31-3-2022 Empa

The Landmark Trial SGLT2i
EMPA-REG-OUTCOME
Dr Muhammad Tawheed
General Practitioner
For internal use only. Strictly confidential. Do not copy or distribute.

Speaker Disclosure
· I am contracted by Boehringer Ingelheim to conduct this session.
· I have no financial interest in Boehringer Ingelheim.

Medical history
Case
Scenario
• Mr Ali is 48-year-old man , Engineer
• HTN for 4 years not compliant e TTT Program
• Former smoker for 1 year
• Recently over last 3 m C/O easily fatigue , increased
thirsty and intermittent SOB

O/E & +ve Cardiometabolic parameters
Ali
• HbA1c: 8.6% & FBS = 224mg
• CBC : no polycythaemia
• BP: 164/101 mmHg
• Fasting LDL: 155 mg/dl
• BMI: 31.8 kg/m2
• eGFR: 81 ml/min/1.73 m2
• Album/Cr.
Ratio :78mg/L.
• ECG >> LVH
• Current Medications : Atenolol 50mg od not
regularly

What is the next?

For internal use only. Strictly confidential. Do not copy or distribute. 6
Global impact of an elevated hypertension
In 2015, elevated systolic BP was the leading

preventable cause of premature death globally
~10 million deaths are reported due to elevated blood pressure
disability adjusted life-years

>200 million
4.9 million ischemic heart disease
hemorrhagic stroke
2 million
ischemic stroke
1.5 million
Williams B, et al. Eur Heart J. 2018;39:3021–3104.

Global prevalence of T2DM , IDF Atlas 2019

Diabetes is an epidemic of our global
Its burden on our societies is growing everywhere around the world
 Approximately 9% of adults worldwide

are estimated to have diabetes. 1
 425 million (2017)  629 million (2045)
 Increase by 48% from 2017 to 2045
 Every 8 seconds,
one person dies from diabetes. 1
 4 million deaths per year (2017)
 Health expenditure on diabetes is

expected to grow by 7% from 2017 to
2045%1
 $727 billion (2018)  $776 billion (2045)
1. International Diabetes Federation. IDF Diabetes Atlas, 7th edition, 2017.
2. Ryden L, Grant PJ, Anker SD, et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD - summary. Diabetes & vascular disease research 2014;11(3):133-73.
9
T2D is a global pandemic and a
major risk factor for complications
Associated complications of T2D2
Macrovascular Microvascular
• CV disease, e.g. stroke, • Diabetic nephropathy
MI, PVD. • Diabetic retinopathy
• Diabetic neuropathy
Risk of developing CV disease is

2015 2040 2 to 4 times higher
Global diabetes in people with diabetes
incidence1 compared with people without DM3
CV, cardiovascular; T2D, type 2 diabetes
1. International Diabetes Federation. IDF Diabetes Atlas. 7th ed. 2015. www.idf.org/diabetesatlas; 2. World Health Organization. Diabetes Program – About
diabetes. www.who.int/diabetes/action_online/basics/en/index3.html; 3. World Heart Federation. Diabetes. 2016. www.world-heart-federation.org/
cardiovascular-health/cardiovascular-disease-risk-factors/diabetes/ (all websites accessed May 2016)

DM in HTN patients

Complications related to uncontrolled
type 2 diabetes especially in HTN:

End Organ Damage expected in HTN patients e
DM

What is diabetes mellitus?
• A chronic health condition, which occurs when the
pancreas
is no longer able to make insulin (Type 1).
• Or the body cannot make enough or good use

of the insulin it produces (Type 2).

Risk Factors for T2DM

Pathophysiological mechanisms contribute to
Decreased
incretin effect
Impaired insulin Increased
secretion lipolysis
Increased Increased
glucagon Hyperglycaemia glucose
secretion reabsorption
Increased hepatic
glucose
production
Decreased
glucose uptake
Neurotransmitter
dysfunction
Adapted from DeFronzo RA. Diabetes 2009;58:773–95

Cardiovascular
risk in patients
with T2D

CV disease is the #1 cause of death
in patients with T2D1
Cause of death in patients with T2D2
Other
23%
CV disease 52%
14%
Cancer
11 Kidney disease
%
Mean follow-up was 9.4 years for men and 9.8 years for women; N=709
1. International Diabetes Federation. IDF Diabetes Atlas. 7th edn. 2015. www.idf.org/diabetesatlas (accessed Mar 2016);
2. Morrish NJ et al. Diabetologia 2001;44 Suppl 2:S14

Coronary artery disease is a prevalent comorbidity of
CV disease
Approximately two-thirds of patients with CV disease…
…have Coronary Artery Disease

Analysis of 60 studies with 4,549,481 patients with T2D
CV, cardiovascular disease; T2D, type 2 diabetes
Einarson TR et al. Cardiovas Diabetol 2018;17:83

CV disease occurs early and is the leading
cause of mortality in patients with T2D
CV disease can occur

10−15 years earlier Despite advances in standard
in patients with diabetes compared of care, most patients with T2D
with those without diabetes 1 die from CV disease2

1. Booth GL et al. Lancet 2006;368:29; 2. Morrish NJ et al. Diabetologia 2001;44(Suppl 2):S14
20
CV disease in patients with T2D is responsible for
more deaths than cancer* in the general population
• 2.5 times more deaths than cancer*
Deaths due to CV disease

in patients with T2D
Deaths due to cancer*

24-year follow-up of 7461 patients with T2D and 37,271 controls from the Skaraborg Diabetes Register
*Solid tumour cancers only
CV, cardiovascular disease; T2D, type 2 diabetes
Andersson T et al. Diabetes Res Clin Prac 2018;138:81
21
T2D is a CV risk factor that determines the need for
cardioprotection
Patients with diabetes and at least one

other CV risk factor or target organ
damage, should be considered at very
high CV risk…
2016 European Guidelines on cardiovascular
disease prevention in clinical practice
– European Society of Cardiology

