Original Approach to Cardio-Renal-Metabolic

Protection in Type-2 Diabetes Mellitus

Empagliflozin + Linagliptin Combination in Focus
Sustainable Development Goals Aim to Reduce NCD Deaths (WHO)

Available: https://www.who.int/data/gho/data/themes/topics/sdg-target-3_4-noncommunicable-diseases-and-mental-health . Accessed 23rd Dec 2024.

Top 10 Causes of Death in India (India State Level Disease Burden Initiative)

Available from GBD India Compare: https://vizhub.healthdata.org/gbd-compare/india. In: Disease burden initiative in India Accessed 23rd Dec 2024.
To Achieve India’s Commitment to Reduce Premature NCD Deaths…

Available: https://sdghealthindia-mohfw.in/dashboard. Accessed 23rd Dec 2024.

… a Holistic Patient-centric Approach to Manage T2DM is Essential
Heart Failure Atherosclerotic CVD

Fluid Overload Dyslipidemia

CVD
Neurohumoral
Dysfunction Cardiomyopathy

Hypertension Dysfunctional Fat

Patient
eGFR Decline Insulin Resistance

CKD T2DM
Albuminuria ß-cell Dysfunction

Anaemia Hyperglycaemia
Endothelial CVD cardiovascular disease
Image is a schematic representation of interconnected Dysfunction CKD chronic kidney disease
pathophysiology of cardio-renal-metabolic disorders T2DM type-2 diabetes mellitus
Adapted: Braunwald E. Eur Heart J. 2024 Dec 19:ehae775.
Holistic Cardio-Renal-Metabolic Risk Reduction is Essential in T2DM
• Nearly 1 out of 9 Indian adults have T2DM (ICMR-INDIAB 17).1
• Indian adults are prone to develop T2DM a decade earlier, with high levels of
dysfunctional fat and insulin-resistance, as compared to Caucasians.2
• Nearly 1 out of 3 people with T2DM have CVD globally.3
• Nearly 1 out of 2 people with T2DM have left-ventricular diastolic dysfunction.4
• Nearly 1 out of 3 Indian people with T2DM have CKD.5
• Nearly 1 out of 10 Indian people with T2DM have rapid eGFR decline* (CARRS).6
• Complications of T2DM increase the health-expenditure by nearly 2-4 times.7
• T2DM increases risk of premature CV death by 3 to 4 times (CURES-150).8
CKD: sustained eGFR <60 mL/min/1.73m 2 or UACR ≥30 mg/g present for at-least 3 months.
*Rapid decline in eGFR: Defined as eGFR decline of >3 mL/min/1.73m 2 per year, as per CARRS study analysis.
Please see footnotes for references.
 Screening for Cardio-Renal-Metabolic (CRM) Risk Status in Adults

 Measurement of BMI and waist circumference: annually

 Metabolic Syndrome components (BP, triglycerides, HDL-cholesterol, glycemia):

every 3-5 years, more frequently with progressive CRM risk levels
 Advanced liver fibrosis related to MASLD using FIB-4 index: every 1-2 yrs

