cardio metabolic ds

1. Duo to reduce Metabolic Load

2. 2
WHAT RECENT EVIDENCES SUGGEST OF BLOOD GLUCOSE CONTROL ?

3. Multiple Metabolic Abnormalities Contribute To
Hyperglycemia In T2DM
b-cell
a-cell
Impaired Insulin
Secretion
Increased
Glucagon Secretion
Increased HGP
Neurotransmitter
Dysfunction
Increased Glucose
Reabsorption
Increased
Lipolysis
Insulin Resistance
Decreased Glucose
Uptake
Rapid Gastric
Emptying
Reduced
Incretin Effect
Adapted from DeFronzo, Diabetes. 2009;58:773-795
TZD
TZD
TZD
SFU
GLP-1 RA
GLP-1 RA
DPP-4 Inhibitors
GLP-1 RA
GLP-1 RA
DPP-4 Inhibitors
SGLT-2
Inhibitors

4. 4
Despite Availability Of Multiple OADs,
CVD & CKD Risk Appears To Be Very High In People With Diabetes
1. Packer M. Diabetes Care. 2018; 41:11-13, 2. Wanner C. Am J Cardiol. 2017;120:S59-S67, 3. idf.org. Retrieved 2020-04-29, 4. Wang T et al. Diabetes Metab Syndr. 2019;13:612-615
HF
T2DM
ASCVD
CKD
35% to 45% of patients with HF
have CKD1
20% to 44% of patients with
T2DM have CKD2,3
76% of T2D patients have
CKD & CVD4
12% - 45% of patients with HF
have T2DM1, 2
8.9% of the Indian population
has diabetes3
32% of patients with CAD have
T2DM2
In India, diabetes appears to be more of CV & renal risk than hyperglycemic risk

5. Diabetes control is never only about glucose control
Deaths
65% of deaths are due to
CV disease
Coronary heart disease
deaths
Increase 2-4 fold
.
Stroke risk
Increase 2-4 fold
Heart Failure
Increases 2-5 fold
Diabetes is the risk multiplier

6. T2DM Is Usually Complicated By Multiple Cardio-renal-metabolic
Conditions
Cardiovascular
Renal
Metabolic
Hypertension
Coronary heart disease
Acute coronary syndrome
Chronic Kidney disease
Hyperkalaemia
T2D
Hyperlipidaemia
Non-alcoholic fatty liver
disease
obesity

8. Type 2 diabetes, cardiovascular and renal disease are closely interconnected
8
Acute or chronic disorder of
one can induce dysfunction
in the other
The risk for CV death increases as CKD develops in patients with T2D
Elderly CKD patients are more likely to die of heart disease than
advance to ESRD
Hyperglycaemia
Glucose,ACEs,Lipids,BP,ROS,inflammation,fibrosis,RAAS,SNS

9. 9
Is the management only
about treating high blood
glucose ?
Or we are carrying the entire metabolic load with us ?

10. METABOLIC LOAD
10
The so called “Indian
Phenotype”
Insulin Resistance
CRP
“Thin fat Indian”
High TG,Low HDL,low
HDL
Increased susceptibility
to T2DM and CAD
Obesity
Hyperglycaemia
Hypertension
2014 Jan;63(1):53-5. doi: 10.2337/db13-1592

11. Pertinent partner to metformin, in providing
meaningful glycaemia control without
increasing risk for hypoglycemia, and in
improving the metabolic profile of patients
11
Combination therapy with a DPP4i + SGLT2i
Address the metabolic load

12. Complementary Glucose-lowering Activities Of DPP4-i
And Sglt2-i In Type 2 Diabetes Mellitus
12

13. In recent times, SGLT-2i and DPP4i has been endorsed in
various guidelines

14. MOA: SGLT2i and DPPi
14
Reduce reabsorption of filtered glucose in the proximal convoluted tubule and increase
renal glucose excretion a
Physiological effect on glucagon reduction and increase insulin secretion in a glucose-
dependent manner b
SGLT-2
inhibitor
DPP-4
inhibitor
a. Rosenwasser RF, el al. Diabetes Metab Syndr Obse. 2013;6:453-467
b. Garber AJ, et al. Diabetes Obes Metab. 2007;9:166-174

