Heart Failure Outcomes in

Clinical Trials of Glucose

Lowering Agents in Patients
with Diabetes
Ridwan Rasyid, MD
Resource person :
dr. A.C Iksan, SpPD
ABSTRAK
 Heart Failure & Diabetes
Diabetes major risk of HF
Framingham, Diabetic patients risk HF
Men 2.4 x
Women 5 x
24 40 % HF patients have Diabetes.
HF patients with diabetes compared to non diabetic :
40% Mortality risk in 3 years
30% Hospitalization risk
 Left Ventricular Dysfunction &
Diabetes
LV dysfunction is found in 40% of diabetes patients
Several mechanism :
Micro circulatory dysfunction
Metabolic derangements with lipotoxicity
RAAS activation
Disturbed calcium handling
Endothelial dysfunction
Diabetes associated co morbidities :
Hypertension
Dyslipidaemia
Renal Impairment
 Glycemic Control & Heart Failure
Incidence of Cardiovascular Outcomes, Hospitalization &
Mortality in HF & Diabetes HbA1c
Little evidence glycemic control reduces incidence of HF
Recent Studies HbA1c 10.3% improved LV systolic function
Absolute improvement of LV systolic function HbA1c
reduction
Decreased BMI & Metformin additional independent
predictor of increased LV function
Glycaemic control no impact on HF , but reduction in MI
 Glucose Lowering Agents
n
s ul i GLP-1
In ZD DDP-IV inhibitor
T -1
P a Glukosidase Alfa Inhibitor TZD
GL ilure
n
u lfo
S
or t