 UACR and serum creatinine/cystatin-C based eGFR levels: annually, more

frequently as required
 Subclinical HF (echocardiogram and/or cardiac biomarkers): likely based on age /
comorbidity / risk
 Social determinants of health
Coronary Artery Calcium scan may be considered in intermediate CVD risk, to guide intensification of preventive therapies.
Adapted: American Heart Association Presidential Advisory. Circulation. 2023 Oct; 148: 1606-35.
A Prototype 38-years old Male Patient
Medical history Recently diagnosed with T2DM and dyslipidemia on routine checkup
Follows sedentary lifestyle; no other complaints or medical history
BMI; Waist Circumference 31 Kg/m2; 42 inches
Peripheral pulses; BP (clinic) Feeble tibial and dorsalis-pedis pulses in both limbs; 120 / 80 mmHg
Hb, Platelet count 9 g/dL; 2,00,000 / µL
Glycemic profile HbA1c 8.5%; FPG 165 mg/dL; PPG 252 mg/dL; Fasting insulin 32
mIU/mL
Lipid Profile Total-c 210 mg/dL; LDL-c 136 mg/dL; HDL-c 32 mg/dL; TG 210 mg/dL
Liver Enzymes SGOT 45 IU/L; SGPT 38 IU/L
Kidney Profile UACR Nil; S. creatinine 0.9 mg/dL; eGFRCKD-EPI 112 mL/min/1.73 m2
USG Abdomen Grade 1 fatty liver
Exercise ECG Treadmill test positive, s/o silent myocardial ischemia
Current therapy Metformin 1g BD
Dysfunctional Fat and Insulin Resistance is High in Early T2DM

Indian People with New-onset T2DM

 Diagnosed at younger age

 Lesser obesity, but higher adiposity

 Higher central adiposity

 More insulin resistance

 Greater cardio-metabolic risk

WHR: waist: hip ratio
SS/TR: subscapular : triceps skinfold thickness
Midarm: midarm circumference
Yajnik CS. Nutr Rev. 2001;59(1 Pt 1):1-9. HOMA: Homeostasis Model Assessment
Yajnik CS. Eur J Clin Nutr. 2018;72(4):469-73
Unnikrishnan AG et al. PLoS ONE 17(3): e0263619. https://doi.org/10.1371/journal.pone.0263619.
A Prototype 55-years old Female Patient
Medical history Diagnosed with T2DM 2 years ago
K/c/o Hypertension and Dyslipidemia for 10+ years
On probing, increasing breathlessness on exertion
Current BMI; BP (clinic) 32 Kg/m2; 120 / 80 mmHg
Recent Hb; HbA1c 9 g/dL; 8.1%
Lipid Profile Total-c 173 mg/dL; LDLc 92 mg/dL; HDLc 44 mg/dL; TG 185 mg/dL
Liver Enzymes SGOT 130 IU/L; SGPT 150 IU/L
Kidney Function UACR 90 mg/g; S. creatinine 1.12 mg/dL; eGFRCKD-EPI 60 mL/min/1.73 m2
Resting ECG S/o left ventricular hypertrophy

Doppler Echocardiography LVEF 58%; Grade-2 diastolic dysfunction

Current therapy Metformin, Telmisartan, Amlodipine, Hydrochlorothiazide,
Atorvastatin in tolerated doses
Nearly 1 out of 2 People with T2DM have Diastolic Dysfunction
Meta-Analysis of 27 Echocardiography-based Studies

46% People with

T2DM have LVDD

LVDD: Left Ventricular Diastolic Dysfunction. Bouthoorn S et al. Diabetes & Vascular Disease Research. 2018; 15(6): 477-93.
 eGFR and Albuminuria Levels Represent Prognostic Risks for CV
Death and Kidney Events in Patients with T2DM (ADVANCE)
Observational sub-analysis of ADVANCE study
CV Death Kidney Events‡

25
5.93 22.20

Risk of kidney event (HR)

6 20
Risk of CV death (HR)

5
15
16.19
4 3.37 16.13
3.61
3 10

2 2.87 2.52 1.85

3.95
5
1 7.82 3.17
1.96 1.22 eGFR <60 0.89 eGFR <60
0 0 0.4 eGFR 60-
A3 (severely 1.00 eGFR 60-89 A3 (severely
increased) 5 1.00 89
increased)
Baseline A2 (moderately Baseline
A2 (moderately increased) eGFR ≥90
increased) eGFR ≥90
eGFR † A1 (normal to mildly eGFR †
A1 (normal to mildly increased)
increased)

