Improving standards of care

for those with type 2 diabetes

Issues of
drug selection
as second
line treatment
in T2DM
Dr Harry Howlett FRCP Edin
London United Kingdom

WE LIVE IN A WORLD OF GUIDELINES

FOR MANAGING T2DM
INTERNATIONAL DIABETES FEDERATION (IDF)
2005 and 2011/12
AMERICAN GUIDELINES (ADA)
2006, 2008, 2009, 2012, 2015
EUROPEAN GUIDELINES (EASD)
2006, 2008, 2009, 2012, 2015
AACE/ACE GUIDELINES
2009, 2013
NATIONAL GUIDELINES (NICE UK)
2003, 2005, 2009, 2015

Getting to Goal

Job done

GUIDANCE Study 7,597 T2DM patients

Percent

Gap exists between checking HbA1c and achieving target

HbA1c <7%

Leicester Diabetes Centre 2012

Stone MA et al. Diabetes Care. 2013 ; 36: 2628-38

Guidelines

Guidelines
on
Diabetes
management

Failing to deliver
HbA1c targets
Is this the fault
of guidelines?

Barriers to Diabetes Care

N
IO
T
I
D
N
O
C
X
E
L
CHRONIC COMP
E
R
A
C
G
N
I
D
N
A
M
G DE
QUIRIN
REDisease
Therapeutic
Regimen
Process
D
N
A
S
N
O
I
T
A
IC
L
P
M
O
C
ID
O
V
A
TO
S
E
M
O
C
T
U
O
H
T
L
GOOD HEA

Clinical Practice

Patient Adherence

Primary Endocrinopathies:
Treating a Moving Target
DISEASE
Insulin
Resistance
Ins
uli
n

Ac
ti

Type 2
Diabetes

b-cell
Dysfunction
a
mi
e
yc
l
g
r
pe
y
H

on

Insulin
Concentration

Insulin
Resistance

b-cell Failure

Euglycaemia
Normal

IGT Obesity

Diagnosis Of T2DM

Progression of T2DM

Treatment Approaches
Clinical Practice

Diet +
Metformin

COMPLEX
OHA 3 INSULIN INSULIN

HbA1C %

9
8
7

HbA1C < 7% approach

Diagnosis

+5 yrs

+10 yrs

+ 15 yrs

Campbell. Br J Cardiol 2000; 7: 625-31

Treatment Approaches
Clinical Practice

Diet +
Metformin

OHA 3

INSULIN

COMPLEX
INSULIN

HbA1C %

9
Failure based treatment
of symptoms approach

8
7

HbA1C < 7% approach

Diagnosis

+5 yrs

+10 yrs

+ 15 yrs

Campbell. Br J Cardiol 2000; 7: 625-31

Barriers to Diabetes Care

Disease Process

Clinical Practice

Therapeutic Regimen

Patient Adherence

Antihyperglycaemic therapy in type 2

diabetes : ADA / EASD recommendations

Metformin
High Efficacy
Low risk of Hypos
Weight neutral/loss
GI/Lactic acidosis
Low cost
Reduces CVD events
Metformin
Inzucchi SE et al. Diabetes Care 2015;38:140-149

UKPDS

Robert Turner Rury Holman

UKPDS Trial
Intervention
1977 - 1997

Clinical Outcomes
for Metformin

Diabetes-related deaths
-42%

1997 - 2007

-30%

All Cause Mortality

-36%

POST-Trial
Monitoring

-27%

Legacy
effect

Myocardial Infarction
-39%
CV Complications and
Survival reduced
versus other therapies

-33%
CV Complications and
Survival reductions
maintained
UKPDS 34. Lancet 1998; 352: 854-65
UKPDS 80. NEJM 2008; 359: 1577-89

ADA-EASD
Audit of Anti-Diabetic Agents
Titration of Metformin
1) Start low 500mg/day
2006

2) Increment slowly 2000mg/day

2008

2009

3) Reduce dose if GI side effects develop

4) Maximum dose is 3000mg/day given bid, tid
5) Consider once-a-day longer acting
formulation if standard metformin is not
suitable
Metformin XR from 2005 onwards in the UK

UK Clinical Experience
with Metformin XR
To determine
if patients with a history
of metformin intolerance
Liverpool

could tolerate 2000mg

Clatterbridge

London

extended release
metformin

Isle of Wight

Retrospective chart review

Prospective follow-up

Feher. Br J Diabetes Vasc Dis 2007; 7: 225-8

Metformin XR Tolerability Results

UK
Location

Patient
No

Tolerant
No (%)