Piepoli MF et al. Eur Heart J 2016;37:2315
22
What can
pharmacotherapy do to
help DM patients?
23
The ‘Ominous Octet’ which contribute to hyperglycaemia
How we combat them?
DPP4-i
GLP-1 RAs
DPP4-i Decreased
GLP-1 RAs incretin effect
TZDs
SUs, Glinides Impaired insulin Increased
Metformin
secretion lipolysis
DPP4-i Increased Increased

GLP-1 RAs glucagon Hyperglycemia
Normoglycemia glucose
secretion reabsorption
SGLT2-i
Increased
hepatic
Metformin glucose
production Decreased
glucose uptake TZDs
Metformin
Neurotransmitter
GLP-1 RAs dysfunction
Adapted from DeFronzo RA. Diabetes 2009;58:773–95

Normal Glomerulus

Mechanism of Action of SGLT2Is

Recent studies about cardioprotective effects of some
anti-DM phramacotherpaies

The CV effects of Empagliflozin were studied
in a CV outcomes trial published in the NEJM
EMPA-REG OUTCOME® was a randomised, double-blind, placebo-controlled CV outcomes trial1
Years
7020 Patients 42 Countries 3.1 observation time
Results were achieved on top of standard of care1

Patients’ CV risk factors, including glucose, were actively managed in placebo and Jardiance ® treatment arms
95%* 81%* 89%* 98%*

Antihypertensive Lipid-lowering Anticoagulants1 Glucose-lowering
therapy1 therapy1 medications2
*Patients receiving therapy at baseline

CV, cardiovascular
1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Zinman B et al. Cardiovasc Diabetol 2014;13:102

Patients’ CV risk factors, including glucose,
were actively managed in placebo and
Jardiance® treatment arms
Patients receiving therapy at baseline
95% 81% 89% 98%

Anti- Lipid- Anticoagulants/ Glucose-
hypertensives1 lowering1 Antiplatelets1 lowering2
ACEi/ARBs 81% Statins 77% ASA 83% Metformin 74%

Beta-blockers 65% Fibrates 9% Clopidogrel 11% Insulin 48%
Diuretics 43% Ezetimibe 4% Vitamin K 6% Sulphonylurea 43%
antagonists
Ca-channel blockers 33% Niacin 2% DPP-4 inhibitors 11%
Other 8% TZDs 4%
GLP-1 RA 3%
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASA, acetylsalicylic acid; CV, cardiovascular;
DPP-4, dipeptidyl peptidase‑4; GLP-1 RA, glucagon-like peptide-1 receptor agonist; TZD, thiazolidinedione
1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Zinman B et al. Cardiovasc Diabetol 2014;13:102

Patients received Jardiance® or placebo
on top of standard of care
for CV and T2D management
Placebo + SOC (n=2333)

Randomised
Screening
and treated Jardiance® 10 mg + SOC (n=2345)
(N=11,531)
(n=7020) Pooled*
Jardiance® 25 mg + SOC (n=2342)
• Adults with T2D • Glucose-lowering therapy was to remain

• BMI ≤45 kg/m2 unchanged for the first 12 weeks
• HbA1c ≥7% and ≤10%†
•
• The trial was to continue until at least
Established CV
disease‡ 691 patients experienced an adjudicated
primary outcome event
*Data from both doses of Jardiance® were pooled for statistical analysis versus placebo; †Stable background therapy for ≥12 weeks before randomisation: for
insulin, dose was to remain unchanged by >10% from the dose received 12 weeks before randomisation); for drug-naïve: HbA1c ≥7% and ≤9%;
‡
Including coronary artery disease, peripheral artery disease, or a history of MI or stroke
BMI, body mass index; CV, cardiovascular; HbA1c, glycated haemoglobin; MI, myocardial infarction; SOC, standard of care; T2D, type 2 diabetes
Zinman B et al. N Engl J Med 2015;373:2117

In addition to T2D,
all patients had established CV disease
99%
Any CV
disease*
76% 47% 25% 23% 21% 10%

Coronary History Coronary History of PAD Heart
artery of MI artery stroke† failure‡
disease bypass graft
Data are from patients treated with ≥1 dose of study drug

*Established CV disease including coronary artery disease, peripheral artery disease, or a history of MI or stroke; †Placebo, n=2332;
‡
Based on narrow standardised MedDRA query ‘cardiac failure’
CV, cardiovascular; MedDRA, Medical Dictionary for Regulatory Activities; MI, myocardial infarction; T2D, type 2 diabetes

Empagliflozin reduced CV death by 38%
on top of standard of care*
in patients with T2D and established CV disease†
Placebo + SOC
HR 0.62 (n=2333)
Patients with event (%) (95% CI 0.49, 0.77)
p<0.001‡
Jardiance® + SOC
38%
(n=4687) RRR in
CV death
Time (months)
Early and sustained reduction in CV death
Pooled data from 10 mg and 25 mg doses of Jardiance ®. The primary endpoint of the EMPA-REG OUTCOME ® study was a composite of CV death, non-fatal MI
and non-fatal stroke (i.e. 3-point MACE). *SOC included CV medications (e.g. antihypertensive agents, lipid-lowering therapies and anticoagulants) and
glucose‑lowering agents given at the discretion of the physician; †Including coronary artery disease, peripheral artery disease, or a history of MI or stroke;
‡
Nominal p‑value. CV, cardiovascular; HR, hazard ratio; MACE, major adverse CV events; MI, myocardial infarction; RRR, relative risk reduction;
SOC, standard of care; T2D, type 2 diabetes. Zinman B et al. N Engl J Med 2015;373:2117

Empagliflozin reduced the risk of CV death inT2D patients
with CVD, most commonly CAD1,2
The EMPA-REG OUTCOME® Trial represents a clinically relevant T2D population

where1:
95% of patients had hypertension1
82% of patients were dyslipidaemic 1
76% of patients had CAD—the most common type of CVD among
patients studied in the trial 1
Empagliflozin demonstrated a 38% relative risk reduction in CV death in patients with

type 2 diabetes and established CV disease in the
EMPA-REG OUTCOME® Trial1,3
References: 1. Zinman B, Wanner C, Lachin J, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. 2. Zinman B, Inzucchi SE, Lachin JM, et al.
Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™). Cardiovasc Diabetol. 2014;13(102). doi:10.1186/1475-2840-13-
102. 3. JARDIANCE [summary of product characteristics]. Ingelheim am Rhein, Germany: Boehringer Ingelheim International GmbH; May 2018.

