Why and how to intensify diabetes treatment in Type 2 diabetes

Strategic choices to be made...

Päivi Maria Paldánius

Novartis Pharmaceuticals

My disclosures

• Employee and share-owner of Novartis

– Worldwide Brand Medical Director Diabetes and Metabolism

• Research scientist at the Children’s hospital, Helsinki University Central Hospital

3

Status: The world of diabetes as we know it today

Variable patient journeys across the disease spectrum worldwide Multiple challenges requiring ample evidence (WHY) and management

strategies (HOW) in diverse populations at different stages of disease

Global challenges in diabetes management are equally faced locally, on all levels and various populations individualising treatment targets, often with multiple co-morbidities but access

to different resource settings

tackling clinical inertia, intensifying early enough or avoiding aggressive approach when applicable

Converting the science from controlled studies into real-world settings

Optimising therapy choices, verifying the future of T2DM management and access to care, for everybody

SCIENTIFIC RATIONALE

5

T2DM is a progressive disease with early onset of

foundation for complications

years

Complications

Postprandial glucose

Fasting glucose

0

100

200

Insulin Risk of diabetes

Impaired islet cell function

Insulin resistance

–10 0 10 15 20 25 30 5 –5

Diabetes

10

15

20

5

Glu

co

se

mm

ol/l

Pro

po

rtio

na

l a

mou

nt o

f n

su

linin

in r

ela

tion

to

no

rma

l (%

)

Pre diabetes

(IFG / IGT) NGT

IFG: impaired fasting glucose; IGT: impaired glucose tolerance

Adapted from International Diabetes Center. Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center; 2000.

6

Complex disease: The Ominous Octet

Pancreas

Decreased insulin secretion

Liver

Increased HGP

Brain

Neurotransmission Dysfunction

Muscle

Decreased glucose uptake

Increased insulin secretion

Islet-α cell

Kidney Increased glucose reabsorption

Adipose tissue

Increased lypolysis

Hyperglycemia

Decreased incretin effect

Gastrointestinal tissues

. Adapted from DeFronzo, R.A.. Diabetes. 2009; 58: 773–795

7

Insulin response to glucose in healthy individuals

Insulin

capacity

ED50

Glucose sensitivity

Glucose concentration (mmol/L)

Insulin

secre

tory

respon

se

4.5 5.0 5.5 6.0 6.5 7.0

ED50=effective dose at 50%

Adapted from Ireland JT et al. Diabetes today: a handbook for the clinical team. Ed. HM + M Publishers. 1979, pp15–6;

Adapted from Davidson MB. West J Med 1985;142:219–29

8

Insulin response to glucose in individuals with high capacity but low sensitivity (IGT)

High insulin

capacity

ED50

Reduced

glucose

sensitivity

ED50=effective dose at 50%; IGT=impaired glucose tolerance

Adapted from Ahrén B. Diabetes 2009;58:726–31; Adapted from Davidson MB. West J Med 1985;142:219–29

Glucose concentration (mmol/L)

Insulin

secre

tory

respon

se

4.5 5.0 5.5 6.0 6.5 7.0

9

Loss of insulin sensitivity is an early phenomenon

even within normoglycaemic range

% o

f re

fere

nce

cat

ego

ry

NFG IFG Diabetes

100

75

50

25

0

<5.0

5.0

-5.4

5.5

-5.9

6.0

-6.4

6.5

-6.9

7.0

-7.4

7.5

-7.9

8.0

-8.4

8.5

-8.9

≥9.0

Fasting plasma glucose [mM]

1st phase

insulin secretion

Ref.

MatsudalSI

InsAUC30/GluAUC30

InsAUC120/GluAUC120

Ref.

% o

f re

fere

nce

cat

ego

ry

MatsudalSI

InsAUC30/GluAUC30

InsAUC120/GluAUC120

100

75

50

25

0

125

<5.0

5.0

-5.9

6.0

-6.9

7.0

-7.9

8.0

-8.9

9.0

-9.9

10

.0-1

0.9

11

.0-1

1.9

12

.0-1

2.9

≥13.0

NFG IFG Diabetes

1st phase

insulin

secretion

OGTT 2-hour plasma glucose [mM]

AUC, area under curve; IFG, impaired fasting glucose; Ins, insulin; NFG, normal fasting glucose, OGTT, oral glucose tolerance test Stančáková A et al. Diabetes 58:1212-21, 2009

(N=6414)

10

Isolated IFG and IGT: differences in pathophysiology?

