VERIFY: New Evidence

Exploring Clinical Implications of

Timely Treatment Intensification

M-GALVU-04-10-2019-PH1910744058
Disclosures
• Please indicate your professional disclosures.
Outline

• Importance of good glycemic control

• Why Early Intensification?

• Why combination therapy?

• Why vildagliptin and metformin?

• Why single pill?

• Will there be Hypoglycemia and weight gain?

 • Importance of
• Good Glycemic Control
 Good glycemic control
can lead to significant reduction in risk of complications
Improved glycemic control can lead to a sustained reduction in risk of any
diabetes-related endpoint* or microvascular disease over a 10-year period2

Each 1% reduction in HbA1c is associated with1 Extended follow-up for a further 10 years
is associated with2
30 30

20 37% 20

21% 24%
10
14% 10 15%
9%
Any diabetes- Myocardial Microvascular Any diabetes- Myocardial Microvascular
related endpoint infarction complications related endpoint infarction complications

UKPDS: Patients with newly diagnosed T2DM were randomly assigned to a conventional (dietary) or intensive therapy
(sulfonylurea, insulin or metformin) for glycemic control. For post-trial monitoring, patients (N = 3277) were asked to attend
annual UKPDS clinics for 5 years1
UKPDS, United Kingdom Prospective Diabetes Survey
*Diabetes-related endpoint defined as sudden death, death from hyperglycemia or hypoglycemia, fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, renal failure, amputation, vitreous
hemorrhage, retinal photocoagulation, blindness in one eye or cataract extraction

1. Stratton IM, et al. BMJ. 2000;321(7258):405-12.

2. Holman RR, et al. New Engl J Med. 2008;359:1577–89
 6

Few Filipinos Achieve HbA1c Targets

DiabCare 2008 Survey

Only 15% achieve the Less than 11% achieve the

ADA target of HbA1c AACE target of HbA1c
<7% <6.5%

15%
15% 10.6%

Uncontrolled diabetes Uncontrolled diabetes

At HbA1c target At HbA1c target

Jimeno CA et al. Philippine J Int Med. 2012;50:15-22.

 Why
Early Intensification?
Early treatment intensification is recommended to prevent progression of disease

Traditional stepwise
approach
• prolonged hyperglycemia
• increased risk of
complications

Del Prato, et al. Int J of Clin Pract. 11 OCT 2005 DOI: 10.1111/j.1742-1241.2005.00674.
Adapted with permission from Campbell IW, Need for intensive early glycaemic control in patients with type 2 diabetes. Br J Cardiol 2000; 7: 625–631
Early combination
approach
• same sequence but each
stage brought forward
• provide “better and more
rapid glycemic control.”
 6-Month Delay in Therapy Intensification
Increases Cardiovascular Risk in Patients with Type 2 Diabetes

Increased risk delayed

6-month delay in vs. immediate therapy
therapy intensification intensification
+ 2 OAD or OAD +
insulin
Diagnosis HbA1C 20% 26%
5
T2DM >7% after
years
n = 110,543 1 year
Immediate therapy
intensification
Cardiovascular Myocardial
+ 2 OAD/OAD +
disease infarction
insulin

UK Clinical Practice Research Datalink (2015)

 Why
Combination Therapy?
Multiple pathogenic abnormalities contribute to
hyperglycemia and T2DM complications
 Why
Vildagliptin + Metformin?
History of Type 2 DM
 Vildagliptin + metformin combination for early treatment
intensification

Vildagliptin provides powerful HbA1c

Vildagliptin addresses key reductions, with results from
underlying defects of T2DM1 randomised clinical trials consistent
with that seen in the real world2–5

Vildagliptin is associated with a low

Vildagliptin is well tolerated with an
risk of hypoglycaemia and weight
established safety profile6–8
neutrality2,3

1. Adopted from Ahrén B, et al. Diabetes Obes Metab 2011;13:775–83; 2. Adopted from Bosi E, et al. Diabetes Care 2007;30:890–5;
3. Adopted from Ferrannini E, et al. Diabetes Obes Metab 2009;11:157–66; 4. Adopted from Mathieu C. Int J Clin Pract 2013;67:947–56;
5. Adopted from Ahrén B, et al. Diabetologia 2014;57:1304–7; 6. Adopted from Schweizer A, et al. Vasc Health Risk Manag 2011;7:49–57;

7. Adopted from Schweizer A, et al. Diabetes Obes Metab 2010;12:485–94; 8. Adopted from Ligueros-Saylan M, et al. Diabetes Obes
Metab 2010;12:495–509
 Why
Single Pill?
Single-pill Combinations May Improve Compliance

100
* · Low compliance in chronic diseases
77% such as diabetes may adversely affect
80 clinical outcomes
Adherence Rate (%)

