Mechanism

treatment

comparator

All cause death

Coronary event

Amputations

Cardiovascular death

Death from cancer

Fatal MI

Heart failure

Long term death

Fatal stroke

Non fatal stroke

Non fatal MI

stroke (fatal and non fatal)

myocardial infarction (fatal and non fatal)

hospitalisation for heart failure

cardiovascular events

cardiac event (fatal and non fatal )

A CHANGER

vomiting

diarrhoea

Adverse events leading to treatment discontinuation

non cardiovascular death

macrovascular events

microvascular events

nephropathy

retinopathy

macrovascular or microvascular events

fatal HF

Peripheral vascular events

all cause death, MI, stroke

change in HbA1c (%)

change in body weight (kg)

long term cardiovascular events

vision loss

severe hypoglycemia

HbA1c

all hypoglycemia

HbA1c < 6.5%

HbA1c <7%

treatment-emergent adverse events (TEAEs)

serious adverse events

severe adverse events

change in daily mean glucose, mmol/L

change in FSG, mmol/L

Alogliptin

diabetes type 2, in all type of patients

vs placebo

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.88 [0.71 1.09]	p=1.00	0	5380	1	EXAMINE,
All cause death	0.88 [0.71 1.09]	p=1.00	0	5380	1	EXAMINE,
Coronary event	no data
Amputations	no data
Cardiovascular death	0.85 [0.66 1.10]	p=1.00	0	5380	1	EXAMINE,
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
hospitalisation for heart failure	no data
cardiovascular events	0.96 [0.81 1.13]	p=1.00	0	5380	1	EXAMINE,
cardiovascular events	0.96 [0.81 1.13]	p=1.00	0	5380	1	EXAMINE,
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	no data
nephropathy	no data
retinopathy	no data
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
EXAMINE, 2013	alogliptin	placebo	patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days

Linagliptin

diabetes type 2, in all type of patients

vs glimepiride

by 54%

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	no data
All cause death	no data
Coronary event	no data
Amputations	no data
Cardiovascular death	1.00 [0.14 7.14]	p=1.00	0	1551	1	CAROLINA,
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
hospitalisation for heart failure	no data
cardiovascular events	0.46 [0.23 0.91]	p=0.04	0	1551	1	CAROLINA,
cardiovascular events	0.46 [0.23 0.91]	p=0.04	0	1551	1	CAROLINA,
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	no data
nephropathy	no data
retinopathy	no data
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
CAROLINA, 2012	linagliptin	glimepiride 1-4 mg QD	patients with type 2 diabetes at elevated cardiovascular risk receiving usual care

Saxagliptin

diabetes type 2, in all type of patients

vs placebo

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	1.11 [0.97 1.28]	p=1.00	0	16492	1	SAVOR TIMI,
All cause death	1.11 [0.97 1.28]	p=1.00	0	16492	1	SAVOR TIMI,
Coronary event	no data
Amputations	no data
Cardiovascular death	1.03 [0.87 1.22]	p=1.00	0	16492	1	SAVOR TIMI,
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	1.11 [0.88 1.40]	p=1.00	0	16492	1	SAVOR TIMI,
myocardial infarction (fatal and non fatal)	0.95 [0.80 1.12]	p=1.00	0	16492	1	SAVOR TIMI,
hospitalisation for heart failure	no data
cardiovascular events	1.00 [0.89 1.12]	p=1.00	0	16492	1	SAVOR TIMI,
cardiovascular events	1.00 [0.89 1.12]	p=1.00	0	16492	1	SAVOR TIMI,
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	no data
nephropathy	no data
retinopathy	no data
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
SAVOR TIMI, 2013	saxagliptin	placebo	patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events

