Less nausea with BYDUREON vs. exenatide bdæ1–3

Patients administered exenatide or liraglutide with background therapy.

Adapted from BYDUREON Approved Product Information1 and Buse et al. 2013.4

Reference 1. BYDUREON Approved Product Information. 2. Drucker DJ et al. Lancet 2006; 368:1696–1705. 3. Blevins T

et al. DURATION-5. J Clin Endocrinol Metab 2011; 96:1301–1310. 4. Buse JB et al. DURATION-6. Lancet 2013;

381(9861):117–124.

� Withdrawal due to nausea or vomiting each occurred in ≈1% of BYDUREON-treated patients1

� Most episodes of nausea were mild to moderate1

BYDUREN associated with less nausea compared to exenatide BD or 1.8mg liraglutideæ‡1–4

‡BYDUREON did not meet primary endpoint of non-infer iority vs 1.8mg liraglutide (upper limit of CI <0.25%) in DURATION-6. 4

æStatistical significance not tested.

� Mostly mild to moderate

� Usually did not lead to withdrawal from

studies

� Injection site reactions were higher in

exenatide once weekly treated patients (16%)

compared exenatide BD treated patients (2%-

7%): pruritus (8%), erythema (4%),

induration (4%) and nodule (3%).

� Asymptomatic nodule formation (up to 77%).

Approximately 73% of the first incidence of

treatment emergent injection site reactions

resolved within 60 days.

Injection-site

Reference 1. BYDUREON Approved Product Information. 2. DeYoung MB et al. Diabetes Technol Ther 2011; 13: 1145-54.

� Small, raised nodules very frequently occur at

the injection site

– Consistent with known properties of

poly (D,L-lactide co-glycolide) polymer

microsphere technology

� Most individual nodules were asymptomatic

and resolved over 4-8 weeks

Injection-site reactions Injection-site bumps

Size of bump

Bump

BYDUREON: Summary of safety and tolerability profile

As with other GLP-1 receptor agonists,1–4 the most frequent adverse drug

reactions (≥5% of patients treated with BYDUREON) were mainly gastrointestinal-

related (nausea, vomiting, diarrhoea and constipation)

In addition, injection-site reactions (pruritus, nodules, erythema, induration),

hypoglycaemia (with a SU) and headache occurred1

Most adverse reactions associated with BYDUREON were mild to moderate in

intensity1

There have been rare, spontaneously reported events of acute pancreatitis and

renal failure. If pancreatitis is suspected, BYDUREON should be discontinued1

Data source comprises 5 trials comparing 2 mg exenatide once weekly to either 10 μg exenatide twice daily (a 30 week study), sitagliptin

and pioglitazone (a 26 week study), and insulin glargine (a 26 week study). Background therapies included diet and exercise and oral anti-

diabetic agents.

BD=twice daily; SU=sulphonylurea; TZD=thiazolidinedione.

Reference 1. BYDUREON Approved product Information. 2. BYETTA Approved product Information. 3. VICTOZA Approved product

Information. 4. LYXUMIA Approved product Information.

PBS listing

Dual combination therapy with

metformin OR a sulfonylurea

Authority Required (STREAMLINED) 6354

Clinical Criteria:

The treatment must be in combination with metformin; OR

the treatment must be in combination with a sulfonylurea

AND

Patient must have a contraindication to a combination of

metformin and a sulfonylurea; OR patient must not have

tolerated a combination of metformin and a sulfonylurea

AND

Patient must have, or have had, a HbA1c measurement

greater than 7% prior to the initiation of a dipeptidyl

peptidase 4 inhibitor (gliptin), a thiazolidinedione

(glitazone), a glucagon-like-peptide-1 or a sodium-glucose

co-transporter 2 (SGLT2) inhibitor despite treatment with

either metformin or a sulfonylurea.

Triple combination therapy with

metformin AND a sulfonylurea

Authority Required (STREAMLINED) 6339

Clinical Criteria:

The treatment must be in combination with metformin

AND

The treatment must be in combination with a sulfonylurea

AND

Patient must have, or have had, a HbA1c measurement greater

than 7% prior to the initiation of a dipeptidyl peptidase 4

inhibitor (gliptin), a thiazolidinedione (glitazone), a glucagon-

like-peptide-1 or a sodium-glucose co- transporter 2 (SGLT2)

inhibitor despite treatment with maximally tolerated doses of

metformin and a sulfonylurea.

BYDUREON PEN: SUMMARY

� BYDUREON is the first approved once weekly GLP-1 re ceptor agonist

� HbA 1c reductions are sustained for up to 6 years vs basel ine †2

� Potential for weight reduction over 6 years vs base line * and low risk of hypoglycaemia ††1,2

� Most common adverse events: gastrointestinal (nause a, diarrhoea, vomiting, constipation), nasopharyngitis, hypoglycae mia, injection site reactions (pruritus, nodules, erythema, indurat ion) 1

†Open-label, uncontrolled extension study in patients administered BYDUREON with background therapy. 43% of patients

remained in the study at Year 6.