Jardiance® reduced hospitalisation for heart failure by
35% on top of standard of care*
in patients with T2D and established CV disease †
Placebo + SOC
HR 0.65
Patients with event (%)
(n=2333)
(95% CI 0.50, 0.85)
p=0.002‡
Jardiance® + SOC
35%
RRR in
(n=4687)
HHF
Time (months)
Early and sustained reduction in HHF
Jardiance® is not indicated for heart failure

Pooled data from 10 mg and 25 mg doses of Jardiance ® used in the EMPA-REG OUTCOME ® trial. *SOC included CV medications (e.g. antihypertensive agents,
lipid-lowering therapies and anticoagulants) and glucose-lowering agents given at the discretion of the physician; †Including coronary artery disease, peripheral
artery disease, or a history of MI or stroke; ‡Nominal p-value. CV, cardiovascular; HHF, hospitalisation for heart failure; HR, hazard ratio; MI, myocardial infarction;
RRR, relative risk reduction; SOC, standard of care; T2D, type 2 diabetes. Zinman B et al. N Engl J Med 2015;373:2117

Empagliflozin significantly reduced the relative risk of
incident or worsening nephropathy* † by 39% on top of
standard of care‡
30
Placebo Empagliflozin
25 HR 0.61
Patients with event (%)

Worsening (95% CI 0.53, 0.70)
p<0.001
nephropathy 20
15
Early separation of curves
for kidney events
10
↓39% RRR 0
0 6 12 18 24 30 36 42 48
Months
Empagliflozin is not indicated for the treatment of chronic kidney disease
*Exploratory endpoint; †Defined as progression to macroalbuminuria, doubling of serum creatinine (accompanied by eGFR [MDRD] ≤45 ml/min/1.73 m 2), initiation
of renal replacement therapy or death from kidney disease; ‡Standard of care included CV medications and glucose-lowering agents given at the discretion of
physicians; Kaplan–Meier estimate
eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease
Wanner C et al. N Engl J Med 2016;375:323

What can clinicians do to help their DM
patients?
American Diabetes association 2020

answered

Choice of second-line
therapy is now based
on the presence of
established ASCVD or
CKD, followed by
Glycaemic efficacy,
Safety, Need for
Weight loss and Cost
ADA, American Diabetes Association; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular; CVD,
cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; GLP-
1 RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycated haemoglobin; HF, heart failure; SGLT2i, sodium-glucose co-transporter-2
inhibitor; SU, sulphonylurea
American Diabetes Association. Diabetes Care 2019;42:S1
Glucose-lowering medications in type 2 diabetes:
Overall approach To avoid clinical
inertia reassess
and modify
FIRST-LINE THERAPY IS METFORMIN AND COMPREHENSIVE LIFESTYLE (INCLUDING WEIGHT MANAGEMENT AND PHYSICAL ACTIVITY) treatment
IF HbA1c ABOVE TARGET PROCEED AS BELOW regularly
(3–6 months)
Without established
NO ASCVD or CKD Without established ASCVD or CKD
Established ASCVD or CKD
Compelling need to minimise hypoglycaemia
Without established ASCVDneed
or CKD
Without established ASCVD
ASCVD predominates Compelling to minimise weight gain or or CKD
HF OR CKD predominates promote weight loss
ASCVD predominates PREFERABLY DPP-4i GLP-1RA SGLT-2i
Compelling need to minimise
†
hypoglycaemia TZD Compelling need to minimise weight gain or
Cost is a major issue ††‡‡
EITHER/
SGLT-2i
HF OR
SGLT-2i with evidence of reducing HF and/or CKD
CKD predominates promote weight loss Cost is a major issue††‡‡
OR DPP-4i GLP-1RA SGLT-2i† TZD GLP-1RA EITHER/
GLP-1RA with proven CVD progression in CVOT if eGFR is adequate ‡
If HbA PREFERABLY
with proven CVD benefit*, 1c above If HbA1c above If HbA1c above If with
HbAgood
1c above
efficacy OREITHER/ SGLT-2i2
EITHER/ OR GLP-1RA
benefit* if eGFR SGLT-2i withtarget evidence of reducing target
HFIf HbA above target target
If HbA1cfor weight loss 8 SU|| TZD‡‡
adequate SGLT-2i If HbA1c above If HbA 1c above above with good efficacy OR SGLT-2i†
OR If SGLT-2i not tolerated or contraindicated or if
†
and/or CKD progressiontarget in CVOT if eGFR target
1c
GLP-1RA with proven