Baseline UACR Baseline UACR

*Average time to follow-up for assessment was 4.3 years; †eGFR in ml/min/1.73 m2. ‡Kidney event: renal death, need for dialysis / transplantation, or doubling of sr.
creatinine. HR, hazard ratio. CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; UACR, urine albumin-to-creatinine ratio.
Adapted from Ninomiya T et al. J Am Soc Nephrol 2009;20:1813
2 out of 5 Patients with T2DM have CKD in Indian Diabetes Clinics
38.6% of T2D Patients have eGFR <60 mL/min/1.73m2 or UACR ≥30 mg/g

Albuminuria Categories
Prognosis of CKD CKD Risk-Category % of Patients
by eGFR and
Albuminuria Normal to Mildly Moderately Severely
Risk-Categories Increased Increased Increased
(KDIGO - 2012) (<30 mg/g) (30 to 300 mg/g) (>300 mg/g)
Low-Risk 61.4%
Chronic Kidney Disease
>90 25.2% 4.9% 3.8%
Moderate Risk 17.2%
60-89 36.2% 8.6% 7.9%
(mL/min/1.73m )2
eGFR Categories

45-59 3.7% 2.1% 2.9% High Risk 14.3%

30-44 0.6% 0.8% 1.9%

15-29 0.1% 0.1% 0.9% Very High Risk 7.1%

<15 0.0% 0.0% 0.4%

Study involved 3426 patients with T2DM, with mean age 52.7 years
CKD is defined as eGFR <60 mL/min/1.73m 2 or UACR ≥30 mg/g
Adapted: Viswanathan V et al. Int J Diabetol Vasc Dis Res. 2017; 5(3): 196-201.
Holistic Approach to Cardio-Renal-Metabolic Care in Early T2DM

Lifestyle Management
Renal Metabolic Smoking / Tobacco cessation
Physical activity
Diet management
Essential Treatment for Risk-factor Control
People Lipid management

CKD
with MASLD
Glycemic control
T2DM Blood-pressure reduction
Weight management
Essential Treatment for Organ-Protection
HF Obesity
SGLT2-i
GLP-1 RA Early, coordinated
RAS-blockade treatment is crucial to
improve patient outcomes
Cardiovascular ns-MRA and quality of life

CRM, Cardiovascular-Renal-Metabolic; CV, cardiovascular; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HF, heart failure; ns-MRA, non-
steroidal mineralocorticoid receptor antagonist; RA, receptor agonist; RAS, renin-angiotensin systems; SGLT2i, sodium-glucose co-transporter 2 inhibitor; T2D, type 2 diabetes.
Méndez Fernandez et al. Front Cardiovasc Med 2023; doi:10:1185707; Medscape, 2023. Available at: https://reference.medscape.com/recap/964090; accessed Nov\ 2023.
Clinical Guidelines Recommend that Combination Therapy Should
be Tailored for the Individual Patient

Glycaemic management: Choose approaches that provide the efficacy to achieve goals:
• Metformin OR agent(s) including COMBINATION therapy that provide adequate EFFICACY to
achieve and maintain treatment goals
• Consider avoidance of hypoglycaemia a priority in high-risk individuals

Combination therapy has several potential advantages, including:

1) ↑ efficacy and durability of glycaemic effect
2) Simultaneously targeting multiple pathophysiological defects
3) Ease of use: Reduced pill-burden; Improved adoption and adherence
4) Addressing multiple goals and individualized priorities for holistic care

*A combination of SGLT2 inhibitor/GLP-1 RA should be considered for additional cardio-renal risk reduction or glycaemic control
Davies MJ et al. Diabetes Care 2022;45:2753
Personalized Care of T2DM with SGLT2-i and DPP4-i Combination

DPP4 inhibition SGLT2 inhibition

↑ β-cell function ↓ Dysfunctional Adiposity
Ease of use ↓ Insulin Resistance
Cardiovascular Safety ↓ in MACE, CV Death in ASCVD
Kidney Safety Improved HF Outcomes
Broad Clinical Improved Kidney Outcomes
Applicability
SGLT2-i and DPP4-i have Distinct but Complementary Effects in the
Pathophysiology of Diabetes

Effect on 8/8
pathophysiological
aspects of Ominous
Octet when added
to Metformin

Thrasher J. Am J Med. 2017 Jun;130(6S):S4-S17. doi: 10.1016/j.amjmed.2017.04.004. PMID: 28526182.

