Vildagliptin + Dapagliflozin + Metformin

In The Management Of T2DM

Definition
Glycemic control is assessed by the A1C measurement, continuous glucose monitoring (CGM)
using time in range (TIR) and/or glucose management indicator (GMI), and blood glucose
monitoring (BGM). (ADA Guidelines 2023)

Glycemic recommendations for adults with diabetes

<7.0%
A1C  (53 mmol/mol) 
80–130 mg/dL 
Pre-prandial capillary plasma glucose 
(4.4–7.2 mmol/L) 
<180 mg/dL 
Peak postprandial capillary plasma glucose
(10.0 mmol/L) 

ADA Guidelines 2023

Epidemiology

One in every four people under 25 has adult-onset diabetes

According to the ICMR’s youth diabetes registry
Praveen PA, et al.; 2016 Sep;10(5):1034-41.
DIABETES & CARDIOVASCULAR DISEASE

John RP et al. Canadian Journal of Cardiology 34 (2018) 575e584

UNMET NEEDS IN T2DM MANAGEMENT
Combinations addressing multiple
pathophysiological, leading to robust
glycemic control

Treatments which provide

Residual risk of CV both glycemic and extra-
death glycemic benefits

Reducing the risk of

hypoglycemia
Oral treatment
options improving
therapy compliance
Reducing the
occurrence of weight
gain

Chadha M et al. Diabetes Ther (2022). https://doi.org/10.1007/s13300-022-01219

RATIONALE FOR DPP4i AND SGLT2i COMBINATION
Safe, rapid, and sustained glycemic control

Complimentary modes of action targets multiple pathophysiologic abnormalities of T2DM

Improves both insulin resistance and beta cell function

Helps reduce body weight and blood pressure (pleiotropic benefits)

Reduces pill burden (adherence and compliance improves)

Overall cost effective

Chadha M et al. Diabetes Ther (2022). https://doi.org/10.1007/s13300-022-01219

COMPLIMENTARY MODES OF ACTION OF DPP4i + SGLT2i

It is preferable to use combination therapies having complimentary mechanisms of action that target
different pathways addressing the multiple pathophysiologic abnormalities of T2DM.
Chadha M et al. Diabetes Ther (2022). https://doi.org/10.1007/s13300-022-01219
 THE OMINOUS OCTET
DPP4i DPP4i
SGLT2i

DPP4i
SGLT2i SGLT2i

DPP4i
DPP4i SGLT2i

Available from https://education.steady.health/hc/en-us/articles/360052231513-The-Ominous-Octet

Seferovi´c PM et al. Eur J Heart Fail. 2020 Feb;22(2):196-213
How Metformin works

 Intestinal absorption of glucose

Dual therapy efficacy

Significant reductions in HbA1c have been shown in studies where Vildagliptin

is added-on to metformin

http://www.vildagliptin.co.uk/Pages/dualcombinationefficacy.aspx
TIME IN RANGE (TIR) : BENEFITS OF DPP4i+SGLT2i
• Glycemic variability (GV) is an emerging target for preventing complications

• TIR – Percentage of time in 24-h when glucose levels are between 70-180 mg/dl

• Higher TIR is associated with better clinical outcomes

• DPP4i and SGLT2i reduces GV and hence have beneficial effects on TIR

• Less frequent TIR evaluation required for DPP4i and SGLT2i therapies due to minimal GV

Complications Favorable T2DM outcomes

Cost of the treatment Compliance

Chadha M et al. Diabetes Ther (2022). https://doi.org/10.1007/s13300-022-01219

Appropriate use of SGLT2i/DPP4i FDC – Based on Glycemic factors

Chadha M et al. Diabetes Ther (2022). https://doi.org/10.1007/s13300-022-01219

Appropriate use of SGLT2i/DPP4i FDC – Based on Glycemic control

Chadha M et al. Diabetes Ther (2022). https://doi.org/10.1007/s13300-022-01219

VILDAGLIPTIN
VILDAGLIPTIN
DCGI approved DPP4 inhibitor

Has intermediate efficacy

Improvement in beta cell

function

Good circadian glycaemic

control 
14 years since approval, hence
vast usage experience
Weight neutral with reduced
hypoglycemic risk

Affordable
 MECHANISM OF ACTION
DPP-4 Inhibitors Improve Glucose Control by Increasing Incretin Levels in Type 2 Diabetes

Ingestion of
food Glucose dependent
 Insulin Insulin
from beta cells increases
(GLP-1 and GIP)
peripheral
glucose
GI tract Release of Pancreas uptake
incretins from
the gut
β-cells Improved Physiologic
α-cells Glucose Control
Hyperglycemia