eGFRCVD
less than adequate † add GLP-1RA with target target for weight loss** SU|| TZD‡‡
proven CV benefit* adequate ‡
with proven CVD benefit*,
benefit* if eGFR OR
GLP-1RA SGLT-2i† If HbA1c Ifabove target
HbA1c above target If HbA1c above target
If HbA1c above target adequate† If HbA1c aboveIf target
SGLT-2i not SGLT-2itolerated† or contraindicated or if† †
SGLT-2i GLP-1RA SGLT-2i†
SGLT-2i† SGLT-2i
eGFR less than adequate† add GLP-1RA with OR
OR OR OR
GLP-1RA If HbA1c above target
proven CV benefit* GLP-1RA
OR OR OR OR DPP-4i
DPP-4i DPP-4i
DPP-4i SGLT-2i† with good efficacy for TZD‡‡ SU||
If further intensification is required or patient is • Avoid TZD in the setting of HF SGLT-2i2 with good efficacy
weight loss** for
now unable to tolerate GLP-1RA and/or SGLT-2i, OR OR
Choose agents demonstrating CV safety:
TZD TZD OR OR weight loss8
choose agents demonstrating CV safety: TZD TZD TZD GLP-1RA TZD‡‡ SU||
If HbA1c above target • Consider adding the other class withIf HbA1c above target
• Consider adding the other class proven CVD benefit* TZD GLP-1RA If HbA1c above target If HbA1c above target
(GLP-1RA and/or SGLT-2i) with proven • DPP-4i (not saxagliptin) in the setting of HF
CVD benefit (if not on GLP-1RA) If HbA1c above target
If HbA1c above target If triple therapy required or SGLT-2i and/or
• DPP-4i if not on GLP-1RA • Basal insulin§ • Insulin therapy basal insulin with
• If further intensification
Basal insulin § is required or patient
• is
SU|| • Avoid TZD in the setting of HF GLP-1RA not tolerated or contraindicated use
If HbA1clowest
above target
acquisition cost
• nowTZD If HbA1c above target regimen with
unable
¶
to tolerate GLP-1RA and/or SGLT-2i, Continue with addition of other agents as outlined above If triple therapy required lowestor SGLT-2i
risk and/or GLP- OR
of weight gain
• SU|| • Consider DPP-4i OR SGLT-2i with
choose agents demonstrating CV safety: Choose agents demonstrating CV safety: PREFERABLY
1RA not tolerated or contraindicated use regimen lowest acquisition cost ‡‡
• Consider adding the other class • Consider adding the Continue
other classwith
withaddition
proven of other
If HbA agents
target as outlined above
DPP-4i (if not on GLP-1RA)
with • Insulin therapy basal insulin with
1c above based on weight neutrality
(GLP-1RA and/or SGLT-2i) with proven CVD CVD benefit* lowest risk of weight gain lowest acquisition cost
benefit • DPP-4i (not saxagliptin) in the setting of HF (if OR
Consider the addition of SU || OR basal insulin: PREFERABLY
• not on GLP-1RA) •
DPP-4i if not on GLP-1RA If HbA
Choose later generation SU with above
1c lower target
risk of hypoglycaemia DPP-4i (if not on GLP-1RA) •
If DPP-4i not tolerated or contraindicated Consider DPP-4i OR SGLT-2i with
or
• Basal insulin§ • Basal insulin§ • Consider basal insulin with lower risk of hypoglycaemia # patient already on GLP-1RA cautious addition
lowest acquisition cost‡‡
based
of: on weight neutrality
• TZD¶ • SU|| ● SU|| ● TZD¶ ● Basal insulin
• *Proven
SU|| CVD benefit means it has label indication of reducing CVD events. For GLP-1RA strongestConsider theforaddition
evidence of SU|| OR basal insulin:
liraglutide>semaglutide>exenatide extended release. For SGLT-2i evidence modestly stronger for empagliflozin>canagliflozin; †Be aware that SGLT-2i vary by
• ‡Both
region and individual agent with regard to indicated level of eGFR for initiation and continued use; Choose later generation
empagliflozin SU
and canagliflozin with
have lower
shown riskinof
reduction HFhypoglycaemia
and reduction in CKD progression in CVOTs; §Degludec or U100 glargine have demonstrated CVD safety;
¶
•
Low dose may be better tolerated though less well studied for CVD effects; ||Choose later generationConsider basal
SU with lower insulin
risk of with lower
hypoglycaemia; #
risk/ of
Degludec hypoglycaemia
glargine #
U300<glargine U100 If DPP-4i
/ detemir<NPH not tolerated or contraindicated or
insulin; **Semaglutide>liraglutide>dulaglutide>exenatide>lixisenatide; ††
If no
specific comorbidities (i.e. no established CVD, low risk of hypoglycaemia and lower priority to avoid weight gain or no weight-related comorbidities); Consider country- and region-specific cost patient
‡‡
already
of drugs. In on GLP-1RA
some countries, cautious
TZDs relatively addition
more expensive andof:
DPP-4i
relatively cheaper
For internal use only. Strictly confidential. Do not copy or distribute. ● SU6 ● TZD5 ● Basal insulin
Overview of major recommendations,
including results from the EMPA-REG OUTCOME® trial
Guideline Latest update Recommendations on empagliflozin use in adult patients with T2D and eCVD
Diabetes
2020 To reduce the risk of major CV events in adults with T2D with clinical CVD in whom glycaemic targets are not met1
To be used preferentially (along with other agents with proven CV benefit) in patients with T2D where ASCVD, HF or CKD
2021
predominates2
To be used preferentially (along with other agents with proven CV benefit) in patients with T2D where ASCVD, HF or CKD
2020
predominates3
2020 To reduce CV death in patients with T2D and established CVD4
Cardiovascular disease
2021 To be considered early in the course of disease to reduce CV and total mortality in patients with T2D and CVD5
2020 To be considered in patients with T2D and established ASCVD to improve CV outcomes6

Overview of major recommendations,
including results from the EMPA-REG OUTCOME® trial
Guideline Latest update Recommendations on empagliflozin use in adult patients with T2D and heart failure or chronic kidney disease
Heart failure
2020 To prevent or delay the onset of HF and prolong life in patients with T2D1
2020 To prevent HF-related outcomes in patients with T2D and established CVD2
Chronic kidney disease
2019 To be used preferentially in patients with T2D and CKD for cardio- and nephroprotection3