 Empagliflozin + Linagliptin Combination Provides Early and Sustained
Glycemic Control in Patients with T2DM on Metformin

8.2
EMPA/LINA 10/5 mg EMPA/LINA 25/5 mg EMPA 10 mg EMPA 25 mg LINA 5 mg
8.0
Adjusted mean (SE) HbA1c (%)

7.8

7.6

7.4

7.2

7.0

6.8

6.6
0 6 12 18 24 30 36 42 48
32 40 52
Weeks
No. of patients
EMPA/LINA 10/5 mg 135 135 134 131 127 125 120 117
EMPA/LINA 25/5 mg 133 132 131 128 123 121 120 116
Empagliflozin 10 mg 137 137 128 128 126 122 118 112
Empagliflozin 25 mg 139 138 136 132 128 122 116 111
Linagliptin 5 mg 128 128 124 123 117 111 96 90

EMPA, empagliflozin; HbA1c, glycosylated haemoglobin; LINA, linagliptin; SE, standard error
DeFronzo RA et al. Diabetes Care 2015;38:384
Empagliflozin Improves Time-in-Range in Uncontrolled T2DM
Benefit on 24-hr CGM is Observed from Day-1 Onwards

**p<0.01; ***p<0.001
for difference vs placebo
in change from baseline

Nishimura et al.
Cardiovascular Diabetology. 2015;14:11.
Linagliptin Improves Post-meal Glycemic Excursions in T2DM

Takahashi H et al. J Diabetes Investig2019; 10: 714-22.

 Empagliflozin Rapidly Clears Gluco-metabolic toxicity and
Improves β-cell Function in People with T2DM

Clinical Fasting Plasma C-peptide β-Cell Function β-Cell Glucose

Parameters Glucose Response (IS/IR index#) Sensitivity@
(mean value, mg/dL) Hyperglycemic clamp Hyperglycemic clamp Hyperglycemic clamp

At Baseline 195 mg/dL 23 ng/mL/hour 88% 0.024

ng/mL per mg/dL

On Day 2 ↓ by 25 mg/dL* ↑ by 48%** ↑ by 73%** ↑ by 42%**

On Day 14 ↓ by 38 mg/dL* ↑ by 61%** ↑ by 112%** ↑ by 54%**

Patients with T2DM (N = 15) received empagliflozin (25 mg/d) for 2 weeks. β-Cell function measured with 9-step hyperglycemic clamp at baseline,
2-days, and 14-days. Lowering plasma glucose concentration with empagliflozin augmented β-cell glucose sensitivity and improved β-cell function.
*p-value <0.05; **p-value <0.01. All values expressed as mean.
# IS/IR index: Insulin Secretion / Insulin Resistance index.
@ β-Cell glucose sensitivity: slope of the line relating C-peptide secretion and plasma glucose concentration.
Al Jobori H et al. J Clin Endocrinol Metab. 2018 Apr;103(4):1402-7.
Empagliflozin with Metformin Results in Sustained Weight-loss
Empagliflozin versus Glimepiride as Add-on to Metformin in T2DM

Ridderstrale M et al. Diabetes Obes Metab. 2018 Dec;20(12):2768-77.