How do we, if at all, address this in newly-diagnosed

T2DM patients?

IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IIFG, isolated impaired fasting glucose; IIGT, Isolated impaired glucose tolerance; Adapted from Laakso M. et al. Diabetologia 51:502-11, 2008; Stancakova A, et al. Diabetes 58:1212-21, 2009

Liver

Muscle

Pancreas

IIFG IIGT

Hepatic glucose production Insulin sensitivity

Insulin secretion (fasting, 1st phase)

Insulin sensitivity

Hepatic glucose production +/- Insulin sensitivity +/-

Insulin secretion (1st phase)

Insulin sensitivity

11

Unmet medical need

- silent disorder early in the disease course

Classic signs or symptoms of diabetes might only

appear after several years of hyperglycaemia

• disease is present 9 to 12 years before diagnosis

• by the time diabetes is diagnosed, up to 80–85% of β-cell

function may have already been lost

CV risk factors present and micro/macrovascular

disease progressing prior to any symptoms or diagnosis

• an estimated delay of 5 years in diabetes diagnosis is

associated with significantly worse incidence of

• all-cause mortality, diabetes-related death, and any diabetes-

related complication (UKPDS)

Harris MI et al. Diabetes Care. 1992; 15:815-819; Bagust A et al. QJM. 2003;96:281-288; DeFronzo RA. Diabetes. 2009;58:773-795; Colagiuri S et al. Diabetes Care. 2002;25:1410-1417

12

Insulin response to glucose in patients with T2DM

ED50

Insulin

capacity

Reduced glucose sensitivity

Reduced insulin capacity

Glucose concentration (mmol/L)

Insu

lin s

ecre

tory

re

sp

on

se

4.5 5.0 5.5 6.0 6.5 7.0

ED50=effective dose at 50% Adapted from Davidson MB. West J Med 1985;142:219–29; Adapted from Turner RC, Holman RR. Lancet 1976;1:1272–4

13

Treatment of T2DM: A therapeutic

approach based upon pathophysiology?

Impaired insulin secretion

Increased lipolysis

Increased HGP Decreased glucose

uptake

Hyperglycaemia

(-) Metformin

TZD

(+) TZD

GLP-1 analogues DPP-4 inhibitors Sulphonylureas

(-) TZD

(+) TZD

Metformin

Pancreas Adipose tissue

Liver Muscle

DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; HGP, hepatic glucose production; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione Adapted from: DeFronzo RA. Diabetes. 2009;58:773–95.

14

Pathophysiology-based algorithm

ADA Pathophysiology-based

Durability No Yes

β cell preservation No Yes

Hypoglycemia Yes No

Weigh gain Yes No

Lifestyle +

Triple Combination

TZD + Metformin + Exenatide

HBA1c < 6%

Treatment of type 2 diabetes based upon pathophysiology

Comparison of the ADA and pathophysiological-based algorithms

Del Fronzo, R.A. Diabetes. 2009; 58: 773–795

15

Targeting: Achieving early glycaemic control

which may generate a good legacy effect M

ed

ian

Hb

A1

c (

%)

0

6

7

8

9

UKPDS 1998

Conventional Metformin

Holman et al 2008

Legacy effect

1997

Difference in HbA1c was lost after first

year but patients in the initial intensive arm

still had lower incidence of any complication:

• 24% reduction in microvascular

complications

• 15% reduction in MI

• 13% reduction in all-cause mortality

2007

MI, myocardial infarction Diabetes Trials Unit. UKPDS Post Trial Monitoring. UKPDS 80 Slide Set. Available at: http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/. Accessed 12 September, 2008; Adapted from Holman RR, et al. N Engl J Med. 2008; 359: 1577–1589; UKPDS 33. Lancet. 1998; 352: 837–853.