Liverpool

22

10 (46)
12a (54)

Intolerant
No (%)

s
t
n
e
i
t
Isle of Wight
24
15
(62)
a
R
p
X
4
n
f
i
o
m
t
r
u
o
o
f
Clatterbridge 3
28
e 23 (82)
M
e
t
3 (11)
a
r
e
l
o
t
b

London
a

21

19 (90)

7 (30)
2 (7)
2 (10)

Tolerant < 1.5g/day b 2 patients lost to follow-up c Tolerant with minor symptoms
Feher. Br J Diabetes Vasc Dis 2007; 7: 225-8

Metformin XR once daily

and improved adherence
Diabetes Audit and Research Centre in tayside, Scotland

Donnelly LA. Diabetes ,Obesity and Metabloism 2009;11:338-342

Switchover to Metformin XR improves

adherence in routine general practice
Adherence

HbA1c

P<0.0001

10.0

HbA1c ( %)

P=0.074

9.0

8.0

7.0

Metformin

Metformin XR

Donnelly LA. Diabetes,Obesity &Metabolism 2009;11:338-342

Metformin XR Dose Related

Improvement in Glycaemia
Fasting Glycaemia
0.5

HbA1C

0
-0.5
-1.0
-1.5
-2.0

Treatment Groups
Treatment Groups

Fujioka DOM 2005; 7: 28-39

Issues with Metformin

Divided dosing Regimen
Metformin XR

Tolerability

Contraindications (1970s)

Contraindications to metformin Questionned

Prof Michael Stumvoll

Benefits
Contraindications
Patients needlessly denied metformin because
contraindications are outdated and defined for
phenformin in the 1970s rather than metformin
Contraindications can damage your health
Holstein A,Stumvoll M. Diabetologia 2005; 48: 2454-9

eGFR level
(ml/min per 1.73 m2)

Action

> 60

No renal contraindication to metformin

Monitor renal function annually

< 60 and > 45

Continue use
Increase monitoring of renal function
(every 3-6 months)
Prescribe metformin with caution

< 45 and > 30

Use lower dose (e.g., 50%, or half-maximal dose)

Closely monitor renal function (every 3 months)

< 30

Stop metformin
Frid A et al Diabetes Care 2010;33:1291-1293
Lipska KJ et al. Diabetes Care 2011;34:1431-1437

Usage of Metformin in T2DM

with renal impairment
NHANES 2011-2012
11.1 Million patients

Metformin Use (%)

100
80
60
40

Almost 900,000 US patients

denied metformin

20

164,000

PRESCRIBE METFORMIN WITH CARE

<30

30-45

>45-60

>60-90

>90

eGFR mL/min
Flory JH. JAMA Internal Medicine online Jan 5th 2015

Metformin reduces risk of heart failure

and improves survival of those with HF

2008
2009

N=3

2009

*
*
*
*

2010
2010

METFORMIN REDUCES
THE INCIDENCE OF NEW
HEART FAILURE

N = 11
METFORMIN IMPROVES
SURVIVAL IN PATIENTS
WITH HEART FAILURE

2010
2011

Papanas N. Expert Opin Pharmacother 2012; 13: 1-8

Guideline support
for metformin use in Heart failure

1/. Canadian Diabetes Association recommend metformin

as first line therapy in HF Can J Diab 2008;32(suppl1):S1-S200
2/. FDA in the US have removed HF as an absolute
contraindication to metformin Inzucchi N. Diabetes Care 2007;30:e129
3/. American Diabetes Association support the use
of metformin in stable HF provided renal function is normal
ADA Standards of Medical Care. Diabetes care 2011;34(suppl1) :S11-S61

Antihyperglycaemic therapy in type 2

diabetes : add-on therapy to metformin

O
MENU T

E
R
A
U
O
TY
U
B
L
L
SUIT A
TA
S
PA

FI

SH

EF
E
B

R
E
K
A
M
IO N
S
I
C
E
D
THE

MB
A
L

EN
K
IC
H
C

BL
A
T
E
G
VE

Metformin

Inzucchi SE et al. Diabetes Care 2015;38:140-149

ADD ON Therapies to Metformin

Drug Class

HbA1c

Sulfonylureas

1.5%

Advantages

Disadvantages

Long experience
Microvascular risk
reduced (UKPDS)
Low cost

Hypoglycaemia
Weight gain
MI preconditioning blunted ?
Low durability

Your clinical judgement

TZDs

No hypoglycaemia
Weightin
gain
and0.5-1.5%
how important
are these
your
Durability
Oedema/Heart failure
Raises HDL
Chol
Bone fractures
clinical
assessment:

Raises LDL Chol (Rosi)

DPP-4 inhibitors

Risk
of Weight gain
No hypoglycaemia
Urticaria

0.5-1.0%

Well tolerated

Acute Pancreatitis ?
Heart Failure hospitalisation ?