Empagliflozin Reduces Hepatic Fat-content in People with T2DM
and MASLD (E-LIFT Study)

E-LIFT Study
(RCT in 42 patients with T2DM and
MASLD; empagliflozin vs. standard
treatment control for 20 weeks)

-4.0% greater absolute reduction in

liver-fat achieved with Empagliflozin
versus Control group (p<0.001)

18% patients in Empagliflozin group

achieved normal liver fat content*,
versus 5% patients in Control group

*Normal Liver Fat Content: <6% on MRI-PDFF

Kuchay MS, Mithal A. Diabetes Care. 2018 Jun 12. pii: dc180165.
Empagliflozin Use Improves Insulin-Sensitivity in People with T2DM
and High Insulin-Resistance
Changes in Insulin-Sensitivity Parameters With Empagliflozin vs. Placebo from Baseline to 12-weeks

HOMA IR Fasting Insulin Level Remnant-like Cholesterol

Empagliflozin Placebo Empagliflozin Placebo Empagliflozin Placebo

10 10 10
4.1
5 3.8
Change from Baseline (%)

Change from Baseline (%)

Change from Baseline (%)

0
0 Series1
Series1 0
Series1 -10 -8.8
-10 -5
-20
-10
-20
P <0.05 P <0.05 -30 P <0.05
-15 -13.7
-23.1 -31.8
-30 -20 -40

Empagliflozin (n = 58) Placebo (n = 51) Empagliflozin (n = 58) Placebo (n = 51) Empagliflozin (n = 58) Placebo (n = 51)
HOMA Insulin RLP-C
IR Baseline 12-wks Baseline 12-wks (mU/mL) Baseline 12-wks Baseline 12-wks (mg/dL) Baseline 12-wks Baseline 12-wks

Mean 3.03 2.33 2.86 2.98 Mean 10.59 9.13 8.81 9.15 Mean 8.06 5.49 7.77 7.08
P-value < 0.05 0.49 (non-significant) P-value < 0.05 0.43 (non-significant) P-value < 0.05 0.36 (non-significant)
Hattori S. J Diabetes Investig. 2018 Jul;9(4):870-4.
Empagliflozin Offers Early Risk-Reduction for CV Death, in Patients
with ASCVD and T2DM (EMPA-REG OUTCOME)

Overall Study Population Asian Patient-Subgroup

38% Relative Risk Reduction 56% Relative Risk Reduction

1. Zinman B et al. N Engl J Med 2015;373:2117 2. Fitchett D et al. J Am Coll Cardiol 2018;71:364. 3. Kaku K, et al. Circ J.
2017;81(2):227-34.
Empagliflozin Reduces Risk of First and Recurrent CV Events in
Patients with T2DM and Atherosclerotic CVD (EMPA-REG OUTCOME)

21% ↓ in Risk of Myocardial Infarction events, with Empagliflozin vs Placebo

Empagliflozin Placebo Rate Rate Ratio Clinical P-value

(events per (events per Ratio (95% CI) Effect
1000 pt-yr) 1000 pt-yr)

Major Adverse 0.78 22%

44.9 57.6 < 0.05
CV Events (3P-MACE) (0.67, 0.91) ↓ in risk

0.79 21%
Myocardial Infarction 19.6 24.9
(0.62, 0.99) ↓ in risk
< 0.05

MI or Coronary 0.80 20%

46.3 58.2 < 0.05
Revascularization (0.67, 0.95) ↓ in risk

*This secondary analysis of EMPA-REG OUTCOME study is 1

based on total events, including first and recurrent events.
Favours Favours
Risk-reduction for MI events included consistent effects on
Empagliflozin Placebo
type-1 as well as type-2 MI events.
Adapted: McGuire DK et al. Lancet Diabetes Endocrinol 2020; 8: 949-59.
EMPA-REG OUTCOME Study First Demonstrated Kidney Protection
with SGLT2-inhibition, in Patients with T2DM and CVD