16

VADT was a multi-site, randomised, controlled trial in patients (N=1,791) who had a suboptimal response to therapy for T2D. Patients received either intensive (n=892) or standard glucose control (n=899) (patients with a BMI of ≥27 were started on metformin and rosiglitazone; those with a BMI of <27 were started on glimepiride and rosiglitazone. The intensive-therapy group were started on maximal doses, and the standard-therapy group were started on half of these doses. Insulin was added if patients in the intensive-therapy group did not achieve HbA1c <6% and if patients in the standard-therapy group did not achieve HbA1c <9%. Further changes in medication were based on protocol guidelines and local assessment). Median follow-up was 5.6 years. The primary outcome (major CV events) was non-significantly lower in the intensive-therapy group compared with the standard-therapy group. Long-term follow-up data is being collected from national data registries. BMI=body mass index Hayward et al. N Engl J Med 2015;372:2197-206; Duckworth et al. N Engl J Med 2009;360:129–39

Long term benefits of glucose control –

The VADT follow up (better late than never?)

0.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

10.0 Standard therapy

Intensive therapy

0 3 5 7 9 11 13 15

Year since start of study

Med

ian

gly

cate

d h

aem

ogl

ob

in le

vel (

%)

17

VADT was a multi-site, randomised, controlled trial in patients (N=1,791) who had a suboptimal response to therapy for T2D. Patients received either intensive (n=892) or standard glucose control (n=899) (patients with a BMI of ≥27 were started on metformin and rosiglitazone; those with a BMI of <27 were started on glimepiride and rosiglitazone. The intensive-therapy group were started on maximal doses, and the standard-therapy group were started on half of these doses. Insulin was added if patients in the intensive-therapy group did not achieve HbA1c <6% and if patients in the standard-therapy group did not achieve HbA1c <9%. Further changes in medication were based on protocol guidelines and local assessment). Median follow-up was 5.6 years. The primary outcome (major cardiovascular events) was non-significantly lower in the intensive-therapy group compared with the standard-therapy group. Long-term follow-up data is being collected from national data registries. CI=confidence interval Hayward et al. N Engl J Med 2015;372:2197-206; Duckworth et al. N Engl J Med 2009;360:129–39

Long term benefits of glucose control –

The VADT follow up

Outcome Standard therapy Intensive therapy

Hazard Ratio

(95% CI) P Value

Events

No. of

participants/

total no.

Rate

per 1000

person-yr

Events

No. of

participants/

total no.

Rate

per 1000

person-yr

Primary outcome: major

cardiovascular event

288/688

52.7 253/703 44.1 0.83 (0.70–0.99) 0.04

Secondary outcome

Death from

cardiovascular causes

83/818 11.3 74/837

10.0 0.88 (0.64–1.20)

0.42

Death from any cause 258/818 30.3 275/837 32.0 1.05 (0.89–1.25) 0.54

Effect of intensive glucose control on the rate of major cardiovascular events and mortality*

*The primary outcome was the time of the first major cardiovascular event (a composite of heart attack, stroke, new or worsening congestive heart failure, amputation for ischaemic gangrene, or death from cardiovascular causes) and was analysed in the survey cohort. Mortality outcomes were analysed in the complete cohort.

18

INTERVAL: Ambitious mean target reductions set by the

investigators, independent of the baseline factors

- no ‘true’ individualisation in most of the patients; too late to

target lower glycaemia?

Mean (SD)

Baseline HbA1c, % 7.9 (0.72)

Mean reduction (SD)

Range

Overall -0.86 (0.54) -4.4 to -0.1

HbA1c ≤8% -0.67 (0.35) -2.4 to -0.1

HbA1c >8% -1.15 (0.65) -4.4 to -0.2

In this elderly cohort (70+ years old, mean age 75), the mean individualized HbA1c targets set by the investigators were around 7.0% for both the treatment groups, 0.9% (range –4.4 to –0.1) lower than the mean baseline HbA1c of 7.9%.

18

Strain WD et al. Lancet. 2013 May 23. [Epub ahead of print].

