Cardiovascular safety of anti-diabetic drugs.Cardiovascular Outcome Trials ( CVOTs ) in Diabetes

Magdy El-Masry
Prof . of Cardiology , Tanta University

The Triumvirate = triad = trio
Pathogenesis of type 2 diabetes: the triumvirate.
Insulin resistance in muscle and liver and impaired insulin secretion represent the core
defects in type 2 diabetes
1999 The Triumvirate

The ominous octet. Multiple defects contribute to the development
of glucose intolerance in type 2 diabetes. HGP, hepatic glucose production.
2008 The ominous octet

Pathophysiological abnormalities targeted by currently available antidiabetic medications.
DPP4i, dipeptidyl peptidase-4 inhibitor; GLP1 RA, glucagon-like peptide-1 receptor agonist; HGP, hepatic glucose
production; MET, metformin; SGLT2i, sodium glucose co-transporter 2 inhibitor; TZD, thiazolidinedione.
The Ominous Octet : How Pathophysiology And Therapy Merge

Managing type 2 diabetes in the primary care setting:
beyond glucocentricity.

Glucocentricity
The irrational belief that lowering blood sugar using
virtually any pharmacological means will produce a
reliable reduction in adverse outcomes
glu-co-cen-tricity |ˈgloōkō senˈtrisitē
noun
Improving Diabetes Outcomes : Beyond Glucocentricity

History of diabetes medications.
John R. W hite, Jr. Diabetes Spectr 2014;27:82-86
©2014 by American Diabetes Association

Target organs and action mechanism of antidiabetic drugs.
Nature Reviews Endocrinology 12, 337–346 (2016)
The mechanism for metformin action remains uncertain: metformin might target the liver to reduce gluconeogenesis and skeletal muscles
to enhance peripheral glucose utilization, with a possible role in the gut to increase levels of glucagon-like peptide 1 (GLP-1) . Sulfonylureas
and meglitinides increase insulin secretion in the pancreas. Thiazolidinediones (TZDs) act as insulin sensitizers in skeletal muscle, adipose
tissue and the liver..GLP-1 receptor (GLP-1R) agonists (GLP-1RA) target the pancreas to increase insulin secretion and reduce glucagon
production, as well as act in the gut to reduce gastric emptying. Dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4i) increase endogenous
incretin levels by blocking the action of DPP-4 . Sodium–glucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i) reduce renal glucose
reabsorption

Evolving concepts in the perception of safety issues related to anti-diabetic drugs.
(i.e., research priority and clinical implications )

Primum non nocere is a Latin phrase that means "first, do no harm."

Completed and ongoing CVOTs in type 2 diabetes.

3-P MACE: 3 - point major adverse cardiac events (composite of cardiovascular death,
nonfatal stroke and nonfatal myocardial infarction)
4-P MACE: Composite of 3-P MACE plus unstable angina, ACS, hospitalization for HF.

 Unknown = cardiovascular outcome data is currently unavailable.
 Improves Outcomes = published data demonstrates cardiovascular
benefit with use in the treatment of type 2 diabetes.
 Worsens Outcomes = published data demonstrates cardiovascular
harm with use in the treatment of type 2 diabetes.
 Neutral = published data demonstrates neither benefit nor harm
in cardiovascular endpoints with use in the treatment of type 2
diabetes.

Biguanide
Metformin
Cardiovascular Impact
Improves Outcomes:
 Metformin
Cardiovascular Outcomes Data
A subanalysis of the UKPDS trial found good glycemic
control with metformin with about 10 years of use MAY
reduce the risk of CV mortality , especially in obese
patients, NNT = 14 [Evidence level A; high-quality RCT].
Pooled data demonstrate possible reduced CV mortality
with a NNT = 56,compared to other DM medications or
placebo [Evidence level A; high-quality meta-analysis].

Sulfonylureas
( first generation )
Chlorpropamide
Tolazamide
Tolbutamide
Unknown:
􀁸 Chlorpropamide
􀁸 Tolazamide
Worsens Outcomes:
 Tolbutamide
Tolbutamide: use has been associated with increased CV
mortality compared to diet alone or diet plus insulin.