Doubling of Serum Creatinine accompanied by eGFR <45 mL/min/1.73m 2; RRT, renal replacement therapy; eGFR, estimated glomerular filtration rate; MDRD,
Modification of Diet in Renal Disease study equation. Source: Kadowaki T et al. J Diabetes Investig 2018. doi: 10.1111/jdi.12971
 Empagliflozin Consistently Improves Kidney Disease Outcomes
in Patients with Diabetes and CKD (EMPA-KIDNEY)
Kidney Disease Progres- Kidney Disease Progres- Kidney Failure
sion in Diabetes with CKD sion in Diabetic in Diabetes with CKD
Nephropathy
75 50
45% risk-reduction 44% risk-reduction 41% risk-reduction
Rate per 1000 patient-years

Rate per 1000 patient-years

Rate per 1000 patient-years
80
Hazard Ratio 0.55 Hazard Ratio 0.56 40 39 Hazard Ratio 0.59
60 59 67
(95% CI 0.44-0.71) (95% CI 0.43-0.74) (95% CI 0.44-0.79)
60
30
45 24
36 42
40 20
30

20 10
15
0
0 0 Placebo Empagliflozin
Placebo Empagliflozin Placebo Empagliflozin
Kidney Disease Progression Kidney Disease Progression in Patients with Kidney Failure
Sustained ≥50%↓ in eGFR from randomisation, Diabetic Nephropathy (Diabetic Kidney Disease) Sustained eGFR<10 mL/min/1.73m²,
sustained low eGFR, end-stage kidney disease, as the primary diagnosis of CKD Maintenance dialysis, or Kidney transplantation
or death from kidney failure Adapted: N Engl J Med 2022 Nov 4. doi: 10.1056/NEJMoa2204233. Lancet. 2022 Nov 6. DOI: 10.1016/S0140-6736(22)02074-8.
Empagliflozin Prevents Rapid eGFR Decline Consistently Across Baseline
eGFR or UACR Levels in People with T2DM and CVD (EMPA-REG OUTCOME)

Odds of Rapid Decliner of eGFR (>3 mL/min/1.73m2/year) by Baseline eGFR / UACR Levels

Post hoc analysis of EMPA-REG OUTCOME study involving patients with T2DM and established CVD, with eGFR ≥30 mL/min/1.73m 2
Adapted: Hadjadj S et al. Kidney Medicine. 2023 Dec 18:100783.
Empagliflozin Facilitates Regression of Albuminuria in Patients with
T2DM and CVD with Prior Albuminuria (EMPA-REG OUTCOME)

Patients with Prior Microalbuminuria Patients with Prior Macroalbuminuria

Regression to Normoalbuminuria Regression to Normo / Microalbuminuria

43% ↑ Likelihood 82% ↑ Likelihood

with Empagliflozin with Empagliflozin

UACR: Urine Albumin-Creatinine Ratio. Normoalbuminuria: UACR <30 mg/g. Microalbuminuria: UACR ≥30 to ≤300 mg/g. Macroalbuminuria: UACR >300 mg/g.
Cherney DZI et al. Lancet Diabetes Endocrinol. 2017 Aug;5(8):610-21.
SGLT2-inhibition has Favourable Effect on Cardio-Renal Anemia

KIDNEY HEART
SGLT2-i
↑ Erythropoietin ↑ Energy Production

BONE MARROW
↑ Erythropoiesis ↑ Iron Bioavailability
↑ Erythroferrone

LIVER ↑ Iron absorption from the duodenum

↓ Hepcidin ↑ Iron release from reticulo-endothelial cells
Restoration of iron bioavailability and erythropoiesis homeostasis with SGLT2-inhibitors: SGLT2-inhibitors restore erythropoietin production by unloading the kidney
and improving the tubulointerstitial microenvironment. Improved erythropoiesis increases the production of erythroferrone from erythroblasts in the bone marrow,
suppresses hepcidin production in the liver, and increases iron bioavailability. Sano M. Int J Mol Sci. 2023 Mar 22; 24(6): 5983.
Empagliflozin Improves Haemoglobin and Lowers Uricaemia in Patients
of T2DM and CVD with eGFR <60 mL/min/1.73m2 (EMPA-REG OUTCOME)

