T2DM and its impacts on the body. Management of T2DM, Role of SGLT2inhibitors. Empagliflozin and EMPA-REG trial.

1. SGLT2 inhibitors in Management of DM
No disclosures

2. 70% of Mortality in
diabetics due to CV disease
Reference: www.IDF.org
Diabetes – mostly a Silent Disease / syndrome

3. • Overall Prevalence: 26.3% of which 19.2% had
known diabetes, and 7.1% were newly
diagnosed diabetics
• Urban: 28.3%, Rural: 25.3% 3
• The Global prevalence of DM – 9.3% with > half (50.1%) of adults
undiagnosed
• Approx 463 million adults (20-79 years) with DM worldwide
• By 2045 this will rise to 629 million
Prevalence of DM in Pakistan
(National Diabetes Survey of Pakistan) – BMJ Open 2017
Reference: IDF Diabetes Atlas, 9th edition 2019
Prevalence of diabetes, pre-diabetes and associated risk factors: second National Diabetes Survey of Pakistan (NDSP), 2016–2017.
BMJ open. 2018 Aug 1;8(8):e020961.

4. Non-
modifiable
• Age
• Ethnicity
• Family history
• h/o GDM
• Other medical
condition
Risk factors for T2DM

5. Islet b-cell
Impaired
Insulin Secretion
↓ Glucose Uptake
Islet a-cell
↑ Glucagon Secretion
↑ Glucose Reabsorption
↓Incretin Effect
Hyperglycemia
↑ Lipolysis
Neurortransmitter
dysfunction
T2DM – a progressive disease with multiple pathophysiological defects
The OMINOUS OCTET
↑Hepatic Glucose
production

6. Management of T2DM

7. Treatment of T2DM
Diagnosis
Therapeutic Lifestyle Change (Diet & Exercise)
Combination Therapy - Oral Drug with Insulin
Combination Therapy - Oral Drugs Only*
Monotherapy*
* Exception: HbA1C > 9 in T2DM at Diagnosis, Acute Hyperglycemia, Pregnancy
Personalizing the choice of
glucose-lowering treatment

8. 0
15
30
45
UKPDS 35: Significant Risk Reduction for T2DM Complications
with Each 1% Reduction in Mean HbA1c
Risk Reduction with 1% Decline in Updated HbA1c
Micro-
vascular
disease
PVD
MI Stroke
CHF
Cataract
extraction Death
related to
diabetes
P <0.0001P <0.0001 P=0.035 P=0.021 P <0.0001
37%
43%
14% 12%
16%
19% 21%
CHF=congestive heart failure; HbA1c=hemoglobin A1c; PVD=peripheral vascular disease; MI=myocardial infarction. Adapted from Stratton IM, et al. BMJ. 2000; 321: 405–412.
N=3642
Intervention to effect better control means fewer complications

9. Major Concerns with TherapySulfonylureas
Meglitinide
Hypoglycemia
Sulfonylureas
Meglitinides
Thiazolidinediones
Weight gain
Cardiovascular
safety of OADs?
 A majority of patients with T2DM may fail to attain A1C goal with the
conventional treatment paradigm

10. We need anti-diabetic drugs which provide CV benefits..
ADA says;
• About 2 of every 3 people with T2DM
die of heart disease or stroke
10
Years
Life expectancy in T2DM
CVD – main cause of death
(> 70% T2DM patients)

11. *Nissen SE et al. Effects of rosiglitazone on the risk of MI and death from cardiovascular causes. NEJM. 2007

12. ASCVD, or high/ very high CV risk
(TOD or multiple risk factors)
ASCVD, or high/ very high CV risk
(TOD or multiple risk factors)
A. T2DM – Drug naïve patients B. T2DM – on METFORMIN
SGLT2i or GLP-1 RA Mono Add SGLT2i or GLP-1 RAMetformin Mono Continue Metformin Mono
If HbA1c above target
Add Metformin
Consider adding the
other class (GLP-1
RA or SGLT2i) with
proven CV benefits
• DPP4i if not on GLP-
1 RA
• Basal insulin
• TZD (not in HF
patient)
• SU
If HbA1c above target
Consider adding the
other class (GLP-1
RA or SGLT2i) with
proven CV benefits
• DPP4i if not on GLP-
1 RA
• Basal insulin
• TZD (not in HF
patient)
• SU
If HbA1c above target
European Heart Journal (2019)00,1-69 doi;10,1093/curheartj/ehz486
If HbA1c above target If HbA1c above target
2019
GUIDELINES

13. Sodium Glucose linked Transporter – SGLT
• Primarily expressed in
kidney
• Responsible for majority
of renal glucose
reabsorption (90%)
• Responsible for small
portion of renal glucose
reabsorption (10%)
• Prominent role in intestinal
glucose absorption

14. 2011 – Dapagliflozin
2013 – Canagliflozin
2014 – Empagliflozin
2017 – Ertugliflozin
[Note: Sotagliflozin (dual SGLT1/SGLT2 inhibitor).
If approved, it would be the first oral treatment
in combination with insulin to treat T1DM]
• SGLT-2 inhibitors: Newest class of
diabetes medications – lower blood sugar
by getting rid of sugar through the urine