Sulfonylureas
(second generation)
Gliclazide
Glipizide
Glimepiride
Glyburide
Unknown:
􀁸 Gliclazide
􀁸 Glipizide
􀁸 Glimepiride
􀁸 Glyburide
Glimepiride: CAROLINA, CARdiovascular Outcome study
of LINAgliptin versus glimepiride in patients with T2D is
ongoing to evaluate the long-term impact of glimepiride
on CV morbidity and mortality.

Meglitinides
(Glinides)
Nateglinide
Repaglinide
Unknown:
􀁸 Nateglinide
􀁸 Repaglinide
Nateglinide: No outcome data for inpatients with T2D.
However, the NAVIGATOR trial found nateglinide use in
patients with impaired glucose tolerance and at high risk
for CV events had a neutral effect on cardiovascular
outcomes [Evidence level A; high-quality RCT]

Alpha-glucosidase
inhibitors
Acarbose
Cardiovascular Impact :
Unknown:
􀁸 Acarbose
Cardiovascular Outcomes Data :
Acarbose: The ACE (Acarbose Cardiovascular Evaluation)
trial is ongoing to evaluate if acarbose reduces CV
morbidity and mortality in patients with impaired glucose
tolerance and established CHD or ACS.

Thiazolidinediones
( Glitazones )
Pioglitazone
Rosiglitazone
Improves Outcomes:*
Pioglitazone
Neutral:*
 Rosiglitazone
*based on CV morbidity and mortality
outcomes, but note increased risk of
heart failure associated with use.
Pioglitazone and Rosiglitazone are known for their
associated risk of heart failure with a meta-analysis
determining an NNH of approximately 50 patients treated
with either agent for approximately two years [Evidence
level A; high-quality meta-analysis]

Pioglitazone: The primary endpoint in the PROactive trial
was not improved with pioglitazone. A secondary endpoint
found use of pioglitazone for about three years in patients
with T2D and macrovascular disease (e.g., MI, stroke, PCI)
may reduce the risk of all-cause mortality, non-fatal MI,
and stroke (NNT = 50)[Evidence level A; high quality RCT].
 Subgroup analysis found use of pioglitazone for about
three years in patients with T2D and a previous stroke
may reduce the risk of recurrent fatal or nonfatal stroke
(NNT = 22) [Evidence level A; high quality RCT].

Rosiglitazone: The RECORD trial found adding
rosiglitazone to metformin or a sulfonylurea for at least
five years did not affect overall CV morbidity or mortality
[Evidence level A; high-quality RCT].
Pioglitazone: The IRIS trial found use of pioglitazone for
about five years in patients with prediabetes and a history
of stroke (with mild impairment) or TIA may reduce the
risk of a future stroke or MI (NNT = 36)[Evidence level A;
high-quality RCT].

Dipeptidyl peptidase-4(DPP-4) inhibitors
( Incretin enhancers , oral ) “Gliptins”
Worsens Outcomes:
 Alogliptin
 Saxagliptin
Neutral:
Sitagliptin
Unknown:
􀁸 Linagliptin
Alogliptin
Saxagliptin
Sitagliptin Linagliptin

Alogliptin: The EXAMINE trial found alogliptin use in
patients with T2D and a history of a recent ACS, did not
increase major adverse CV events, compared to placebo
[Evidence level A; high-quality RCT].
Alogliptin is associated with an increased risk of heart
failure-related admissions, NNH = 167 [Evidence level A;
high-quality RCT].

Saxagliptin: The SAVOR-TIMI 53 found saxagliptin use in
patients with T2D at high risk for CV events; neither
reduced nor increased the risk of CV death,
MI, or ischemic stroke, compared to standard therapy
[Evidence level A; highquality RCT].
 Saxagliptin was associated with an increased risk of
heart failure-related admissions, NNH = 143 [Evidence
level A; high-quality RCT].