Guideline summary: recommendations on
Empagliflozin use in patients with T2D and CVD
Diabetes
ADA and Diabetes Canada recommend the use of agents that have been proven to reduce
the risk of CV events for patients with T2D and established CVD 1,2 (such as Empagliflozin)
CV disease
ESC recommend the use of an SGLT2 inhibitor early in the course of management of
patients with T2D and CVD to reduce CV and total mortality 3
Heart failure
ESC suggest Empagliflozin be considered for patients with T2D and established CVD for
the prevention of heart failure 4,5
NOTE: this summary is for CV disease-related guidance only. Wording has been paraphrased and/or abridged. Please refer to the original
documents for full details
ADA, American Diabetes Association; CCS, Canadian Cardiovascular Society; CV, cardiovascular; CVD, cardiovascular disease; ESC,
European Society of Cardiology; SGLT2, sodium glucose transporter 2; T2D, type 2 diabetes
1. American Diabetes Association. Diabetes Care 2021;41:S1; 2. Diabetes Canada. Can J Diabetes 2021;42:S162;
3. Piepoli MF et al. Eur Heart J 2016;37:2315; 4. Ezekowitz JA et al. Can J Cardiol 2017;33:1342; 5. Ponikowski P et al. Eur Heart J 42
2016;37:2129
Safety and
tolerability

Jardiance® demonstrated safety and tolerability
Common AEs in phase III trials
• Overall incidence of AEs

10 9.3
was similar to placebo
Adverse events (%)
8 7.6 7.6
• Common AEs included
6 – hypoglycaemia,
4.1 3.7
4 3.4 3.2 – genital infections,
2 0.9 1.0 – urinary tract infections,
0 – increased urination and
– pruritus
• In patients taking SGLT2 inhibitors,
rare cases of diabetic ketoacidosis
Placebo Jardiance® 10 mg Jardiance® 25 mg
have been reported
SGLT2, sodium-glucose co-transporter-2; T2D, type 2 diabetes
For a complete list of contraindications, warnings and precautions, please refer to the summary of product characteristics
Boehringer Ingelheim Jardiance® (empagliflozin) summary of product characteristics. June 2018

Incidence of hypoglycaemia with Jardiance®
was similar to placebo when used as
monotherapy or added to metformin
32
28 27.1
Insulin and Sulphonylureas are known to
Patients with confirmed
24 cause hypoglycaemia2
hypoglycaemia* (%)
20.6 19.5
20 • Incidence of hypoglycaemic events*
16.1 was increased vs placebo
16
11.5 when Jardiance® was added
12
8.4 to a sulphonylurea or insulin
8
• When Jardiance® is used in
4 1.8 1.4 combination with a sulphonylurea or
0.5
0 with insulin,
Add-on to MET1 Add-on to MET Add-on to basal a lower dose of the sulphonylurea or
+ SU2 insulin 2
insulin may be considered to
Placebo Jardiance® 10 mg Jardiance® 25 mg reduce the risk of hypoglycaemia
*Confirmed events; plasma glucose ≤70 mg/dl and/or requiring assistance. MET, metformin; SU, sulphonylurea. 1. Häring H-U et al. Diabetes Care 2014;37:1650;
2. Boehringer Ingelheim Jardiance® (empagliflozin) summary of product characteristics. June 18

The safety profile of Jardiance® was confirmed
in patients with T2D and established CV disease*
in EMPA-REG OUTCOME®
Overall incidence of AEs, including diabetic ketoacidosis and bone fracture, was similar to
placebo ®
Placebo + SOC
®
Jardiance 10 mg + SOC Jardiance 25 mg + SOC
n (%) (n=2333) (n=2345) (n=2342)
Confirmed hypoglycaemic AEs 650 (27.9) 656 (28.0) 647 (27.6)
Urinary tract infection 423 (18.1) 426 (18.2) 416 (17.8)
Complicated urinary tract infection 41 (1.8) 34 (1.4) 48 (2.0)
Genital infection 42 (1.8) 153 (6.5) 148 (6.3)
Decreased renal function 155 (6.6) 121 (5.2) 125 (5.3)
(including acute kidney injury)
Volume depletion 115 (4.9) 115 (4.9) 124 (5.3)
Bone fractures 91 (3.9) 92 (3.9) 87 (3.7)
Venous thrombotic events 20 (0.9) 9 (0.4) 21 (0.9)
Diabetic ketoacidosis 1 (<0.1) 3 (0.1) 1 (<0.1)
Treated set (patients randomised and treated with ≥1 dose of study drug); *Including coronary artery disease, peripheral artery disease, or a history of MI or
stroke. CV, cardiovascular; MI, myocardial infarction; SOC, standard of care; T2D, type 2 diabetes

Lower limb amputations in SGLT2 inhibitor
CVOTs
Event rate per
1000 patient-years
Comparator Placebo HR (95% CI)
EMPA-REG OUTCOME®1 6.5 6.5 1.00 (0.70,1.44)
DECLARE-TIMI 58*2 - - 1.09 (0.84, 1.40)
CANVAS Program3 6.30 3.37 1.97 (1.41, 2.75)
0.25 1 4
Favours study drug Favours placebo

Direct comparison of trials should be interpreted with caution due to differences in study design, populations
and methodology. *Represents all amputation events, including LLA events
1. Inzucchi SE et al. Diabetes Care 2018;41:e4; 2. Wiviott SD, et al. N Engl J Med 2018;
DOI: 10.1056/NEJMoa1812389; 3. Neal B et al. N Engl J Med 2017;377:644
47
Bone fractures in SGLT2 inhibitor CVOTs
Event rate per

1000 patient-years
EMPA-REG OUTCOME®1 0.15 0.16 0.94 (0.73, 1.21)
DECLARE-TIMI 582 - - 1.04 (0.91, 1.18)
CANVAS Program3,4 15.4 11.9 1.26 (1.04, 1.52)
0.25 1 4

Direct comparison of trials should be interpreted with caution due to differences in study design, populations and
methodology
1. Data on file. For internal use only; 2. Wiviott SD, et al. N Engl J Med 2018; DOI: 10.1056/NEJMoa1812389;
3. Neal B et al. N Engl J Med 2017;377:644; 4. Presented at the American Diabetes Association 77th
Scientific Sessions, June 12 2017, San Diego, CA, USA
48
Volume depletion across SGLT2 inhibitor CVOTs
Event rate per

1000 patient-years
EMPA-REG OUTCOME®1 0.2 0.2 1.00 (0.80, 1.25)
DECLARE-TIMI 582 - - 1.00 (0.83, 1.21)
CANVAS Trial*3 20.6 18.5 1.44 (1.09, 1.90)
0.25 1 4