54% · SPCs can reduce risk of

60
non-compliance by up to 26%1
40 · Switching to an SPC from
combination therapy improves
20 treatment adherence2
· Improved glycemic control was
0 obtained with an SPC in patients with
Free Single-pill T2DM3
Combination Combination
(n=1815)† (n=105)†

SPC=single-pill combination; T2DM=type 2 diabetes mellitus

P <0.001 vs combination therapy. †Previously treated patients receiving glyburide or metformin monotherapy.
1. Bangalore S, et al. Am J Med. 2007; 120: 713–719.
2. Melikian C, et al. Clin Ther. 2002; 24: 460–467;
3. Blonde L, et al. Diabetes Obes Metab. 2003; 5: 424–431.
Fixed-dose combination DPP-4i + metformin improves
compliance and may provide additional improvement in
glycemic control
• The likelihood of compliance was
significantly increased when using
Vildagliptin+Metformin FDC vs free-dose
combination, with the OR for compliance
with FDC vs free-dose combination at 18.9
(p<0.001).1
• The GIFT study showed that switching from
free-dose combination to FDC DPP-4i +
metformin resulted in a 0.3% lower HbA1c
(p<0.01).2
• A European retrospective database review
showed that the relative mean % HbA1c
level associated with being on a DPP-4
FDC rather than free-form independent of
the physician perception of patient
1. Rombopoulos et al. Int J Endocrinol. 2015;2015:251485.
compliance was 0.25% lower (p<0.002). 3
2. Bajaj et al. Curr Med Res Opin. 2019 May;35(5):869-878.
3. Benford et al. Adv Ther. 2012 Jan;29(1):26-40.
Copyright ADA & EASD 2018
Stepwise therapy (i.e. adding medications to metformin to maintain
HbA1c at target) is supported by clinical trials. While there is
some support for initial combination therapy due to the
greater initial reduction of HbA1c than can be provided by
metformin alone, there is little evidence that this approach is
superior to sequential addition of medications for
maintaining glycemic control or slowing the progression of
diabetes.

Copyright ADA & EASD 2018

 Dangers of
Hypoglycemia & Weight Gain
 Hypoglycaemia and weight gain are major limiting factors to
achieving intensive glycaemic control in people with T2DM1

Fear of hypoglycaemia is Concerns about weight

a major concern for gain and hypoglycaemia
patients, and may affect may make physicians
their attitude to treatment.1,2 reluctant to intensify
treatment.3,4

1. Adopted from Briscoe VJ, et al. Clin Diabetes 2006;24:115–21; 2. Adopted from Pramming S, et al. Diabet Med 1991;8:217–22;
3. Adopted from Cryer PE. Diabetologia 2002;45:937–48; 4. Adopted from Khunti K, et al. Diabetes Care. 2013;36:3411–7
 Evidence of NO Weight Gain
Adjusted mean change (±SE) in body weight from BL to week 24 1
-0.59 -1.62 -1.17 -1.19
0.0
body weight (kg)
Mean change in
• Metformin2
• Causes weight loss by reducing food
intake.
• Primarily acts on the central nervous
system to reduce appetite by attenuating
hypothalamic AMPK activity, which
decreases NPY (orexigenic) and
increases POMC (anorectic) expression.
• Diabetes Prevention Program - within
the first 3 years, metformin treatment of
1700 mg/day induced weight loss of
approximately 2.9 vs. 0.42 kg in the
control group. This effect persisted up to
8 years.
Vildagliptin 50 mg bid
Metformin 1000 mg bid
Vilda + LD Met FDC (50/500 mg bid)
Vilda + HD Met FDC (50/1000 mg bid)
• Vildagliptin3
• Weight neutrality established in studies
where it was given:
• as monotherapy, or
• in dual combination with metformin, an
SU (glimepiride), a TZD (pioglitazone)
or insulin (with or without metformin),
• or in triple combination with a SU and
metformin.
1. Bosi E et al. Diabetes Obes Metab. 2009;11:506–15.
2. Malin & Kashyap. Curr Opin Endocrinol Diabetes Obes. 2014 Oct;21(5):323-9.
3. Galvus Product Information
 Evidence of NO Hypoglycemia
Vilda + HD Met FDC Vilda + LD Met FDC Vilda 50 mg bid Met 1000 mg bid
Event (50+1000 mg bid) (50/500 mg bid)
n=292 n=290 n=297 n=292
Diarrhea 19 (6.5%) 21 (7.2%) 7 (2.4%) 32 (11.0%)
Headache 16 (5.5%) 18 (6.2%) 16 (5.4%) 13 (4.5%)
Dizziness 15 (5.1%) 14 (4.8%) 8 (2.7%) 12 (4.1%)
Nausea 19 (6.5%) 14 (4.8%) 7 (2.4%) 17 (5.8%)
Abdominal pain 2 (0.7%) 2 (0.7%) 6 (2.0%) 10 (3.4%)
Constipation 6 (2.1%) 2 (0.7%) 10 (3.4%) 5 (1.7%)
Hypoglycemia 0 (0.0%) 0 (0.0%) 2 (0.01%) 2 (0.01%)
Severe Hypoglycemia 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.01%)