19

IMPORTANCE OF EARLY

INTENSIFICATION ESPECIALLY IN

YOUNGER PATIENTS

20

Why early intervention

- especially in younger patients with most to gain

Diabetes is affecting a younger population more than ever before

• due to increased rates of obesity and an increased shift to western lifestyles

There is a growing epidemic of people with T2DM below the age of 50

• T2DM is more aggressive in younger patients with earlier disease onset

• these patients should still have a long life expectancy and a good QoL

• Majority will be in developing countries or those less prepared to address the

increasing incidence of T2DM

• Yet, also more developed countries seem less prepared as knowledge alone

doesn’t lead to appropriate action

20

21

Despite having detailed knowledge, we don’t follow

even the most established evidence-based

recommendations*

2

1

You must sit down if you:

1. Are still smoking

2. Don’t sleep at least seven hours every night

3. Haven’t exercised at least five times a week for

30 min

4. Took an elevator instead of stairs to this meeting

5. Have been talking into your mobile while driving

6. Don’t brush your teeth at least twice a day...

*references to applicable individual recommendations available per request while this is a conceptual exercise for demonstration of human dimensions of inertia in absence of motivation

22

If ‘‘clinical inertia’’ was an intervention associated

with this increased risk of complications, it would

rapidly be withdrawn pending safety analyses.

However, the lack of appropriate escalation of

treatment is accepted in every day practice.

Strain WD et al. Clinical Inertia in Individualising Care for Diabetes: Is There Time to do More in Type 2 Diabetes? Diabetes Ther DOI 10.1007/s13300-014-0077-8

23

INERTIA- clinical inertia- patients/physician inertia

In the study of physics, INERTIA describes

resistance to movement

When applied to medicine, the word ‘inertia’ is

similarly used to describe resistance to change

More specifically, it is the difference between the

medical care that could be aspired to and what is

actually achieved

Clinical inertia can and usually is being

implemented by both the treating physician and

the patient

CLINICAL INERTIA is “a failure to initiate or

intensify treatment in a timely manner in

people with diabetes whose health is likely to

improve with this intensification”

24

7.2 years

6.7 years

Adapted from Adapted from Del Prato S et al Int J Clin Pract. 2005 ;59(11):1345-55. Khunti K, et al. DiabCare 2013;36:3411–17

The true numbers behind conventional treatment

intensification (in those with HbA1c > 7.0%)

7

6

9

8 Hb

A1c (

%)

10

OAD*

monotherapy

OAD triple

combination

OAD +

insulin

OAD

Dual therapy

Duration of diabetes

HbA1c = 7%

*OAD = oral antidiabetic

2.9 years

8.7% 8.5% 9.1%

9.7%

25

Real-world data: HbA1c at treatment

intensification (mono to dual therapy)

1. Bader G et al. ADA abstracts 2449-PO. 72nd Scientific Sessions: 2012;June: 61(suppl 1). 2. Inzucchi SE et al. Diabetologia 2012;55:1577-1596.

The point at which combination therapy is prescribed varies by region, but is consistently higher than the guideline recommendation of 7.0% (or even 6.5%)...

26

Contributing also to an unnecessary high prevalence of

complications at monotherapy failure (which could have at least partially been preventable)?

57,2

52,9

51,5

50,5

68,9

67,5

45,2

49,4

44,7

50,0

38,4

36,2

42,9

37,7

48,3

41,2

51,0

47,6

32,0

36,2

48,0

49,0

22,6

19,8

13,1

11,0

12,1

7,6

18,3

18,6

5,0

6,5

9,6

8,3

5,1

3,8

7,4

7,3

8,9

10,0

9,3

10,3

4,4

6,7

6,4

6,5

3,8

3,6

0,0

10,0

20,0

30,0

40,0

50,0

60,0

70,0

80,0

Vildagliptin (28442)

Comparator (15349)

Vildagliptin (1661)

Comparator (740)

Vildagliptin (15582)

Comparator (6491)

Vildagliptin (3065)

Comparator (781)

Vildagliptin (2513)

Comparator (2266)

Vildagliptin (5621)

Comparator (5071)

Overall East Asia Europe Latin America Middle East India

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Hypertension

Lipids Disorders

Macrovascular

Microvascular

27

The impact of a 12 month inertia on outcomes

• a T2DM cohort of 110,543 UK patients, treated between May 1990

and January 2010

Paul et al. Cardiovasc Diabetol 2015;14:100 doi:10.1186/s12933-015-0260-x

Patients with HbA1c ≥

7.0% not receiving therapy

intensification within 1 year

At 5.3 years, significantly increased risk of: MI 67% (CI 39–101%) Stroke 51% (CI 25–83%) HF 64% (CI 40–91%) Composite CVE 62% (CI 46–80%)

26% of all patients

28

Modern approach to hyperglycaemia

OAD + basal

insulin

OAD + multiple daily

insulin injections

Diet and

exercise OAD

monotherapy OAD

combinations

OAD up-titration

7

6

9

8

10

ACTION

POINT:

HbA1c = 7%

HbA1c = 6.5%

OAD, oral antidiabetes drug Del Prato S et al Int J Clin Pract. 2005 ;59(11):1345-55..