Direct comparison of trials should be interpreted with caution due to differences in study design, populations and methodology
*Data from the CANVAS trial only
1. Data on file. For internal use only; 2. Wiviott SD, et al. N Engl J Med 2018; DOI: 10.1056/NEJMoa1812389;
3. Neal B et al. N Engl J Med 2017;377:644; 4. Presented at the American Diabetes Association 77th
Scientific Sessions, June 12 2017, San Diego, CA, USA 49
Jardiance® provides convenient
once-daily oral dosing for patients with T2D
In patients who tolerate

Starting dose Increase to Jardiance® 10 mg and need
10 mg once daily 25 mg once daily* additional glycaemic control*
Jardiance® can be taken with or without food, at any time of the day
Tablets are not actual size. *The maximum daily dose is 25 mg

; SGLT2, sodium-glucose co-transporter-2; T2D, type 2 diabetes
Boehringer Ingelheim . Jardiance® (empagliflozin) summary of product characteristics. 2017

Summary

Jardiance® is approved to provide additional
cardioprotection* for your patients with T2D
and established CV disease†
Patients with T2D and established CV Jardiance® also provides

disease are at high risk of CV death1 established HbA1c efficacy3
• High risk remains despite SOC therapy • With added benefits of reductions in
body weight and blood pressure‡
Jardiance® reduced CV death by 38%, Jardiance® demonstrated safety and

on top of CV and glucose-lowering SOC2 tolerability in a range of patients with T2D3
• Jardiance® also reduced • With convenient, once-daily oral dosing
hospitalisation for heart failure by 35%‡
For a complete list of contraindications, warnings and precautions, please refer to the summary of product characteristics
*Jardiance® is the only T2D agent approved to reduce the risk of CV death; †Including coronary artery disease, peripheral artery disease, or a history of MI or stroke; ‡Jardiance® is not indicated for heart failure, weight
loss or blood pressure reduction. CV, cardiovascular; HbA1c, glycated haemoglobin; MI, myocardial infarction; SOC, standard of care; T2D, type 2 diabetes. 1. Ryden L et al. Eur Heart J 2013;39:3035; 2. Zinman B et
al. N Engl J Med 2015;373:2117; 3. Boehringer Ingelheim. Jardiance® (empagliflozin) summary of product characteristics. 2017

Other expected Extra-Glycemic benefits of
SGLT2is

Hints before starting Empagliflozin
• can be initiated in patients with (GFR) <45 mL/min with monitoring and
should be discontinued at GFR persistently below < 30 mL/min.
• Encourage extra fluid intake of 300ml to avoid dehydration.
• Encourage urogenital hygiene especially in females.
• CI in recurrent UTI.
• CI in Hx of ketoacidosis and if needed, patient should be educated and
monitored well.
• Use with caution in polycythaemia to avoid hemoconcentration.
• Still Not approved in T1DM.

Clinical case

Medical history
Case
Scenario
• Mr Ali is 48-year-old man , Engineer
• HTN for 4 years not compliant e TTT Program
• Former smoker for 1 year
• Recently over last 3 m C/O easily fatigue , increased
thirsty and intermittent SOB

O/E & and +ve Cardiometabolic
Ali parameters
• HbA1c: 8.6% & FBS = 224mg

• CBC : no polycythaemia
• BP: 164/101 mmHg
• Fasting LDL: 155 mg/dl
• BMI: 31.8 kg/m2
• eGFR: 81 ml/min/1.73 m2
• Album/Cr.
Ratio :78mg/L.
• ECG >> LVH
• Current Medications : Atenolol 50mg od not
regularly

ECG >>> LVH

What are the Pharmacological options to
Ali improve Ali’s glycaemic control?
A. Add a SU Glimepiride?
B. Add Metformin only? VOTE NOW

C. Add a TZD?
D. Add Metformin+Empagliflozin as SPC ?
E. Add Basal Insulin?
For internal use59

only. Strictly confidential. Do not copy or distribute.
Glucose-lowering medications in type 2 diabetes:
Overall approach To avoid clinical
inertia reassess
and modify
FIRST-LINE THERAPY IS METFORMIN AND COMPREHENSIVE LIFESTYLE (INCLUDING WEIGHT MANAGEMENT AND PHYSICAL ACTIVITY) treatment
IF HbA1c ABOVE TARGET PROCEED AS BELOW regularly
(3–6 months)
Without established
NO ASCVD or CKD Without established ASCVD or CKD
Compelling need to minimise hypoglycaemia
Without established ASCVDneed
or CKD
Without established ASCVD
ASCVD predominates Compelling to minimise weight gain or or CKD
HF OR CKD predominates promote weight loss
ASCVD predominates PREFERABLY DPP-4i GLP-1RA SGLT-2i
Compelling need to minimise
†
hypoglycaemia TZD Compelling need to minimise weight gain or
Cost is a major issue ††‡‡
EITHER/
SGLT-2i
HF OR
SGLT-2i with evidence of reducing HF and/or CKD
CKD predominates promote weight loss Cost is a major issue††‡‡
OR DPP-4i GLP-1RA SGLT-2i† TZD GLP-1RA EITHER/
GLP-1RA with proven CVD progression in CVOT if eGFR is adequate ‡
If HbA PREFERABLY
with proven CVD benefit*, 1c above If HbA1c above If HbA1c above If with
HbAgood
1c above
efficacy OREITHER/ SGLT-2i2
EITHER/ OR GLP-1RA
benefit* if eGFR SGLT-2i withtarget evidence of reducing target
HFIf HbA above target target
If HbA1cfor weight loss 8 SU|| TZD‡‡
adequate SGLT-2i If HbA1c above If HbA 1c above above with good efficacy OR SGLT-2i†
OR If SGLT-2i not tolerated or contraindicated or if
†
and/or CKD progressiontarget in CVOT if eGFR target
1c
GLP-1RA with proven