Haemoglobin Level (g/dL) Serum Uric Acid Level (mg/dL)

Empagliflozin 10mg vs. Placebo

+0.82 g/dL (95% CI 0.65, 1.00)

Empagliflozin 10mg vs. Placebo

-0.32 mg/dL (95% CI -0.50, -0.13)

Mean (SD), g/dL Placebo Empagliflozin 10mg Mean (SD), mg/dL Placebo Empagliflozin 10mg
Baseline 13.32 (0.07) 13.19 (0.06) Baseline 7.01 (0.07) 6.85 (0.08)
164 weeks 13.06 (0.06) 13.89 (0.06) 164 weeks 6.77 (0.07) 6.45 (0.07)

Analysis in 1,819 patients with T2DM and established CVD, with eGFR <60 mL/min/1.73m 2 at baseline. Values in tables expressed as mean (standard deviation)
Wanner C et al. Circulation. 2018 Jan 9;137(2):119-29.
SGLT2-i and Cardio-Renal Outcomes in T2D with ASCVD
Summary for Patients with T2D and Atherosclerotic CVD in SGLT2-i CV Outcome Trials
Comparison of studies should be interpreted with caution due to differences in study design, populations and methodology

Major Adverse CV All-cause Hospitalization Chronic Kidney

CV Events Death Mortality for HF Outcomes

EMPA-REG 14% 38% 32% 35% 46%

OUTCOME risk-reduction risk-reduction risk-reduction risk-reduction risk-reduction

CANVAS Program 18% No significant No significant 32% 41%

risk-reduction risk-reduction risk-reduction risk-reduction risk-reduction

DECLARE TIMI 58
No significant No significant No significant 22% 45%
risk-reduction risk-reduction risk-reduction risk-reduction risk-reduction

VERTIS CV
No significant No significant No significant 30% 34%
risk-reduction risk-reduction risk-reduction risk-reduction risk-reduction*

Adapted: McGuire DK et al. JAMA Cardiol. doi:10.1001/jamacardio.2020.4511 . Published Online, Oct 7 2020.
*Cherney DZI et al. Diabetologia. 2021 Jun;64(6):1256-17.
Empagliflozin Demonstrates Lower Risk of ESKD, CV Death or HHF, with
Similar Risk of MI/Stroke versus GLP1-RA in Routine T2DM Care (EMPRISE)
Cardio-Renal Outcomes with Empagliflozin vs. GLP1-RA in Patients with T2DM

Incidence Rate of Clinical Events (per 1000 patient-years)

Empagliflozin GLP1-RA

50
(per 1000 patient-years)

45 HR: 0.75
40 HR: 0.77 (95% CI 0.60, 0.94)
Incidence Rate

35 (95% CI 0.69, 0.86) HR: 0.88 HR: 0.99

30 26.5 (95% CI 0.78, 0.99) (95% CI 0.92, 1.07)
25 HR: 0.81
18.3 19.7 (95% CI 0.67, 0.97)
20 15.4
14.2 13.6 13.1 13.4
15
10 5.3 6.5
5
0
CV Death or HHF ESKD CV Death All-Cause Mortality MI or Stroke
Across 2 groups of comparable patients with T2DM receiving either empagliflozin or GLP1-RA (n = 1,41,541 in each group, matched for similar baseline characteristics across
143 key clinical variables), in comparison to GLP1-RA, empagliflozin use was associated with similar risks of MI or stroke, and lower risks of CV Death or HHF, ESKD, CV Death,
and All-Cause Mortality. These findings complement existing trial evidence by directly comparing empagliflozin with alternative cardioprotective agents and incorporating
broad patient populations in clinical practice, using robust and generalizable methodology.
EMPRISE Real-World Study. Please see footnotes for details. Htoo PT et al. Cardiovascular Diabetology. 2024; 23: 57.
 Linagliptin Demonstrated Compelling Evidence of Heart-Failure Safety
in a High-risk Population (CARMELINA®)
Hospitalisation for Heart-failure: Event-rates in DPP4-i CVOTs