Sitagliptin

diabetes type 2, in all type of patients

vs placebo

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	1.01 [0.90 1.14]	p=1.00	0	14671	1	TECOS,
All cause death	1.01 [0.90 1.14]	p=1.00	0	14671	1	TECOS,
Coronary event	no data
Amputations	no data
Cardiovascular death	1.03 [0.89 1.19]	p=1.00	0	14671	1	TECOS,
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	0.97 [0.79 1.19]	p=1.00	0	14671	1	TECOS,
myocardial infarction (fatal and non fatal)	0.95 [0.81 1.11]	p=1.00	0	14671	1	TECOS,
hospitalisation for heart failure	no data
cardiovascular events	0.99 [0.89 1.10]	p=1.00	0	14671	1	TECOS,
cardiovascular events	0.99 [0.89 1.10]	p=1.00	0	14671	1	TECOS,
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	no data
nephropathy	no data
retinopathy	no data
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
TECOS, 2015	sitagliptin phosphate, one 50 mg or one 100 mg tablet (dose dependant on renal function) orally, once daily	placebo	patients with Type 2 Diabetes Mellitus having a history of cardiovascular disease and a hemoglobin A1c (HbA1c) of 6.5% to 8.0%

Exenatide

diabetes type 2, in all type of patients

vs placebo

by 14%

by 9% [demonstrated]

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.86 [0.77 0.97]	p=0.04	0	14752	1	EXSCEL,
All cause death	0.86 [0.77 0.97]	p=0.04	0	14752	1	EXSCEL,
Coronary event	no data
Amputations	no data
Cardiovascular death	0.88 [0.76 1.02]	p=1.00	0	14752	1	EXSCEL,
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	0.85 [0.70 1.03]	p=1.00	0	14752	1	EXSCEL,
myocardial infarction (fatal and non fatal)	0.97 [0.85 1.10]	p=1.00	0	14752	1	EXSCEL,
hospitalisation for heart failure	0.94 [0.78 1.13]	p=1.00	0	14752	1	EXSCEL,
cardiovascular events	0.91 [0.83 1.00]	p=0.04	0	14752	1	EXSCEL,
cardiovascular events	0.91 [0.83 1.00]	p=0.04	0	14752	1	EXSCEL,
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	no data
nephropathy	no data
retinopathy	no data
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
EXSCEL, 2017	subcutaneous injections of extended-release exenatide at a dose of 2 mg once weakly	placebo	patients with type 2 diabetes, with or without previous cardiovascular disease

Liraglutide

diabetes type 2, in all type of patients

vs placebo

by 15%

by 21%

by 12% [demonstrated]

by 15%

by 20%

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.85 [0.74 0.98]	p=0.04	0	9340	1	LEADER,
All cause death	0.85 [0.74 0.98]	p=0.04	0	9340	1	LEADER,
Coronary event	no data
Amputations	no data
Cardiovascular death	0.79 [0.66 0.95]	p=0.04	0	9340	1	LEADER,
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	0.87 [0.71 1.07]	p=1.00	0	9340	1	LEADER,
myocardial infarction (fatal and non fatal)	0.86 [0.73 1.01]	p=1.00	0	9340	1	LEADER,
hospitalisation for heart failure	0.88 [0.73 1.06]	p=1.00	0	9340	1	LEADER,
cardiovascular events	0.88 [0.78 0.99]	p=0.04	0	9340	1	LEADER,
cardiovascular events	0.88 [0.78 0.99]	p=0.04	0	9340	1	LEADER,
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	0.85 [0.74 0.99]	p=0.04	0	9340	1	LEADER,
nephropathy	0.80 [0.67 0.94]	p=0.04	0	9340	1	LEADER,
retinopathy	1.15 [0.87 1.53]	p=1.00	0	9340	1	LEADER,
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
LEADER, 2016	Maximum dose of 1.8 mg liraglutide, injected subcutaneously once daily	placebo	subjects with type 2 diabetes

Lixisenatide

diabetes type 2, in all type of patients

vs placebo

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.94 [0.78 1.13]	p=1.00	0	6068	1	ELIXA,
All cause death	0.94 [0.78 1.13]	p=1.00	0	6068	1	ELIXA,
Coronary event	no data
Amputations	no data
Cardiovascular death	no data
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
hospitalisation for heart failure	no data
cardiovascular events	1.02 [0.89 1.17]	p=1.00	0	6068	1	ELIXA,
cardiovascular events	1.02 [0.89 1.17]	p=1.00	0	6068	1	ELIXA,
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	no data
nephropathy	no data
retinopathy	no data
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
ELIXA,	lixisenatide	placebo	patients with T2DM and a recent ACS event