Risk of Hypoglycaemia
GLP-1 agonists

1.5-2.0%

No hypoglycaemia
GI side effects
Severity
of
co-morbidities
Well tolerated
Acute pancreatitis ?
Thyroid neoplasm ?

SGLT2 Inhibitors

Long-term
safety of new
agentsinfections
0.5-1.0% No hypoglycaemia
Genitourinary
Weight loss
Blood pressure fall

Polyuria
Volume depletion/hypotension
Raises LDL Chol

Cost of medication to the patient

Adapted from Inzucchi SE et al Diabetologia 2015 ; 35: 140-149

GRADE Glycemic Reduction Approaches in

Diabetes. A comparative Effectiveness Study
NIH sponsored prospective
Safety and Efficacy Trial
Patients on metformin
randomised to Sulfonylurea (glimepiride)
DPP-4 Inhibitor ( sitagliptin)
GLP-1 agonist (liraglutide)
Insulin (Glargine)

Washington

Clinicaltrials.gov/ct2/show/NCT01794143

IDF treatment algorithm to aid drug selection

in treatment programmes worldwide

SIMPLE TO FOLLOW
LOW COST

www.idf.org/treatment-algorithm 2011-people-type-2-diabetes
and Global guidelines for type 2 diabetes 2012

Clinical experience with Sulfonylureas

SAFETY AND
LONG-TERM USE
Sulfonylureas
Thiazolidinediones
Incretin agents
SGLT2 inhibitors

58 years
15 years
8 years
2 years

UKPDS

Clinical Outcomes for

glibenclamide 1977-1997

Heart Attack

Microvascular
Complications

F/NF (n=21)
Complications

22%
Reduction
(p=0.056)

34%
Reduction
(p=0.017)

18%
Reduction
(p=0.018)

ADVANCE : Reduction of new and progressive nephropathy with gliclazide

ACCORD : Glimepiride

UKPDS 33 Lancet 1998; 352: 837-53

Myocardial Infarction Hazard Ratio

(fatal or non-fatal myocardial infarction or sudden death)

Intensive (SU/Ins) vs. Conventional glucose control

Holman R, et al. N Engl J Med. 2008; 359: 1577.

Use of sulfonylureas post-MI

(n=1181 hospital survivors followed up 2.2 years then 4.1 years)

Melbin LG. Eur Heart J 2008; 29: 166-176

MORTALITY RISK OF SULFONYLUREAS IN HIGH RISK

PATIENTS POST - MI
Hazard ratio ( 95%CI)

Metformin(155/888)*

0.65(0.47-0.90)

Death(47/271)**

Deaths
and
Cancer
deaths

0.70(0.47-1.03)

CV Death(31/182)**

0.25(0.08-0.83)

Cancer Death(6/31)**

Sulfonylureas(250/823)*
1.09(0.84-1.42)

Death(79/239)**

1.30(0.95-1.77)

CV Death(57/156)**

0.67(0.28-1.61)

Cancer Death(11/26)**
Insulin(631/442)*

1.03(0.80-1.31)

Death(208/110)**

0.92(0.69-1.24)

CV Death(137/76)**

2.05(0.95-4.43)

Cancer Deaths(27/10)**

0.05
*No of patients**No of endpoints

Non-fatal MI
or stroke
( p=0.00001)
and cancer
deaths
0.20
0.50 1.00
2.00 4.00
Drug better
Drug worse

Mellbin et al. EASD Stockholm Diabetologia 2010;53: Supplement 1,S22

MORTALITY RISK OF SULFONYLUREAS

IN HIGH RISK PATIENTS PRE- MI

FRANCE

Antidiabetic
medication

%
mortality

Sulfonylureas

3.9%

Other OHAs

6.4%

Lifestyle

8.4%

Insulin

9.4%

Conclusion: in this nationwide registry of patients hospitalised for acute MI,

no hazard was associated with the use of SUs before the acute episode

Safety Issues
Sulfonylureas and Hypos
Pioglitazone and Bladder Cancer
Rosiglitazone and MI
DPP4s,Heart failure & Mortality
Pancreatitis