• Hypoglycemia does not usually occur in patients receiving

vildagliptin+metformin alone, but could occur when caloric intake is deficient,
when strenuous exercise is not compensated by caloric supplementation, or
ethanol use.2
• In clinical studies, the incidence of hypoglycemia was uncommon in patients
receiving vildagliptin 50 mg once or twice daily in combination with metformin
and in patients receiving placebo and metformin. No severe hypoglycemic
events were reported in the vildagliptin arms.2
1. Bosi E et al. Diabetes Obes Metab. 2009;11:506–15. (Table, adapted)
2. Galvus Product Information
Pharmacological approach for management of T2DM

Drugs in combination to Treatment targeting the Early treatment

act on the multiple pathogenic abnormalities intensification to
pathophysiological defects and not simply reducing prevent/slow the decline of β-
HbA1c cell function

Early combination therapy as a strategic approach

Synergistically tackle multiple pathophysiological mechanisms potentially resulting in
more
durable treatment effect, without increasing the risk of adverse events
Vildagliptin Efficacy in Combination with
MetfoRmIn For EarlY Treatment of T2DM
 Introducing: VERIFY

• The VERIFY trial (Vildagliptin Efficacy in combination

with metfoRmIn For earlY treatment of type 2
diabetes mellitus) compared initial combination
therapy of metformin and vildagliptin to sequential
addition of vildagliptin after treatment failure with
metformin

• This trial may shed light on unanswered

questions such as the effect of Vildagliptin on
preservation of B-cell function and, possibly, the
“price” of clinical inertia on long-term glycemic control
A.Cahn and W. Cefalu, Diabetes Care Volume 39, Supplement 2,
August 2016
VERIFY in the context of the other studies
- Addressing early diabetes vs. later stage disease and
populations
 To combine or not to combine at the
start of glucose-lowering therapy:
that is the question

Q1. Primary Outcome Q2. Secondary Outcome

Do those with type 2 diabetes
benefit from having
combined therapy at the
beginning of their
pharmacological treatment?
Do those with type 2 diabetes
Q3. Does benefit more from having
it combined therapy at the
beginning of their
matter?
pharmacological treatment
compared to a sequential
additive strategy?
VERIFY study design

• A randomised, double-blind, two arm, parallel-group study consisting of:

• a screening visit;
• a 3-week run-in period; and,
• a 5-year treatment period, with a primary defined ‘failure’ threshold,
during which patients’ treatment is consecutively intensified, if clinically
indicated
Del Prato S et al, Diabet Med. 2014;31:1178–84; Matthews DR et al. Diabetes Obes Metab. 2019;21(10):2240–47.
VERIFY study design
Age eGFR
18–70 years ≥60 mL/min

Key inclusion
BMI criteria T2DM diagnosis
22–40 kg/m2 ≤24 months

HbA1c Drug-naïve /
6.5%–7.5% max 4 weeks of
(48–58 mmol/mol)
metformin

Matthews DR et al. Diabet Med. 2019;36:505-13; Del Prato S et al. Diabet Med. 2014;31:1178-84.
 Baseline characteristics
Early Initial
Variable combination monotherapy
N=998 N=1003
Women 55% 51%
Age 54.1 (9.5) 54.6 (9.2)
T2DM duration, months* 3.3 (1.0–9.8) 3.4 (0.9–10.4)
HbA1c, % 6.7 (0.4) 6.7 (0.5)
FPG (mmol/L)* 6.9 (6.1–7.8) 6.9 (6.2–7.9)
BMI (kg/m2) 31.2 (4.8) 31.0 (4.7)
Weight (kg)* 85.0 (72.8–97.3) 84.0 (72.0–97.0)

Baseline eGFR (MDRD), mL/min/1.73m2

Normal (≥90) 43.3% 44.3%

Current smoker 15.4% 13.6%

Data is presented as mean (SD), unless specified. *Median (IQR). The baseline demographics and clinical characteristics were similar between the treatment arms.

Matthews DR et al. Lancet. 2019. doi.org/10.1016/S0140-6736(19)32131-2

 VERIFY study design

Metformin + Vildagliptin Time to failure

Rate of failure is is the Primary
RANDOMISATION

Early combination
calculated in each Outcome
strategy group by an
It addresses the first
assessment of those
Time to failure question –
failing as a proportion
of all those in that Q1: Do those with type 2
group. diabetes benefit from
Metformin + Placebo having combined therapy at
the beginning of their
Initial monotherapy pharmacological treatment?