Hb

A1c (

%)

Duration of diabetes 0

29

ADOPT study: progression of hyperglycaemia in

T2DM with monotherapy

Time (years)

6.0

7.6

8.0

6.8

0 1 2 3 4 5

Hb

A1

c (

%) 7.2

0

Rosiglitazone: 0.07 (0.06 to 0.09)

Metformin: 0.14 (0.13 to 0.16)*

Glyburide: 0.24 (0.23 to 0.26)*

6.4

Treatment difference (95% CI)

Rosiglitazone vs metformin: –0.13 (–0.22 to –0.05); p=0.002

Rosiglitazone vs glyburide: –0.42 (–0.50 to –0.33); p<0.001

Annualised slope (95% CI)

*Significant difference rosiglitazone vs other treatment groups with Hochberg adjustment. Kahn SE, et al. N Engl J Med. 2006;355:2427–2443

30

It is not known how the initial difference in the

glycaemic control would evolve over time

No long-term data related to the effect of

combination therapies on the durability of

glycaemic control are available in patients with

more preserved β-cell function,

• i.e. newly diagnosed, or treatment-näive patients with

mild hyperglycaemia.

Guidelines don’t, so far, advocate early combinations

ADOPT study: progression of hyperglycaemia in

T2DM with monotherapy -would early intervention with a combination be the answer?

31

Profiles of Anti-diabetic Medications: we have a good

arsenal of tools for lowering of glycaemia...

Source: Garber et al. Endocr Pract.2016;22:84-113

32

...while there are multiple barriers to

effective and sustainable T2DM care

Weight gain

• Induced by life-style or anti-diabetic therapies

Fear and/or events of hypoglycaemia

• Mostly induced by anti-diabetic therapies

Poor adherence to therapy and lifestyle advise

Clinical inertia and lack of individualisation

UKPDS. Lancet 1998; 352 (9131): 854-865, Amiel SA et al. Diab Med 2008; 25(3):245-54, Guisasola AF. Diabetes Obes Metab 2008;10: S1:25-32, Weyer C et al. J Clin Invest 1999; 104(6):787-794, Khunti K et al. Diabetes Care 2013;36(11):3411-17, Strain WD et al. Diabetes Res Clin Pract. 2014;105:302–12

In the Time2DoMore programme main reasons triggering a change in

treatment were hypos or lack of glycaemic control, often due to lack of

compliance with diet and exercise regimen.

33

Selecting the appropriate therapeutic agent for individual

patients...

o Reduction in HbA1c

o Risk of hypoglycemia

o Impact of pathophysiologic

mechanisms

o (DO I REALLY CARE...?)

o Changes in body weight, lifestyle, sexual function...

o CV risk vs. QoL vs.... o Safety profile vs tolerability o Friendly use: tailored for

me and to my busy life... o Cost vs immediate vs long-

term benefit

Adapted from Nathan DM, et al. Diabetes Care 2009;32:193–203

34

Time to do more signposts

The health outcomes for people with diabetes are a

function of the communication between the healthcare

professionals and people with diabetes acting as a team

It is the duty of that team to establish realistic shared

goals and a contract in order to achieve these objectives

Individualising care needs to be personalised to all

aspects of the needs of the person with diabetes, not

simply chasing glycaemic, blood pressure or lipid

targets

We call on purchasers and providers to incentivise good

management in early disease in order to optimise quality

of life for people with diabetes

2014 ©Novartis Pharma AG - Time 2 Do More is a trademark owned by Novartis AG Adapted from: Strain WD et al. Diabetes Res Clin Pract. 2014;105:302–12.