15. The Potential Synergistic Mechanisms Of
SGLT2i Combined With Dpp-4i
SGLT2i DPP4i
UGE↑,
Activity of NHE,
Glucotoxicity,
Plasma volume,
Glomerular
Hyperfiltration↓
Sensitivity of
beta cell ↑,
Insulin resistance
↓
Sympathetic
tone↓,
Activity of NHE,
Hemoglobin,
Haematocrit↑
Endogenous
(hepatic)
glucose,
glucagon↑
Endogenous
(hepatic)
glucose,
glucagon↓
Oxidative
stress,
Inflammation
↓
Endothelial
function,
macrophage
infiltration
↓, calcium
deposition↓
Insulin
secretion
↑,Incretin
effect, GLP-1,
GIP ↑
Counteraction
SBP, eGFR, Albuminuria ↓
Body weight↓
Serum uric acid ↓
Hyperglycemia, serum uric
acid, SBP, Hypo. Risk ↓
Cardiovascular risk↓ Weight neutrality
Gut
Kidney Pancreas Cardiovascular
Synergistic
effects
Biomedicine & Pharmacotherapy 127 (2020) 110192
UGE: urinary glucose excretion; NHE: Na+/H+ Exchanger

16. SGLT 2 Inhibitors In Combination With DPP-4
Inhibitors
▷ SGLT2i’s leads to an increase in glucagon concentration and a
substantial increase in EGP/HGP
▷ DPP-4 inhibitors inhibit the release of glucagon
▷ Decreasing EGP/HGP by slowing down the degradation of
GLP-1, GIP, and other endogenously released incretin
hormones
Co-administration of SGLT2i’s and other OAD’s (DPP-4i’s) should be considered
when the therapeutic effect of SGLT2 inhibitors alone was unsatisfactory
Biomedicine & Pharmacotherapy 127 (2020) 110192

17. Complementary Benefit From Combination
Activation Of Reno-hepatic Axis
Glucosuria produced by SGLT2i stimulates endogenous
glucose production (EGP) and that the increase in EGP off sets
by ~ 50 % the amount of glucose lost in the urine.
Prescriber November 2017
prescriber.co.uk

18. Activation of the Reno-Hepatic Axis
EGP
Physiologic control mechanism where
by the kidney speaks to the liver such
that the increase in EGP
Diabetes Care Volume 38, March 2015

19. Complementary mechanism of action of SGLT-2i
and DPP-4i
DPP-i
SGLT-2 i
R.M. Goldenberg et al. / Can J Diabetes 41 (2017) 6–9

20. Diabetic patient with hypertension and
dyslipidemia are at higher risk
Majority of
T2DM patients
are
uncontrolled
and at early
cardio risk
20
Avg HbA1c despite treatment
risk of developing heart attack within next 10
years
Risk of HF
Risk of developing nephropathy
8.6
40
%
40 %
4

21. Sandeep R. Das et al. J Am Coll Cardiol 2020;76:1117-1145
T2D and has ≥ of the following :
ASCVD,HF,DKD,at high risk of ASCVD

22. 22
Proposal for merging the glucocentric and the cardiocentric view of
T2DM treatment
Lancet 394, 1519–1529 (2019).

23. Pleiotropic effects → Cardiovascular protection
DPP-4 inhibition SGLT-2 inhibition
Scheen AJ Nat rev cardiol 2013;10:73-84 Inzucchi SE et al. Diab Vasc Dis Res 2015;12:90-100

24. SGLT2 inhibition and direct effects on
Na+/H+ exchange in the myocardium
Verma and McMurray (2018) Diabetologia DOI 10.1007/s00125-018-4670-7

25. Cardiovascular protection by SGLT2 inhibitors
Verma and McMurray (2018) Diabetologia DOI 10.1007/s00125-018-4670-7

26. DECLARE TIMI-58
Key Efficacy Outcomes and Their Components
N Engl J Med 2019;380:347-57.
• In DECLARE TIMI-58, the largest trial, which included a broad
representation of 1°and 2° prevention patients:
• Dapagliflozin reduced CVD/HHF, was safe with regards to MACE and
appeared to reduce renal events
• ↓CVD/HHF was consistent regardless of ASCVD or HF

27. Primary composite outcome
Diabetes No Diabetes
• CV Death/HF hospitalization/Urgent HF visit
P interaction0.80
McMurray J et al. ESC 2019
The Kaplan-Meier curves for heart failure endpoints separated within
months, suggesting an early benefit of dapagliflozin, likely via its diuretic
effect.