Placebo DPP-4 inhibitor

3.5
3.04
3.0 2.77
Per 100 patient-years

2.69
2.5 2.28
2.0
1.71
1.5 1.36
1.09 1.07
1.0

0.5

0.0
TECOS SAVOR-TIMI 58 EXAMINE CARMELINA®
(sitagliptin)1 (saxagliptin)1 (alogliptin)1 (linagliptin)2

Comparison of trials should be interpreted with caution due to differences in study design, populations and methodology
CVOT, cardiovascular outcomes trial; DPP-4, dipeptidyl peptidase-4; HHF, hospitalisation for heart failure
1. Filion KB & Suissa S. Diabetes Care 2016;39:735; 2. Rosenstock J et al. JAMA 2019;321:69
 Linagliptin has Proven a Reassuring Cardiovascular Safety Profile in
CARMELINA Cardio-Renal Outcome Trial

3P-MACE HHF
HR (95% CI) HR (95% CI) p-value HR (95% CI) HR (95% CI) p-value

SAVOR-TIMI 531 1.00 (0.89, 1.12) 0.99 1.27 (1.07, 1.51) 0.007

EXAMINE2,3 0.96 (n/a, 1.16) 0.32 1.07 (0.79, 1.46) 0.657

TECOS4 0.99 (0.89, 1.10) 0.84 1.00 (0.83, 1.20) 0.98

CARMELINA®5 1.02 (0.89, 1.17) 0.7398 0.90 (0.74, 1.08) 0.2635

0.5 0.5

Favors DPP-4 inhibitor Favors placebo Favors DPP-4 inhibitor Favors placebo
 Linagliptin has Conclusively Proven Long-term Kidney-Safety in Patients
with T2DM and High Cardio-Renal Risk (CARMELINA®)1
Hazard Ratio (95% CI) Hazard Ratio (95% CI) p-value

Kidney Composite Outcome

(Prespecified and Adjudicated)

ESKD, renal death or ≥40% eGFR decrease 1.04 (0.89, 1.22) 0.6164

ESKD or renal death 0.87 (0.69, 1.10) 0.2371

Prespecified microvascular composite outcome* 0.86 (0.78, 0.95) 0.0032

Albuminuria progression 0.86 (0.78, 0.95) 0.0034

0.5

Favors linagliptin Favors placebo

CV, cardiovascular; CVOT, cardiovascular outcomes trial; DPP-4, dipeptidyl peptidase-4;

eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; VEGF, vascular endothelial growth factor
*ESKD, renal death, ≥50% decrease in eGFR, albuminuria progression, use of retinal photocoagulation or intravitreal injections of an anti-VEGF therapy for diabetic
retinopathy, or vitreous hemorrhage or diabetes-related-blindness
1. Rosenstock J et al. JAMA 2018; doi: 10.1001/jama.2018.18269
ADA, 2025

Adapted: American Diabetes Association Professional Practice Committee. Diabetes Care 2025; 48(Supplement_1): S181-S206
ADA, 2025

Adapted: American Diabetes Association Professional Practice Committee. Diabetes Care 2025; 48(Supplement_1): S181-S206
Empagliflozin + Linagliptin Combination is Easy to Administer in T2D

10 mg Empagliflozin + 25 mg Empagliflozin +
5 mg Linagliptin 5 mg Linagliptin
10 mg 5 mg 25 mg 5 mg

Ease of Use
+ With complementary pharmacotherapeutic profiles,
a small pill of 8 mm can be consumed once daily in
the morning, regardless of food intake

The empagliflozin + linagliptin fixed-dose combination should not be initiated and should
be discontinued in patients with an eGFR persistently below 30 ml/min/1.73 m2
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PC-IN-104475 Last Reviewed on dated 02 January 2025; Valid till: 31 December 2025

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