35

THE FUTURE

36

GRADE study - The Glycaemia Reduction Approaches

for Diabetes: a comparative Effectiveness study

2000 Drug-naive subjects

T2DM < 3 years

HbA1c 6.5-9%

5500 Met-treated or drug-naive (after 2000 drug-naive randomized) HbA1c

6.5-9%

Met run-in: initiate and/or titrate Met to 1000 (min) to 2000(max) mg/day

1000 sequential therapy 1000 early combination

therapy

5500 combination therapy

SU 200

TZD 200

DPP-IV 200

GLP-1 200

Insulin 200

1000 1000 5500

Comparison of sequential vs

early combination therapy in

2000 subjects, 1000 per group

Comparison of combination

therapies in 6500 subjects, 1300

per group

200 SU 1100

200 TZD 1100

200 DPP-IV 1100

200 GLP-1 1100

200 Insulin 1100

Ran

do

miz

e

Ran

do

miz

e R

an

do

miz

e

The primary metabolic outcome will be time to failure defined as HbA1c >7%, subsequently confirmed, after having been treated with metformin and started on the second randomly assigned medication (intention-to-treat) DPP-IV, dipeptidyl peptidase IV; GLP-1, glucagon like peptide-1, Met, metformin; OAD, oral anti-diabetic drug; SU, sulphonylurea; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione Clinicaltrial.gov NCT01794143

37

Patient population:

• ADOPT- like design, 2000 patients with newly diagnosed (<24 mo) T2DM and HbA1c 6.5–7.5%

• Period 1 is double-blinded (until end of the study), period 2 is single-blinded and Period 3 is open label • intensification of treatment with OAD instead of insulin in Period 3 leads to discontinuation

Primary objectives (co-primaries):

• Initial treatment failure rate and rate of loss in glycaemic control (HbA1c) over time

Other end-points:

• Progression of and change in HbA1c, FPG, safety and tolerability, 2 hr meal AUC glucose and annual 2 hr

meal ISR/G ClinicalTrials.gov Identifier: NCT01528254

Del Prato S et al, Diabet Med. 2014 May 23. doi: 10.1111/dme.12508

Visits every 3 monthly

HbA1c > 7.0% (twice)

Screening

Vilda 50 mg bid + MET ad 1000 mg bid

Vilda 50 mg bid + MET ad 1000 mg bid

5 years

+ (basal) insulin

+ (basal) insulin

At investigator discretion

Run-in : 3 wks

Period 1 Period 2 Period 3

VERIFYING THE FUTURE: Vildagliptin Efficacy in combination with

metfoRmIn For earlY treatment of T2DM

Ran

do

miz

ati

on

ME

T 5

00

mg

/d

ME

T 1

00

0m

g/d

ME

T 1

50

0m

g /d

Placebo bid + MET ad 1000 mg bid

Vilda 50 mg bid + MET ad 1000 mg bid

38

Potential implications

• VERIFY is the first study to investigate the long-term clinical

benefits of initial combination treatment versus the standard-

of-care MET monotherapy followed by addition of OAD

• addressing key pathophysiological features of the disease

at diagnosis

• It will provide valuable data on the durability of glycaemic

control, beta-cell function, insulin resistance, safety and

tolerability

• It will explore for early changes in the vasculature of patients

with T2DM early in the course of the disease

• Addressing primary clinical objective for treatment of

hyperglycaemia

• It has potential to change the way we treat type 2 diabetes and

its complex pathophysiology in the future

My perspective on optimal T2DM treatment selection criteria

• Early intervention and timely maintenance of glycaemic control at all stages still remains the most effective way to reduce the burden of long-term complications

• A modern approach to achieve an ideal risk-to-benefit ratio requires prompt intervention aiming at individualised treatment targets and a careful selection of medications to treat diabetes or its complications

• Effective treatment of type 2 diabetes requires multiple interventions but also drugs used in combination to correct multiple pathophysiological defects

• Treatment should be based on known pathogenic abnormalities (not simply on reduction of glycaemia) and started early in the natural history of T2DM to prevent progressive β-cell failure

• Optimal therapy of T2DM should also target these multiple mechanisms without increased risk of hypoglycaemia, weight gain or other tolerability issues which in turn induce reduce adherence and worse outcomes

Thank you for your attention.