Semaglutide

diabetes type 2, in all type of patients

vs placebo

by 26% [demonstrated]

by 36%

by 76%

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	1.05 [0.74 1.49]	p=1.00	0	3297	1	SUSTAIN 6,
All cause death	1.05 [0.74 1.49]	p=1.00	0	3297	1	SUSTAIN 6,
Coronary event	no data
Amputations	no data
Cardiovascular death	0.98 [0.65 1.48]	p=1.00	0	3297	1	SUSTAIN 6,
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
hospitalisation for heart failure	no data
cardiovascular events	0.74 [0.58 0.95]	p=0.04	0	3297	1	SUSTAIN 6,
cardiovascular events	0.74 [0.58 0.95]	p=0.04	0	3297	1	SUSTAIN 6,
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	no data
nephropathy	0.64 [0.46 0.89]	p=0.04	0	3297	1	SUSTAIN 6,
retinopathy	1.76 [1.11 2.79]	p=0.04	0	3297	1	SUSTAIN 6,
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
SUSTAIN 6, 2016	once-weekly semaglutide (0.5 mg or 1.0 mg)	placebo	patients with type 2 diabetes who were on a standardcare regimen

Glargine

diabetes type 2, in all type of patients

vs control

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.98 [0.89 1.07]	p=1.00	0	12537	1	ORIGINE,
All cause death	0.98 [0.89 1.07]	p=1.00	0	12537	1	ORIGINE,
Coronary event	no data
Amputations	0.89 [0.60 1.32]	p=1.00	0	12537	1	ORIGINE,
Cardiovascular death	1.00 [0.89 1.13]	p=1.00	0	12537	1	ORIGINE,
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	1.03 [0.88 1.20]	p=1.00	0	12537	1	ORIGINE,
myocardial infarction (fatal and non fatal)	1.02 [0.88 1.19]	p=1.00	0	12537	1	ORIGINE,
hospitalisation for heart failure	0.90 [0.77 1.05]	p=1.00	0	12537	1	ORIGINE,
cardiovascular events	1.02 [0.94 1.11]	p=1.00	0	12537	1	ORIGINE,
cardiovascular events	1.02 [0.94 1.11]	p=1.00	0	12537	1	ORIGINE,
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	0.97 [0.90 1.05]	p=1.00	0	12537	1	ORIGINE,
nephropathy	no data
retinopathy	no data
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
ORIGINE, 2012	insulin glargine (with a target fasting blood glucose level of ¡Ü95 mg per deciliter	standard care	with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes

Aleglitazar

diabetes type 2, in all type of patients

vs placebo

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	1.08 [0.85 1.37]	p=1.00	0	7226	1	ALECARDIO,
All cause death	1.08 [0.85 1.37]	p=1.00	0	7226	1	ALECARDIO,
Coronary event	no data
Amputations	no data
Cardiovascular death	1.15 [0.88 1.51]	p=1.00	0	7226	1	ALECARDIO,
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
hospitalisation for heart failure	no data
cardiovascular events	0.96 [0.83 1.11]	p=1.00	0	7226	1	ALECARDIO,
cardiovascular events	0.96 [0.83 1.11]	p=1.00	0	7226	1	ALECARDIO,
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	no data
nephropathy	no data
retinopathy	no data
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
ALEPREVENT,	aleglitazar 150 ìg	placebo	patients with T2D or prediabetes with established, stable CV disease
ALECARDIO, 2014	aleglitazar 150 ìg daily	placebo	patients hospitalized for ACS (myocardial infarction or unstable angina) with type 2 diabetes

Canagliflozin

diabetes type 2, in all type of patients

vs placebo

by 97%

by 33%

by 14% [demonstrated]

by 40%

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.87 [0.74 1.02]	p=1.00	0	10142	1	CANVAS,
All cause death	0.87 [0.74 1.02]	p=1.00	0	10142	1	CANVAS,
Coronary event	no data
Amputations	1.97 [1.41 2.75]	p=0.04	0	10142	1	CANVAS,
Cardiovascular death	0.87 [0.72 1.06]	p=1.00	0	10142	1	CANVAS,
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	0.87 [0.69 1.09]	p=1.00	0	10142	1	CANVAS,
myocardial infarction (fatal and non fatal)	0.89 [0.73 1.09]	p=1.00	0	10142	1	CANVAS,
hospitalisation for heart failure	0.67 [0.52 0.87]	p=0.04	0	10142	1	CANVAS,
cardiovascular events	0.86 [0.76 0.98]	p=0.04	0	10142	1	CANVAS,
cardiovascular events	0.86 [0.76 0.98]	p=0.04	0	10142	1	CANVAS,
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	no data
nephropathy	0.60 [0.47 0.77]	p=0.04	0	10142	1	CANVAS,
retinopathy	no data
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
CANVAS, 2017	canagliflozin	placebo	participants with type 2 diabetes and high cardiovascular risk