15. SGLT2 inhibitors
Glycosuria
Net calorie loss of ≈
200 – 300 Kcal/day
Weight loss
Glucose acts as
Osmotic Diuretic
Dehydration
BP reduction
http://diabetes.diabetesjournals.org/content/61/9/2199.full
http://www.medscape.com/viewarticle/760248http://www.diabetesincontrol.com/art
icles/91-/14495-sglt2-inhibitors-a-new
http://spectrum.diabetesjournals.org/content/22/2/92.full.pdf
http://www.micromedexsolutions.comhttp://www.diabetes.co.uk/diabetes-
medication/sglt2-inhibitors.htm
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.ht
http://diabetes.diabetesjournals.org/content/61/9/2199.full
http://www.medscape.com/viewarticle/760248http://www.diabetesincontrol.com/articles/91-
/14495-sglt2-inhibitors-a-new http://spectrum.diabetesjournals.org/content/22/2/92.full.pdf
http://www.micromedexsolutions.comhttp://www.diabetes.co.uk/diabetes-medication/sglt2-
inhibitors.htmhttp://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.ht

16. Complements
actions of other
Anti-diabetic
agentsReduces
HbA1c
Reversal of
Glucotoxicity
No
Hypoglycemia
Reduces BP
Promotes
Weight
Loss
Corrects a novel
pathophysiological
defect
Improves
Glycemic Control
and CVRFs

17. Safety and Efficacy of SGLT2 inhibitors
• Genital/ Urinary Tract Infection
• Intravascular Volume depletion/ Hypotension
• Electrolyte Imbalance (Na+, K+, Ca++)
• Nocturia
• Reduced effectiveness with decreased renal function
• Minimal risk of Hypoglycemia but consider tapering Insulin or SU if
adding an SGLT2i

18. EMPA-REG is a large CV outcome trial on Empagliflozin
N Engl J Med 2015;373:2117-2128.
 3P-MACE, 3-point major adverse cardiovascular events. CV, cardiovascular; T2D, type 2 diabetes
Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720; Zinman B. EASD 2015; Oral
presentation
Empagliflozin in addition to standard of care reduced CV risk and
improved overall survival in adults with T2D at high CV risk
↓ 3P-MACE
14%
↓ CV death
38%
↓ All-cause
mortality
32% 35%
↓ Heart failure
hospitalisations
39%
↓ Incident or
worsening
nephropathy
EMPAGLIFLOZIN is the first type 2 diabetes pill that goes
beyond lowering A1C to reduce the risk of CV death for
adults who have T2DM and heart disease.(Mosley JF, et al. P T. 2015;40:451-462)
42
countries
590
sites

19. CANVAS
Trial1
1. Bruce Neal et al. Canaglflozin and CV and renal events in T2 diabetes – The CANVAS Trial. NEJM 2017; 377:644-657
2. Perkovic V, et al. "Canagliflozin and renal outcomes in diabetic nephropathy". The New England Journal of Medicine. 2019. 380(24):2295-2306.
3. AHA news 2018
Canagliflozin reduces risk of CV events, renal decline, HF
hospitalizations but increases risk of amputations in T2DM with high
CV risk.
CREDENCE2 In patients with type 2 diabetes and kidney disease, canagliflozin
reduces the risk of kidney failure and CV events.
EMPA-
HEART
Study3
Treating patients with type 2 diabetes and a history of stable CAD with
empagliflozin (SGLT2i), significantly reduces left ventricular mass.

20. DECLARE-
TIMI 58
Trial1
1. Remo HM Furtado, et al. Dapagliflozin and cardiovascular outcomes in patients with T2DM and previous MI. Subanalysis from DECLARE-TIMI 58 Trial.
Circulation May 2019; 139:2516-2527.
2. John JV McMurray, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. DAPA-HF. NEJM Nov 2019; 381:1995-2008.
Dapagliflozin appears to robustly reduce the risk of MACE and CV
death/ hospitalization for heart failure in patients with T2DM and
previous MI.
DAPA-HF
Trial2
Among patients with HFrEF, the risk of worsening heart failure or death
from cardiovascular causes was lower among those who received
dapagliflozin than among those who received placebo, regardless of
the presence or absence of diabetes.

21.  Based on FDA guidelines, all new diabetes medicines need to be tested
for CV safety.
 Metformin is the best first-line most agreed time tested OAD, but new
guidelines (ESC2019) recommend SGLT2i or GLP-RA as 1st line OAD in
patients with ASCVD, or high/ very high CV risk (TOD or multiple risk
factors) in drug naïve patients and as add-on to metformin.
 CV disease is a major problem in diabetics and > 70% of mortality in
T2DM is due to CVD.
 In patients with T2DM & high CV risk, SGLT2i given in addition to
standard of care, ↓ risk of CV events, heart failure hospitalization or CV
death, with a consistent benefit observed in both those with and without
heart failure at baseline.

22. THANKS FOR YOUR ATTENTION!
HAVE A HEALTHY AND HAPPY LIFE
Prof Dr Taj Jamshaid
Email: drjamshaid1@gmail.com