Cardiologists and diabetes.Target organs and action mechanism of antidiabetic drugs.Cardiovascular Outcome Trials ( CVOTs ) in Diabetes.Completed and ongoing CVOTs in type 2 diabetes.Diabetes Medications and Cardiovascular Impact.Recommendations for management of diabetes Cardiovascular safety of anti-diabetic drugs.

1. Magdy El-Masry
Prof . of Cardiology , Tanta University

3. 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

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

6. 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

7. Cardiologists and diabetes

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

15. 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

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

20. 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

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

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

28. What Do We Know So Far ?

29. Completed and ongoing CVOTs in type 2 diabetes.

30. 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.

35.  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.

36. 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].

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

38. Sulfonylureas
(second generation)
Gliclazide
Glipizide
Glimepiride
Glyburide
Cardiovascular Impact
Unknown:
􀁸 Gliclazide
􀁸 Glipizide
􀁸 Glimepiride
􀁸 Glyburide
Cardiovascular Outcomes Data
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.

39. Meglitinides
(Glinides)
Nateglinide
Repaglinide
Cardiovascular Impact
Unknown:
􀁸 Nateglinide
􀁸 Repaglinide
Cardiovascular Outcomes Data
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]

40. 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.

41. Thiazolidinediones
( Glitazones )
Pioglitazone
Rosiglitazone
Cardiovascular Impact
Improves Outcomes:*
Pioglitazone
Neutral:*
 Rosiglitazone
*based on CV morbidity and mortality
outcomes, but note increased risk of
heart failure associated with use.
Cardiovascular Outcomes Data
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]

42. Cardiovascular Outcomes Data
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].

43. 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].
Cardiovascular Outcomes Data
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].

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

45. Cardiovascular Outcomes Data
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].

46. Cardiovascular Outcomes Data
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].

47. 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
Cardiovascular Outcomes Data

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

49. Cardiovascular Outcomes Data
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.

50. 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.
Cardiovascular Outcomes Data

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

52. 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.
Cardiovascular Outcomes Data

53. What do the guidelines say?

54. 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

56. 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

57. 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

61. 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