GLP1s and GI disturbances

SGLT2s and Genital Infections

Incretin based therapies

and pancreatitis ( NIH sponsored )

Population based study of 1269 patients

admitted to hospital with acute
pancreatitis matched with 1269 controls all T2DM.
Patients treated with GLP-1 drugs were
at twice the risk of developing
pancreatitis.
Long-term adverse effects of the GLP-1
class on the exocrine pancreas have yet
to be assessed accurately

Singh et al. JAMA Intern Med Feb 25th 2013 online doi:10.1001/jamainternmed.2013.2720
Gale EAM. BMJ 2013; 346:9

New CV outcome data for

the DPP4 inhibitors
Multicentre DB Randomised placebo controlled trials
White WB et al. N Engl J Med 2013 , 2nd September
Scirica BM et al. N Engl J Med 2013, 2 nd September

S
EXAMINE
O
R

Saxagliptin
(n=16,492)

Alogliptin
(n=5,380) No signal of increased CV
death, MI or stroke over
1.5 years (Examine) and 2.1 years
(SAVOR) follow-up.
but alas ......no evidence of CV
BENEFIT and a 29% increased rate
of heart failure leading to
hospitalisation (saxagliptin).

Saxagliptin, Alogliptin and Cardiovascular Outcomes

Post publication analysis :

Alogliptin neither induced new onset

heart failure nor worsened heart failure
in patients with a history of heart failure
after randomisation
19% increase in HF hospitalisation that was non -significant

Letters to the Editor NEJM 2014; 370;483-484

FDA requests informed advice on benefit risk profile

of the DPP4 inhibitors saxagliptin and alogliptin

Heart Failure related Hospitalisation (SAVOR)

Unexpected safety signal not seen in pre-clinical
or pre-marketing studies. Why?- sicker
stribut!!ion ?
dipatients

t
c
i
r
t
s
e
R
?
g
llin
e
b
a
l
n
i
e
g
n
t
a
e
h
k
r
analysis showed
greater
all-cause
mortality
COn-treatment
a
m
m
o
r
f
l
a
w
ithdra
or WWhy?
for saxagliptin.
Major CV events in subgroups ( EXAMINE)
Increased CV risk in patients with renal impairment
diabetes duration > 10 years, or those on insulin. Why?
Endocrinologic and metabolic Drug Advisory Committee meeting April 14th 2015

Advice to the FDA on benefit risk profile

of the DPP4 inhibitors saxagliptin and alogliptin

Heart Failure for both gliptins

Change in labelling to improve safety profile
To undertake mechanistic studies to determine cause (sNDA)
All Cause Mortality ( saxagliptin)
Change in labelling to improve safety profile
Renal impairment ( alogliptin)
Change in labelling to inform about unfavourable
renal changes

WATCH OUT FOR TECOS AT ADA 2015

Endocrinologic and metabolic Drug Advisory Committee meeting April 14th 2015

Saaskatchewan

7620 patients with T2DM plus HF

12% treated with sitagliptin
No increase in all cause hospital admissions
or deaths
12.5% vs 9.0 % increased risk of hospitalisation
for HR
Weir D. J Am Coll Cardiol HF 2014 July 7th

Vildagliptin in Ventricular Dysfunction Diabetes

Trial (VIVIDD)
254 patients with T2DM + HF ( NHYA I -III )

VILDAGLIPTIN
Prof John McMurray

PLACEBO

Follow- up = 1 year

Findings:

No difference in ejection fraction (LVEF)

Unexpected increase in LVEDV, LVESV, stroke volume
Conclusion :
Mixed results with unfavourable signals of decreased systolic function
McMurray J. Heart Failure Congress 2013. Lisbon, Portugal May 25-28 abstract 99

Preference for incretin therapies after metformin

Sulfonylureas out of favour last resort

Guidance too premature and not

evidence based !!
AACE Comprehensive Diabetes Management Algorithm Endocrine Practice 2013;19 No2

Add- on therapies to metformin

Safety Issues
Sulfonylureas and Hypos
UKPDS
Therapy

Major

All

Lifestyle

0.1%

1.2%

Chlorpropamide

0.4%

11.0%

glibenclamide

0.6%

17.7%

Insulin

2.3%

36.5%

UKPDS 33. Lancet 1998;352:837853.