eGFRCVD
less than adequate † add GLP-1RA with target target for weight loss** SU|| TZD‡‡
proven CV benefit* adequate ‡
with proven CVD benefit*,
benefit* if eGFR OR
GLP-1RA SGLT-2i† If HbA1c Ifabove target
HbA1c above target If HbA1c above target
If HbA1c above target adequate† If HbA1c aboveIf target
SGLT-2i not SGLT-2itolerated† or contraindicated or if† †
SGLT-2i GLP-1RA SGLT-2i†
SGLT-2i† SGLT-2i
eGFR less than adequate† add GLP-1RA with OR
OR OR OR
GLP-1RA If HbA1c above target
proven CV benefit* GLP-1RA
OR OR OR OR DPP-4i
DPP-4i DPP-4i
DPP-4i SGLT-2i† with good efficacy for TZD‡‡ SU||
If further intensification is required or patient is • Avoid TZD in the setting of HF SGLT-2i2 with good efficacy
weight loss** for
now unable to tolerate GLP-1RA and/or SGLT-2i, OR OR
Choose agents demonstrating CV safety:
TZD TZD OR OR weight loss8
choose agents demonstrating CV safety: TZD TZD TZD GLP-1RA TZD‡‡ SU||
If HbA1c above target • Consider adding the other class withIf HbA1c above target
• Consider adding the other class proven CVD benefit* TZD GLP-1RA If HbA1c above target If HbA1c above target
(GLP-1RA and/or SGLT-2i) with proven • DPP-4i (not saxagliptin) in the setting of HF
CVD benefit (if not on GLP-1RA) If HbA1c above target
If HbA1c above target If triple therapy required or SGLT-2i and/or
• DPP-4i if not on GLP-1RA • Basal insulin§ • Insulin therapy basal insulin with
• If further intensification
Basal insulin § is required or patient
• is
SU|| • Avoid TZD in the setting of HF GLP-1RA not tolerated or contraindicated use
If HbA1clowest
above target
acquisition cost
• nowTZD If HbA1c above target regimen with
unable
¶
to tolerate GLP-1RA and/or SGLT-2i, Continue with addition of other agents as outlined above If triple therapy required lowestor SGLT-2i
risk and/or GLP- OR
of weight gain
• SU|| • Consider DPP-4i OR SGLT-2i with
choose agents demonstrating CV safety: Choose agents demonstrating CV safety: PREFERABLY
1RA not tolerated or contraindicated use regimen lowest acquisition cost ‡‡
• Consider adding the other class • Consider adding the Continue
other classwith
withaddition
proven of other
If HbA agents
target as outlined above
DPP-4i (if not on GLP-1RA)
with • Insulin therapy basal insulin with
1c above based on weight neutrality
(GLP-1RA and/or SGLT-2i) with proven CVD CVD benefit* lowest risk of weight gain lowest acquisition cost
benefit • DPP-4i (not saxagliptin) in the setting of HF (if OR
Consider the addition of SU || OR basal insulin: PREFERABLY
• not on GLP-1RA) •
DPP-4i if not on GLP-1RA If HbA
Choose later generation SU with above
1c lower target
risk of hypoglycaemia DPP-4i (if not on GLP-1RA) •
If DPP-4i not tolerated or contraindicated Consider DPP-4i OR SGLT-2i with
or
• Basal insulin§ • Basal insulin§ • Consider basal insulin with lower risk of hypoglycaemia # patient already on GLP-1RA cautious addition
lowest acquisition cost‡‡
based
of: on weight neutrality
• TZD¶ • SU|| ● SU|| ● TZD¶ ● Basal insulin
• *Proven
SU|| CVD benefit means it has label indication of reducing CVD events. For GLP-1RA strongestConsider theforaddition
evidence of SU|| OR basal insulin:
liraglutide>semaglutide>exenatide extended release. For SGLT-2i evidence modestly stronger for empagliflozin>canagliflozin; †Be aware that SGLT-2i vary by
• ‡Both
region and individual agent with regard to indicated level of eGFR for initiation and continued use; Choose later generation
empagliflozin SU
and canagliflozin with
have lower
shown riskinof
reduction HFhypoglycaemia
and reduction in CKD progression in CVOTs; §Degludec or U100 glargine have demonstrated CVD safety;
¶
•
Low dose may be better tolerated though less well studied for CVD effects; ||Choose later generationConsider basal
SU with lower insulin
risk of with lower
hypoglycaemia; #
risk/ of
Degludec hypoglycaemia
glargine #
U300<glargine U100 If DPP-4i
/ detemir<NPH not tolerated or contraindicated or
insulin; **Semaglutide>liraglutide>dulaglutide>exenatide>lixisenatide; ††
If no
specific comorbidities (i.e. no established CVD, low risk of hypoglycaemia and lower priority to avoid weight gain or no weight-related comorbidities); Consider country- and region-specific cost patient
‡‡
already
of drugs. In on GLP-1RA
some countries, cautious
TZDs relatively addition
more expensive andof:
DPP-4i
relatively cheaper
For internal use only. Strictly confidential. Do not copy or distribute. ● SU6 ● TZD5 ● Basal insulin
Why Metformin+Empagliflozin be a
Ali suitable option for Ali?
• has proven great efficacy of blood glucose reduction

with very low risk of hypoglycemia.
• Has further BP reduction effect.
• Patient is obese (weight gain unfavourable effect of
TZD , SU and insulin).
• Has many risk factors of ASCVD ( former smoker ,
HTN , DLP , Proteinuria , LVH and Obesity).
For internal use61

What are the Pharmacological options to
Ali improve Ali’s BP control?
A. Continue or Maximize Atenolol?
B. Add CCB to Atenolol? VOTE NOW

C. Stop Atenolol and Initiate ACE/ARB only?
D. Stop Atenolol and initiate ACE/ARB+CCB as SPC ?
E. Add Diuretic to Atenolol?
For internal use62

Initiation of BP-lowering treatment at different initial
office BP levels
Initiation of drug treatment Initiation of drug treatment
Initiation of antihypertensive therapy with a two-drug It is recommended to initiate an antihypertensive
combination may be considered in patients with markedly treatment with a two-drug combination, preferably in
high baseline BP or high CV risk a SPC. The exceptions are frail older patients and
those at low risk and with grade 1 hypertension
(particularly if SBP is <150 mmHg).
2018 guidelines
recommend the same 5
major classes of drugs as
a basis for anti-
hypertensive therapy:
ACEIs/ARBs/
BBs/CCBs/Ds
ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta blocker; BP, blood pressure; CCB, calcium channel blocker; CV, cardiovascular;
D, diuretic; SPC, single-pill combination.