28. Secondary outcomes
Diabetes No Diabetes
• CV death or HF hospitalization
McMurray J et al. ESC 2019

29. Dapagliflozin effect on HF - DECLARE-TIMI 58
The largest CVOT was conducted in patients taking Dapagliflozin (n-17160)
[(CVOT patient population Empagliflozin n=7020), Canagliflozin (n=10142)]
• ~60 % Primary prevention population (Multiple CV risk factors)
• ~40% Secondary Prevention Population (Established CV disease)
Primary prevention patients
(Multiple CV risk factors)
Secondary prevention patients
(Established CV disease)
36% Relative risk reduction
of hHF 22% Relative risk reduction
of hHF
0.7%
Absolute
risk reduction
1.2%
Absolute
risk reduction
N Engl J Med 2019; 381:1995-2008

30. Dapagliflozin Reduces CV Death And Worsening
HF Events In HFrEF Patients
McMurray J et al. ESC 2019
DAPA-HF trial, in HFrEF patients (EF≤40%) both with and without T2DM (n=4744)
Outcome with Dapagliflozin 10 mg once daily on top of standard of care

31. Primary composite outcome
HR 0.75 (0.63,0.90)
CV Death/HF hospitalization/Urgent HF visit
Placebo
Dapagliflozin
Diabetes
Dapagliflozin
Placebo
Dapagliflozin
Placebo
HR 0.73 (0.60,0.88)
No Diabetes
P interaction 0.80

32. SGLT2-i Superiority OAD With CV Risk Aversion
Kosiborod M et al. Journal of American College of Cardiology. 2018;71(23):2628-39
SGLT2i vs Other OADs
Inhibition of SGLT2i versus Other OADs associated with lower risk of

33. Cardiovascular safety data for Vildagliptin
CVOT for Vildagliptin : A study conducted as per
Food and Drug Administration, USA (USFDA)
guidance, showed that vildagliptin does not lead to
an increase in CCV events in a T2DM population
Diabetes Obes Metab 2010;12:485-94.

34. Vildagliptin Improves Endothelium-Dependent Vasodilatation
in Type 2 Diabetes
Four weeks treatment with vildagliptin improves endothelium-dependent
vasodilatation in subjects with type 2 diabetes. This observation might have
favorable cardiovascular implications
Pleun C.M. van Poppel, Diabetes Care. 2011 Sep;34(9):2072-

35. Cardiovascular and heart failure safety profile of vildagliptin:
a meta-analysis of 17 000 patients
• Objective: Meta-analysis of prospectively adjudicated CV events. Patient-level data were
pooled from 40 double-blind, randomized controlled phase III and IV vildagliptin studies
• Primary end point: occurrence of major adverse CV events (MACEs; myocardial infarction,
stroke and CV death).
• Secondary end point: Assessments of the individual MACE components and HF events
(requiring hospitalization or new onset) were secondary endpoints.
* comparator group consisted of 36% placebo, 33% sulphonylurea, 10%
thiazolidinediones, 15% metformin and 6% other treatments
Diabetes, Obesity and Metabolism 2015.
N=9599: Vildagliptin 50 mg once / twice daily
N=7847: Placebo + Active comparators*
Duration : 50.3 weeks

36. 36
• This large meta-analysis indicates that vildagliptin is not associated
with an increased risk of adjudicated MACEs relative to comparators.
• Moreover, this analysis did not find a significant increased risk of HF
in vildagliptin-treated patients.
Diabetes, Obesity and Metabolism 2015.

37. 37
Based on CV risk including Heart Failure
HbA1c criteria applicable as above
SGLT-2 i DPP-4 i
Dapagliflozin with proven CV
and HF benefits
Vildagliptin have CV safety
and pleiotropic benefit
This combination may be preferred over other
conventional therapies in cases of established CV
disease and/ or heart failure risk

38. Clinicians always look out for one molecule which can tackle every
aspect of metabolic disorder like Glucose control, Blood pressure
management, Dyslipidaemia, Weight gain

39. 01
03
02
04
Time tested Insulin secretogogue,
hypoglycemia is the major challenge
Gold standard in diabetes treatment for
glycemic control along with pleotropic
effects,
Disease progression necessitates other
drug addition
Best CV safety and durability
fluid retention – can’t be prescribed to
CV patients
Neutral drug with mild glucose control &
good CV protection
As clinicians were left with limited choices they tend to opt for best suitable
molecule for different patient profile
SU
Met
DPP4i
Pio

40. As it answers every need of clinician
Glucose Control Renal Protection Can be prescribed
to any patient
CV Protection Sustainability

41. A B C D E
Glycemic
control Sustainability
CV
Protection
Shall benefit
every diabetes
patient
Renal
Protection
With combination of Dapagliflozin and Vildagliptin