Sitagliptin: The TECOS trial found adding sitagliptin to
existing DM therapy did not increase the major adverse CV
events, hospitalization for heart failure, or other adverse
events compared to placebo [Evidence level A; high-quality
RCT].
Linagliptin: CAROLINA, CARdiovascular Outcome study of
LINAgliptin versus glimepiride in patients with type 2 DM
is ongoing to evaluate the long-term impact of linagliptin
versus glimepiride on CV morbidity and mortality

Glucagon-like peptide-1(GLP-1) receptor agonists
( Incretin mimetics,injectable )
Albiglutide Liraglutide Lixisenatide
Dulaglutide
Exenatide
Unknown:
􀁸 Albiglutide
􀁸 Dulaglutide
􀁸 Exenatide
Improves Outcomes:
 Liraglutide
Neutral:
 Lixisenatide

Albiglutide: HARMONY Outcomes is ongoing to evaluate
the effects of adding albiglutide to standard blood glucose
lowering therapies on MACE.
Dulaglutide: The REWIND (Researching Cardiovascular
Events with a Weekly Incretin in Diabetes) trial is ongoing
to evaluate if dulaglutide can reduce MACE in patients
with T2D.
Exenatide: The EXSCEL (Exenatide Study of Cardiovascular
Events Lowering Trial) trial is ongoing to evaluate if
exenatide added to usual care impacts CV outcomes in
patients with T2D.

Liraglutide: The LEADER trial [Evidence level A; high-quality
RCT] found adding liraglutide to standard care in patients
with T2D with CV disease or at high CV risk over almost
four years may reduce:
*Death from CV causes, nonfatal MI, or nonfatal stroke,
NNT = 53.
*Death from CV causes, NNT = 77.
*Death from any cause, NNT = 71.
*Liraglutide did not reduce the individual rates of MI,
nonfatal stroke, or hospitalization for heart failure.
Lixisenatide: The ELIXA trial found adding lixisenatide to
conventional therapy in T2D patients with a recent ACS had
a neutral effect on CV outcomes.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors “Flozins”
Canagliflozin Empagliflozin
Dapagliflozin
Unknown:
􀁸 Canagliflozin
􀁸 Dapagliflozin
Improves Outcomes:
 Empagliflozin
Canagliflozin: CANVAS (CANagliflozin cardioVascular
Assessment Study) is ongoing to evaluate the impact of
canagliflozin on CV risk for MACEs

Dapagliflozin: DECLARE-TIMI58 is ongoing to evaluate
the impact of adding dapagliflozin to current DM
therapy on MI, ischemic stroke, and CV death
Empagliflozin: The EMPAG-REG OUTCOME trial [Evidence
level A; highquality RCT] found empagliflozin use for about
three years, when added to standard glucose-lowering
therapy in patients with T2D and underlying CV disease,
may reduce:
 Hospitalization due to heart failure (NNT = 71).
 CV death rates (NNT = 45).
 Overall death rates (NNT = 39).
 Empagliflozin did not reduce the individual rates of MI
or stroke.

L I R A G L U T I D E
E M PA G L I F L O Z I N
M E T F O R M I N P I O G L I TA Z O N E

Metformin, if not contraindicated and if tolerated, is the
preferred initial pharmacologic agent for the treatment of T2D. A
In patients with long-standing suboptimally controlled T2D and
established ASCVD , empagliflozin or liraglutide should be
considered as they have been shown to reduce cardiovascular
and all-cause mortality when added to standard care. Ongoing
studies are investigating the cardiovascular benefits of other
agents in these drug classes. B

In patients with symptomatic heart failure , thiazolidinedione
treatment should not be used. A
In patients with T2D with stable congestive heart failure ,
metformin may be used if eGFR remains >30mL/min but
should be avoided in unstable or hospitalized patients with
congestive heart failure. B

Recommendations Class Level
Metformin is recommended as first-line
therapy, if tolerated and not contra-indicated,
following evaluation of renal function.
I B
In patients with type 2 DM and CVD, the use
of an SGLT2 inhibitor should be considered
early in the course of the disease to reduce
CV and total mortality.
IIa B
Recommendations for management of diabetes

Cardiovascular safety of anti-diabetic drugs.Cardiovascular Outcome Trials ( CVOTs ) in Diabetes

Cardiovascular safety of anti-diabetic drugs.Cardiovascular Outcome Trials ( CVOTs ) in Diabetes

More Related Content

What's hot

Similar to Cardiovascular safety of anti-diabetic drugs.Cardiovascular Outcome Trials ( CVOTs ) in Diabetes

More from magdy elmasry

Recently uploaded

Cardiovascular safety of anti-diabetic drugs.Cardiovascular Outcome Trials ( CVOTs ) in Diabetes