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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.