*BYDUREON is not indicated for weight loss.1

††SUs are associated with an increased risk of hypoglycaemia. When BYDUREON is added to SU therapy, a reduction in the dose

of SU should be considered to reduce the risk of hypoglycaemia.1

Reference 1. BYDUREON Approved Product Information. 2. Henry RH, et al. Poster presented at ADA 2014. 964-P

Swedish Registry outcome data: GLP1a best

All cause † All CVD

CHD CCF

GLP1a

GLP1a GLP1a

DPP4i & TZD

N = 20, 442, 2005-2012. Ekstrom Diab Obes Metab 2016

GLP1 analogue & CV outcome RCT

N = 9340, >50yr & CV factor, 3.8yr f/up, no DPP4i Primary EP = 3-pt MACE: 13.0 vs 14.9%, HR 0.87, p<0.001

Marso, NEJM 2016

New arrivals

Sodium glucose co-transporter (SGLT2) inhibitors

Induce prox tubular glycosuria

Benefits:

•reduce HbA1c 1% with few or no hypo’s used alone

•lower weight & BP

Risks:

•dehydration (esp if on diuretics)

•hypo’s with SU or insulin

•UTIs, vulvovaginitis, balanitis

Cefalu, Lancet Sept 2013

↓GFR →↑retention but ↓efficacy

Kasichayanulaet al, Dapagliflozin

pharmacokinetics in moderate and

severe CKD, BJCP 2012

50mg stat

20mg 1 week

AUC

20mg 1 week

uGluc

loss

SGLT2i & CKD: ↓wt, BP, GFR & uACR

Yale et al. doi:10.1111/dom.12348

Wt

BP

GFR

uACR

Gliflozin guidelines

20% reduction in insulin/ SU if tight control

50% reduction in BP Rx/diuretic if tight control

Daily BP, weight, BSL

Daily groin/apron wash, dry, baby powder

Zinc/castor oil if red, clotrimazole if thrush

MSU pot & cephalexin, pre-emptive Rx if dysuria

Hold SGLT2i if too symptomatic, try alternate daily

Watch for DKA in long-standing T2DM

SGLT2i: CV benefit data

CV † CCF

Zinman, NEJM, Sept 2015

SGLT2i: CKD benefit data

Wanner, NEJM, June 2016

Turning lemonade into Gatorade

SGLT2i class efficacy & safety

More stroke

Less CV †

Less CCF

N= 37,525, 6 regulatory submissions, 7 drugs

Wu, Lancet Diab Endocrin 2016

Therapy PRO CON


GI symptoms/ CKD


DPP4-i (gliptin)


TZD (glitazone)

Low risk of hypo’sCost / Fluid retention / Wt. gain / Fracture risk / ?Bladder ca (pio)

SGLT2-i (gliflozin)

Wt. loss / SBP reduction / Low risk of hypo’s








50

Therapy PRO CON


GI symptoms/ CKD


DPP4-i (gliptin)


TZD (glitazone)

Low risk of hypo’sFluid retention / Wt. gain / Fracture risk / ?Bladder ca (pio)

SGLT2-i (gliflozin)

Wt. loss / SBP reduction / Low risk of hypo’








51

TOO RISKY

TOO WEAK

BASELINE

Therapy PRO CON


GI symptoms/ CKD


DPP4-i (gliptin)


SGLT2-i (gliflozin)

Wt. loss / SBP reduction / Low risk of hypo’






52

HYPOs/WT GAIN

HYPOs/WT GAIN

BASELINE

Homeward bound

Organ-specific effects of obesity

CVA, dementia, carpal tunnel, benign intracranial HTN

Depression, fatigue, isolation, low self-esteem

Dyspnoea, asthma, sleep apnoea, PE

HTN, angina, CCF, varicose veins

Insulin resistance, ↑ lipids & BSL

Gallstones, gastric reflux, fatty liver,

cirrhosis , pancreatitis

Glomerulosclerosis, renal calculi, urine

incontinence

Osteoarthritis, gout, flat feet, plantar fasciitis

Cancer: breast, uterus, cervix, oesophagus,

colon, pancreas, kidney, prostate Male: erectile dysfn.

Female: irregular periods, polycystic ovary, infertility

Skin Candida, acanthosis, hirsutism, stretch,

Healthy lifestyle

Mediterranean diet

Alcohol moderation

Physical activity

Non-smoking

→ Reduced all-cause mortality by 65%Koops, JAMA 2004

Lean Weight: Rule of Thumb

Max lean weight (kg) = Ht (cm) - 100

Height (cm)

155 165 175 185

Weight (kg)

BMI = 25

60 68 76 85

Praise the positive

Eat right

Quantity, quality & value

Pre-meal vinegar as anorectic

Eat like a hippie, not like a truckie

Make food crunchy and colourful

Traffic light detox drink

Move well

Motivation: age 20 vs 50 vs 80

Purpose: fit, strong, flexible, stable

Bird-rocket half-squats

“Seven”

Stay calm

Friends & family

Pets & plants

Movement, music & massage

CRUfAD.org

“This Way Up”

Stay connected

changing directions in diabetes

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