Del Prato S et al, Diabet Med. 2014;31:1178–84; Matthews DR et al. Diabetes Obes Metab. 2019;21(10):2240–47.
 VERIFY study design
Time to failure : Failure defined as HbA1c ≥7.0% (53 mmol/mol)
on 2 consecutive visits

Confirmed Earliest failure is

3 months apart possible at 6
months
Failure at
9
HbA1c months
7.0% No
failure

3 months 6 months 9 months 60 months

Del Prato S et al, Diabet Med. 2014;31:1178–84; Matthews DR et al. Diabetes Obes Metab. 2019;21(10):2240–47.
Time to initial treatment failure

This first failure onto combined therapy is a test of

one agent against two.

Matthews DR et al. Lancet. 2019. doi.org/10.1016/S0140-6736(19)32131-2

Median time to initial treatment failure

Initial monotherapy
Hazard ratio (95% CI): 0·51 (0·45,0·58); 36.1 months
p<0·0001
Patients with an event

Early combination
61.9 months
(%)

Patients at risk
Early combination
983 960 862 815 752 671 597 551 509 478 187
Initial monotherapy
989 937 733 661 576 503 434 377 337 299 108

Matthews DR et al. Lancet. 2019. doi.org/10.1016/S0140-6736(19)32131-2

Time to second failure onto insulin

*Time to switch to period 3 (failure) is from 12 months to infinity

VERIFY study design

Del Prato S et al, Diabet Med. 2014;31:1178–84; Matthews DR et al. Diabetes Obes Metab. 2019;21(10):2240–47.
 By the second failure,
all patients who failed were
on combination therapy

An examination of two strategies:

1. Combination therapy ab initio
2. Metformin - then add a second agent as necessary

Matthews DR et al. Lancet. 2019. doi.org/10.1016/S0140-6736(19)32131-2

Success rates between treatment approaches

Matthews DR et al. Lancet. 2019. doi.org/10.1016/S0140-6736(19)32131-2

Subgroup analysis of time to initial treatment failure

Matthews DR et al. Lancet. 2019. doi.org/10.1016/S0140-6736(19)32131-2

Subgroup analysis of time to initial treatment failure

Matthews DR et al. Lancet. 2019. doi.org/10.1016/S0140-6736(19)32131-2

 Overall safety events

Early combination Initial

Safety Events monotherapy
N=998, n (%)
N=1001, n (%)
Patients with at least one AE 833 (83.5) 833 (83.2)
SAE 166 (16.6) 183 (18.3)
Drug-related AE 159 (15.9) 143 (14.3)
Severe AE 105 (10.5) 106 (10.6)
AEs leading to permanent 41 (4.1) 53 (5.3)
discontinuation of treatment
Death 13 (1.3) 9 (0.9)
Hypoglycaemic events 13 (1.3) 9 (0.9)

Matthews DR et al. Lancet. 2019. doi.org/10.1016/S0140-6736(19)32131-2

Time to first adjudicated macro-vascular event
Initial monotherapy
Hazard ratio (95% CI): 0·71 (0·42,1·19);
{p=0·19}

Early combination

Caveat! Small numbers, and wide confidence limits

Although this is an indicative signal, more dedicated studies are required

Matthews DR et al. Lancet. 2019. doi.org/10.1016/S0140-6736(19)32131-2
VERIFY - Strengths

• Newly-diagnosed type 2 diabetes with low baseline HbA1c

• Diverse, geographically distributed and multiethnic population

• Long study duration

• Well tolerated with no unexpected or new safety findings

• Reproducibility in glycemic durability in an international

heterogenic population
 VERIFY - Key findings

• Early combination treatment reduced by half the risk of time to initial

treatment failure vs. monotherapy strategy
• Median time to failure was 3 years in the initial monotherapy strategy
compared to over 5 years in the early combination strategy
• When all patients were receiving combination therapy, the risk for
time to second treatment failure onto insulin was reduced by 26%

• Both approaches were safe and well tolerated

Early combination therapy for type 2 diabetes
management - what VERIFY tells us

We can ensure earlier and better glycaemic control

…that may be more durable
…with low risk of hypoglycaemia and no body weight gain
…therefore improving patients’ adherence to treatment
…and possibly reducing clinical inertia
…offering more opportunities to address individual
patient needs’;=

Matthews DR et al. Lancet. 2019. doi.org/10.1016/S0140-6736(19)32131-2

Conclusion

The strategy of an early combination treatment approach with

vildagliptin plus metformin in patients with newly diagnosed
type 2 diabetes significantly and consistently improves long-
term glycemic durability compared with metformin monotherapy

M-GALVU-04-10-2019-PH1910744058
Thank you!