Dapagliflozin

diabetes type 2, in all type of patients

vs placebo

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	no data
All cause death	no data
Coronary event	no data
Amputations	no data
Cardiovascular death	no data
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
hospitalisation for heart failure	no data
cardiovascular events	no data
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	no data
nephropathy	no data
retinopathy	no data
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
DECLARE TIMI 58, 2018	Dapagliflozin		adults with T2D at risk of CV events, including patients with multiple CV risk factors or established CV disease

Empagliflozin

diabetes type 2, in all type of patients

by 14% [demonstrated]

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	0.68 [0.57 0.82]	p=0.04	0	7020	1	EMPA-REG OUTCOME,
All cause death	0.68 [0.57 0.82]	p=0.04	0	7020	1	EMPA-REG OUTCOME,
Coronary event	no data
Amputations	no data
Cardiovascular death	0.62 [0.49 0.78]	p=0.04	0	7020	1	EMPA-REG OUTCOME,
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	1.18 [0.89 1.56]	p=1.00	0	7020	1	EMPA-REG OUTCOME,
myocardial infarction (fatal and non fatal)	0.87 [0.70 1.09]	p=1.00	0	7020	1	EMPA-REG OUTCOME,
hospitalisation for heart failure	0.65 [0.50 0.85]	p=0.04	0	7020	1	EMPA-REG OUTCOME,
cardiovascular events	0.86 [0.74 0.99]	p=0.04	0	7020	1	EMPA-REG OUTCOME,
cardiovascular events	0.86 [0.74 0.99]	p=0.04	0	7020	1	EMPA-REG OUTCOME,
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	no data
nephropathy	no data
retinopathy	no data
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
EMPA-REG OUTCOME, 2015	10 mg or 25 mg of empagliflozin once daily	placebo	patients with type 2 diabetes at high cardiovascular risk

Pioglitazone

diabetes type 2, in all type of patients

vs placebo

Endpoint	TE [95% CI]	p val	I2	n	k	trials
All cause death	no data
All cause death	no data
Coronary event	no data
Amputations	no data
Cardiovascular death	no data
Death from cancer	no data
Fatal MI	no data
Heart failure	no data
Long term death	no data
Fatal stroke	no data
Non fatal stroke	no data
Non fatal MI	no data
stroke (fatal and non fatal)	no data
myocardial infarction (fatal and non fatal)	no data
hospitalisation for heart failure	no data
cardiovascular events	no data
cardiovascular events	no data
cardiac event (fatal and non fatal )	no data
A CHANGER	no data
vomiting	no data
diarrhoea	no data
Adverse events leading to treatment discontinuation	no data
non cardiovascular death	no data
macrovascular events	no data
microvascular events	no data
nephropathy	no data
retinopathy	no data
macrovascular or microvascular events	no data
fatal HF	no data
Peripheral vascular events	no data
all cause death, MI, stroke	no data
change in HbA1c (%)	no data
change in body weight (kg)	no data
long term cardiovascular events	no data
vision loss	no data
severe hypoglycemia	no data
HbA1c	no data
all hypoglycemia	no data
HbA1c < 6.5%	no data
HbA1c <7%	no data
treatment-emergent adverse events (TEAEs)	no data
serious adverse events	no data
severe adverse events	no data
change in daily mean glucose, mmol/L	no data
change in FSG, mmol/L	no data

TE: treatment effect; CI: confidence interval; k: nulmber of trials; n: total number of patients

Trial	Studied treatment	Control	Patients
PROACTIVE,	oral pioglitazone titrated from 15 mg to 45 mg	placebo	patients with type 2 diabetes who had evidence of macrovascular disease.
IRIS, 2016

glucose lowering for cardiovascular prevention