Sulfonylureas and Hypos - solutions

REFORMULATION

PATIENT SELECTION

Reformulation of Glibenclamide Tablets

Formulations

Particle Size
Range
10 - 100

Standard 2.5 mg

Absorption slow
Delayed time to peak concn
Take before meals

<6

Absorption very fast

High peak concn but
not maintained
Take with meals

< 21

Absorption fast but

equivalent systemic exposure
(peak concn, bioavailability) to
standard glibenclamide
Take with meals

Micronised 1.75 mg

Met/ Glib 500/2.5 mg

Performance Characteristics

for 75% of particles

Met / Glib FDC tablet versus Metformin + free

glibenclamide co-administered ( Kinetics)
Lower
PPBG

Less
hypos

80
Plasma glibenclamide
(g/L)

Mean AUC ( ug.h.L )

Met + Glib

Met / Glib

434

431

Equivalent systemic exposure

60
40

Metformin + free glibenclamide

co-administered tablets

20

SlametS

Metformin / Glibenclamide
FDC tablet

4
6
8
Time after dosing (h)

10

12

Donahue et al. Clin Pharmacokinet 2002;41:1301-9

Met / Glib FDC tablet versus Metformin + free

glibenclamide co-administered glucose lowering
Reduced postprandial glucose excursions
P=0.012

24%

Donahue et al. Clin Pharmacokinet 2002;41:1301-9

Sulfonylureas for all patients ?

Children

Adults
Eye
s
Kidneys

Elderly

Brain
Heart
Nerves
Lower
limbs

Obese

Complications

Polypharmacy

Avoiding hypoglycaemia with Sulfonylureas

Holstein A et al. Exper Opin Drug Safety 2010

Optimisation of Therapy
- Barriers to Diabetes Care

Clinical Practice

Therapeutic Regimen

Disease Process

Patient Adherence

Medication Survey in UK Patients with

Type 2 Diabetes
Patients with
Adherence Index (AI) > 90%

Days of Drug Exposure

p<0.01

AI 40
(%)

31%

p<0.01
365

34%

Days

30

310

20

13%

10
0

300

302
266

255
200

SU
Alone
n=1329

Met
Alone
n=531

Combined
Therapy
n=1060

SU
Alone
n=1329

Met
Alone
n=531

Combined
Therapy
n=1060

Morris. Diabetic Med 2002.

Identical twins

Which one is adherent ?

C 2015 American Diabetes Association

Retrospective analysis (n >200,000) of T2DM on oral agents

Adherence defined as 80% plus of prescribed medication
Determinants (modifiable)
Duration of diabetes

Pill burden -polypharmacy

Source of medication (GPs)

Level of Education

Out-of-pocket expenses

Income

Determinants ( non-modifiable)
Age

Gender

RESULT = 67%
Kirkman MS et al. Diabetes Care 2015 January 8th. DOI:10.2337/dc14-2098

Major barrier to delivery of care

was the patient and not the system
of care delivery

% of doctors reporting barrier

Assaad-Khalil SH. Int J Clin Pract 2013;67:1144-50

Oral therapies and Dosing

schedule
ONCE A -DAY

MULTIPLE INTAKES

NEWER SULFONYLUREAS

METFORMIN

PIOGLITAZONE

ACARBOSE

GLIPTINS

REPAGLINIDE

SGLT-2 INHIBITORS

NATEGLINIDE

REFORMULATED
GLICLAZIDE MR
METFORMIN XR

Available Fixed Dose

Combinations
to reduce tablet burden
Product
Name

Drug Components

Dosage strengths

Glucovance Metformin +
glibenclamide

250/1.25 500/2.5 500/5.0

1000/5.0

Metaglip

Metformin + Glipizide

250/1.25 500/2.5 500/5.0

Amaryl M

Metformin +
Glimepiride

Competact

Metformin +
Pioglitazone

500/15.0 850/15.0

Eucreas

Metformin +
Vildagliptin

850/50 1000/50

Janumet

850/50 1000/50
Metformin +
Sitagliptin Bailey CJ Day C. Diabetes Obes Metab 2009; 11: 527-33

Tandemact

Schernthaner G. Diabet. Med 2010; 27 : 739-743

Pioglitazone +

30/4.0 45/4.0

Fixed dose combinations - proof of better

adherence
Post monotherapy patients

Adherence rate (%)

p<0.001

Met + glib
co-administered

Met/Glib
FDC tablet
Melikian C et al. Clin Ther 2002;24:460-7

Switchover from Metformin + Glibenclamide

co-administered to the FDC tablet

HbA1C
Separate tablets

Fixed dose combination

Metformin (< 2000 mg/day) +

Glibenclamide* (< 20 mg/day)