S
ibi

G
P-I LP-1

LT
nh

-2
Vi

in
G

hi
bi
to
DD

r
Metfotmin
TZD Metformin
GLP-1 TZD
DDP-IV inhibitor GLP-1
DDP-IV inhibitor
Konsensus Pengelolaan dan Pencegahan DM tipe 2 di Indonesia. Perkeni. 2015
 Insulin
Higher incidence of HF and worse outcomes than oral
But, they are : older, later stage disease
Its unclear if insulin has any effect to CVD outcomes
Insulin has anti-natriuretic effect weight gain precipitate HF
BARI-2D study , UKPDS study No difference in HF outcomes, comparing insulin
vs sulphonylureas
ORIGIN trial, patients with dysglycaemia , insulin vs placebo no difference in
CV outcomes including HF hospitalization
There is no controlled trials that show the safety of insulin in pts with high risk of
developing HF or CV death
 Metformin
Considered the best first line agent for glucose control
Good tolerability, low cost, improved CV outcomes
Lower mortality compared to sulphonylurea
monotherapy
Lower mortality for patients after hospitalization for
HF
Metformin was not associated with lactic acidosis
 Sulphonylureas
Increasing insulin release
Hypoglycemia and weight gain, but not sodium retention
UKPDS trial, insulin and Sulphonylureas VS conventional dietary
based treatment HF incidence not increased
Cleveland Clinic study, Metformin had a lower risk of HF
compared to sulphonylureas
UK GP database, 2nd gen SFU 18 30% increased risk for HF
compared to Metfotmin
CV risk uncertainty, hypoglycemia, weight gain were considered
in choosing SFU not popular
 Thiazolidinediones
TZD fluid retention & peripheral edema (3 -5%)
More frequent if combined with insulin 15%
Mechanism remains controversial
Some studies shows TZD has no direct impact to cardiac functions
Study compare TZD vs Glyburide no change in LV mass & LVEF
Dargie et all 1 yr rosiglitazone to NYHA class I-II no impact but increased
diuretic used
Increased risk of HF reported in some clinical trials:
DREAM trial, rosiglitazone IGT without CVD incidence HF 0,5%
compared to placebo
PROactive study, patients with known CVD hospitalization for pioglitazone
50% compared to placebo, yet no increase for HF related mortality
 Thiazolidinediones (2)
RECORD trial, rosiglitazone + metformin / SFU VS metformin + SFU
CVD death did not differ.
More diuretic prescribed for patients with rosiglitazone.
HF admissions 2x in patients with rosiglitazone & more HF death
Meta analysis of seven studies with TZD HF outcomes increased,
yet CVD death risk was similiar
In 2003, ADA recommend TZD be used with caution for NYHA class I-II
and avoided in later class.
TZD are currently used less frequently due to their side effects
 Glucagon-like peptide 1 receptor
agonists
GLP-1 secreted in response to food ingestion by cell located in distal intestine
secretion of glucose dependent insulin
Benefits : Weight loss, blood pressure, low risk hypoglycemia but uncertain impact of
CVD
FIGHT study, daily liraglutide prior hospitalized HF patients Clinical outcomes,
Hospitalization, Mortality not improved
ELIXA trial, lixisenatide to prior MI diabetic patients no impact on MACE
outcomes, no impact on HF
LEADER trial, liraglutide high risk CVD patients primary outcomes reduced by
13%, CV mortality reduced 22%.
However fewer loop diuretics were initiated in the liraglutide compared to
placebo
Dipeptidyl peptidase-4 Inhibitor
GLP-1 is inactivated by the petidase DPP-4
DPP 4 inhibition GLP 1 availbility increased enhancing the
incretin effect
SAVOR TIMI, saxagliptin :
Increased hospitalization for HF by 27%
HF occurred early in 1st yr of treatment
Prior HF, CKD, increased NT pro bNP greater risk
EXAMINE study, recent MI patients receiving alogliptin
No impact on CV death and hospitalization for HF
Dipeptidyl peptidase-4 Inhibitor (2)
TECOS study, sitagliptin vs placebo :
Did not increase hospitalization for HF
CV mortality and all cause mortality after hospitalization for HF similar and
high
The VIVIDD study, vidagliptin on echo measures LV function
Worsening HF not increased
BNP level decreased
LV systolic and diastolic volume increased on vidagliptin
FDA on 11 February 2014 saxagliptin and alogliptin may increased
risk of HF
 Sodium-Glucose co-transporter 2
inhibitor
Sodium glucose transporters transport sodium and glucose across membrane
SGLT 1 widely distributed ( kidney, brain, myocardium, intestine)
SGLT 2 proximal renal tubule
SGLT2 inhibitor CV effects : reducing systolic BP, weight, HbA1c, uric acid, and triglycerides, and
also increasing HDL
EMPA-REG study, empagliflozin 10 mg, 25 mg and placebo 3yrs observation:
MACE reduced by 14%
CV death reduced by 38%
Also slowed the progression of renal disease
Reduced HF admissions and mortality by one third
And the benefits was seen in a wide range of groups
And the HF outcomes observed with empagliflozin independent of other treatment
 Sodium-Glucose co-transporter 2
inhibitor (2)
Prevention of HF with empagliflozin is probably on of the modes by which CV mortality was
reduced.
Sodium-Glucose co-transporter 2
inhibitor (3)
Sodium-Glucose co-transporter 2
inhibitor (4)
 Conclusions
Patients with diabetes are at a substantially increased risk of dying from CVD and
developing HF.
HF outcomes are not reduced by tight glucose control more by the choice of the
glucose lowering agent
Increased incidence of HF with TZD and DPP 4 inhibitor
SFU and Insulin there are almost no clinical trials data to indicate HF in high risk pts with
established CVD
DPP4 inhibitor & GLP 1 agonist show no inferiority and no reduction in CVD
GLP 1 agonists liraglutide did not significantly lower HF admissions
The SGLT2 inhibitor empagliflozin reduced the incidence of HF and CV death in patients
with or without prior HF.
Conclusions
 Conclusions
Empagliflozin provides new therapeutic strategy that potentially will have a greater impact on CV
than current HF medications.
The choice of glucose lowering agent should be personalized for the severity, risk of
hypoglycemia, presence of renal dysfunction, cost benefit, concerns about weight gain, and also
the risk of CV disease and developing HF
 Key Messages
1. Diabetes is a major risk of developing HF
2. 24 40 % HF patients have Diabetes
3. Patients with diabetes are at a substantially increased risk of dying from CVD and developing HF
4. HF patients with diabetes compared to non diabetic : 40% Mortality risk in 3 years and 30%
Hospitalization risk
5. Several mechanism diabetes to heart failure : Micro circulatory dysfunction, Metabolic
derangements with lipotoxicity, RAAS activation, Disturbed calcium handling, Endothelial
dysfunction
6. Diabetes associated co morbidities : Hypertension, Dyslipidaemia, Renal Impairment
7. Little evidence glycemic control reduces incidence of HF
8. HF outcomes are not reduced by tight glucose control more by the choice of the glucose
lowering agent
 Key Messages
9. Absolute improvement of LV systolic function HbA1c reduction
10. Glycaemic control no impact on HF , but reduction in MI
11. Increased incidence of HF with TZD and DPP 4 inhibitor
12. The SGLT2 inhibitor empagliflozin reduced the incidence of HF and CV death in patients with or
without prior HF.
13. Empagliflozin provides new therapeutic strategy that potentially will have a greater impact on
CV than current HF medications.
14. The choice of glucose lowering agent should be personalized for the severity, risk of
hypoglycemia, presence of renal dysfunction, cost benefit, concerns about weight gain, and
also the risk of CV disease and developing HF
THANK YOU