What other aspects of therapy would you
Ali change?
• Initiate statin therapy.

• Initiate additional or change his BP-lowering therapy
to reach target of <130/80 mmHg in hypertensive DM
patient according ESC recommendations (SPRINT
study).
For internal use64

Rationale for initial two-drug combination and single-
pill combination in most patients
• An initial dual combination therapy provides fast,

efficient and well-tolerated, more consistent and more
effective control
 Monotherapy is usually ineffective and initiation with
it results in inertia in therapy escalation
• A pragmatic and simplified SPC strategy, dual or triple,

provides better compliance and reduces pill burden
ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium channel blocker; RAS, renin angiotensin system;
SPC, single pill combination.

Recommendations for him
Ali
• Metformin+Empagliflozin 1000mg/12.5mg bid Initiated
• He was encouraged for more water intake to prevent
dehydration (extra 300ml water).
• Atorvastatin 20mg.
• Suitable SPC ACE or ARB/CCB was added for more
compliance Telmisartan/Amlodipine 80mg/5mg.
For internal use67

Recommendations
Ali
• Encourage dietary and lifestyle changes.

• Encourage home checking for BP after 2-3 weeks.
• Repeat lab. investigations for his cardio metabolic
parameters after 3-4 months.
• Routine Fundus examination.
• Referral to DM educator nurse.
• Referral to cardiologist for Echo and to dietitian.
For internal use68

Take Home Messages
• Early intervention and intensification of TTT is corner stone to decrease

morbidities and mortalities.
• Identify relevant and hidden risks in order to proper selection of
management plan.
• Assurance of life style modifications ( Diet , Exercises , enough sleep ,
smoking and Alcohol cessation) in. the whole course of Cardio-Metabolic
disorders.
• Following updated Guidelines is cost effective approach.
• Importance of monitoring , follow up and referral to other specialties
(Team Work)

Thank you for your
attention
Q&A

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The Landmark Trial SGLT2i

For internal use only. Strictly confidential. Do not copy or distribute.

· I am contracted by Boehringer Ingelheim to conduct this session.

· I have no financial interest in Boehringer Ingelheim.

For internal use only. Strictly confidential. Do not copy or distribute.

For internal use only. Strictly confidential. Do not copy or distribute.

For internal use only. Strictly confidential. Do not copy or distribute.

For internal use only. Strictly confidential. Do not copy or distribute.

In 2015, elevated systolic BP was the leading

~10 million deaths are reported due to elevated blood pressure

disability adjusted life-years

For internal use only. Strictly confidential. Do not copy or distribute. 7

For internal use only. Strictly confidential. Do not copy or distribute.

 Approximately 9% of adults worldwide

 Health expenditure on diabetes is

Associated complications of T2D2

Risk of developing CV disease is

For internal use only. Strictly confidential. Do not copy or distribute. 10

For internal use only. Strictly confidential. Do not copy or distribute. 11

For internal use only. Strictly confidential. Do not copy or distribute. 12

For internal use only. Strictly confidential. Do not copy or distribute. 13

• Or the body cannot make enough or good use

For internal use only. Strictly confidential. Do not copy or distribute. 14

For internal use only. Strictly confidential. Do not copy or distribute.

Adapted from DeFronzo RA. Diabetes 2009;58:773–95

For internal use only. Strictly confidential. Do not copy or distribute.

Cause of death in patients with T2D2

For internal use only. Strictly confidential. Do not copy or distribute. 18

Approximately two-thirds of patients with CV disease…

…have Coronary Artery Disease

For internal use only. Strictly confidential. Do not copy or distribute. 19

CV disease can occur

CV, cardiovascular; T2D, type 2 diabetes

• 2.5 times more deaths than cancer*

Deaths due to CV disease

Deaths due to cancer*

Patients with diabetes and at least one

CV, cardiovascular; T2D, type 2 diabetes

DPP4-i Increased Increased

Adapted from DeFronzo RA. Diabetes 2009;58:773–95

For internal use only. Strictly confidential. Do not copy or distribute.

For internal use only. Strictly confidential. Do not copy or distribute.

For internal use only. Strictly confidential. Do not copy or distribute.

EMPA-REG OUTCOME® was a randomised, double-blind, placebo-controlled CV outcomes trial1

Results were achieved on top of standard of care1

95%* 81%* 89%* 98%*

*Patients receiving therapy at baseline

For internal use only. Strictly confidential. Do not copy or distribute. 28

95% 81% 89% 98%

ACEi/ARBs 81% Statins 77% ASA 83% Metformin 74%

For internal use only. Strictly confidential. Do not copy or distribute. 29

Placebo + SOC (n=2333)

• Adults with T2D • Glucose-lowering therapy was to remain

For internal use only. Strictly confidential. Do not copy or distribute. 30

76% 47% 25% 23% 21% 10%

Data are from patients treated with ≥1 dose of study drug

For internal use only. Strictly confidential. Do not copy or distribute. 31

For internal use only. Strictly confidential. Do not copy or distribute. 32

The EMPA-REG OUTCOME® Trial represents a clinically relevant T2D population

Empagliflozin demonstrated a 38% relative risk reduction in CV death in patients with

For internal use only. Strictly confidential. Do not copy or distribute.

Early and sustained reduction in HHF

Jardiance® is not indicated for heart failure