-6

-5

-4

-3

HbA1C

-2

-1

Met / Glib Tablets

(2000/< 20 mg/day)

X
0

-1

-2

-3
Months

Months

-4

-5

Last
Rx

Switchover
Duckworth et al. JMCP 2003; 9: 256-262

Switchover leads to improvement

in glycaemic control - HbA1C
All patients (n=72)

Base HbA1C >8% (n=37)

p<0.01

-0.6%

Mean HbA1C (%)

Mean HbA1C (%)

p<0.001

-1.3%

Duckworth et al. JMCP 2003; 9: 256-62

Expanding role of FDCs

UK Polypill Trial - 2010

n
i
r
u
o
f

l
l
i
P
t
r
a
e
H
Red
Aspirin 75mg
Lisinopril 10mg

l
l
i
p
one

Simvastatin 40mg
Atenolol 50mg

How can we improve the achievement of

HbA1c targets?
Education (CME)

Developing quality
measures

Motivating and
supporting patients
on self-management

Effective use of
information
system

Adherence to
medications
Adherence to
guidelines

Personal
feedback to
HCPs

CME, continuing medical education; HCP, healthcare practitioner

Zafar et al. Primary Care Diabetes 2010;4:2037

Conclusions
1/. Be aware that multiple barriers hinder optimisation of
glycaemic control.
2/. Metformin continues to be under-utilised.
3/. Add-on therapies to metformin fall into six categories
and therapy should be individualised.
4/. Adherence is not optimal and solutions include fixed dose
combination tablets and once-a-day tablets.
5/. Recognise that diabetes is a chronic illness that requires much
self-management, and minimise the 125 Billion Euros waste (WHO)
that accompanies long-term diseases

Quick Reminder of 4 barriers

Disease Treatment Regime
Physician and Patient

Can you spot the odd one out ?

RESERVES

Patients on pharm therapya (%)

Patients Treated with Metformin in the

UK 2002-2007 pre- Metformin XR

0m
0
0
1
n
a
s
t
h
t
n
e
s
s
ti
e
a
l
p
se rd of
o
d
i
n
h
i
t
m
for in one
t
e
M
Aug-02

Jly-03

Jly-04

Jly-05

ay
d
/
g

Jly-06

Jly-07

Compufile Market Research Dinlink July 2007

Progressive nature of diabetes means stepwise

increase in therapies to achieve optimal
outcomes in management

Diabetes Severity

Diabetes
progression
Diagnosis
of
diabetes
Insulin
resistant
states
Normal

Pre-diabetes

Mono
therapy

Adjuvant
therapy
with insulin

Insulin
therapy
Dual
tablet
therapy

Treatment Burden

Are all Sulfonylureas the same ?

Nateglinide
Repaglinide

Glibenclamide
Glimepiride
Glipizide

SPECIFICITY
FOR SUR 2A and SUR 2B ?

Sulfonylurea + Benzamido
parts

Benzamido
part

SUR I RECEPTOR
Pancreatic
B-cell

TMD 12-17
Sulfonylurea
Binding
Site

Sulfonylurea
part

r
Ki

TMD 1-5
Benzamido
Binding
Site

Gliclazide
Tolbutamide
Chlorpropamide

6.
2

Potassium
Channel
(opening/closing)

Outcome

Glimepiride
vs Glib

Gliclazide
vs Glib

MI

None

None

CV Mortality

None

Yes

Yes

Yes

All Cause
Mortality

Analysis on raw data only

no adjustment for confounding factors
Simpson SH et al. Lancet Diabetes Endocrinol 2015; 3: 43- 51

Followup period
1997-2009

Insulin + Metformin = 16,910

Insulin + Sulfonylureas = 11,081

No history of stroke or MI
Mogensen et al. Diabetologia 2015; 58: 50-58

Outcomes for Insulin plus SU combination

vs Insulin plus metformin
ALL CAUSE MORTALITY

MACE EVENTS

No significant differences between SUs

Mogensen et al. Diabetologia 2015; 58: 50-58

% change from baseline

Glucovance: b-cell Function during a

Hyperinsulinaemic Clamp

Insulin secretion

1st phase

2nd phase

Glibenclamide 2.5 mg (n=17)

Metformin 500 mg (n=15)
Glucovance 500/2.5 mg (n=18)

Mean final doses

6.6 mg
1500 mg
708/3.5 mg

50%
Less
drug

Bruce et al. Int J Clin Pract 2006; 60: 783 - 90