X
DPP-4
Enzyme  Glucagon
↑insulin and
↓glucagon
from alpha cells reduce hepatic
DPP-4 (GLP-1) glucose
Inhibitor Glucose dependent output
Inactive
incretins DPP-4 = dipeptidyl peptidase 4
Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab Rep 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.
PHARMACOKINETICS OF VILDAGLIPTIN

Available from https://go.drugbank.com/drugs/DB04876

SYSTEMIC REVIEW AND META-ANALYSIS OF VILDAGLIPTIN

Meta-analysis of Sixty-nine studies (28,006 patients)

Compared with placebo, Vildagliptin reduced HbA1c (-0.7%) and it was as effective

as other antidiabetic agents without increasing the risk for hypoglycemia

Vildagliptin did not increase the incidence of pancreatitis, serious adverse events

or death

Vildagliptin is an effective and safe therapeutic option for patients with T2DM, both
as monotherapy and as add-on treatment

Bekiari E et al. Endocrine. 2016 Jun;52(3):458-80.

Cardiovascular Safety of
Vildagliptin
Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) Trial
• Objective: to examine the safety of the dipeptidyl peptidase-4 inhibitor, vildagliptin, in patients
with heart failure and reduced ejection fraction

• 254 patients with T2DM and HF (NYHA class I-III with LVEF <40%)
Class I  10.2% Class II  53.1% Class III  36.7%

• Randomization: Vildagliptin 50 mg BID  n=128

Placebo  n=126

• Primary endpoint: Change in LVEF by echocardiography

• Secondary endpoint: Change in HbA1c
• Aim: To assess the cardiovascular (CV) safety of vildagliptin vs other non-insulin antidiabetic drugs
(NIADs) using real-world data from 5 European electronic healthcare databases.

• Patients with type 2 diabetes aged ≥18 years on NIAD treatment were enrolled.
UK CPRD Gold = 2,13,317 Denmark OPED = 24,648
Sweden NR = 2,55,084 Germany IMS DA = 219862
France IMS DA = 44,893

• Approximately 2.8% of the enrolled patients (n = 7,38,054) used vildagliptin at any time during the
study, with an average follow-up time of 1.4 years.

• The IRRs (for MI, ACS, stroke, CHF and composite CV outcomes) and their 95% CIs were close to 1,
demonstrating no increased risk of adverse CV events, including the risk of CHF, with vildagliptin vs
other NIADs in real-world conditions.
Williams R et al. Diabetes Obes Metab. 2017;19:1473–1478
DAPAGLIFLOZIN
DAPAGLIFLOZIN
DCGI approved SGLT2i

Has intermediate efficacy

Insulin independent action

Multiple pleiotropic benefits

Cardioprotective

Renoprotective

Affordable
MECHANISM OF ACTION

Hinnen D. Therapeutic Advances in Endocrinology and Metabolism, 01 Jun 2015, 6(3):92-102

CRADIAC & RENAL EFFECTS OF SGLT2i

Available from https://www.farxiga-hcp.com/mechanism-of-action

 PHARMACOKINETICS OF DAPAGLIFLOZIN
• Absorption :Tmax, oral: 0.9 to 2 hours 
Bioavailability, oral: 78% 
Effects of food, oral: Cmax reduced and Tmax prolonged, but no effect on AUC

• Distribution : Protein binding: 91% 

• Metabolism: Hepatic - Extensive via UGT1A9 

• Excretion: Renal excretion- 75%, less than 2% unchanged 

Fecal excretion- 21%, 15% unchanged 

• Elimination Half Life: 8.95 to 12.9 hours

Available from Micromedex

 SYSTEMIC REVIEW AND META-ANALYSIS OF
DAPAGLIFLOZIN
Meta-analysis of Ten studies (4,795 patients)

Dapagliflozin treatment was associated with a reduction in HbA1c [weighted mean

difference (WMD): –0.53%], FPG [WMD -1.06 mmol/L] and body weight [WMD -1.63 kg]

Dapagliflozin monotherapy did not lead to hypoglycaemia

Dapagliflozin increased urinary glucose excretion and was associated with an increased
risk of urinary tract infections and genital tract infections

Zhang M et al. Diabetes Metab Res Rev 2014; 30: 204–221

CLINICAL EVIDENCE
FDC of Vildagliptin and Dapagliflozin
Vildagliptin plus metformin

• Provides better reduction of HbA1c levels as compared to glimepiride- metformin

combination without causing weight gain

• Provides superior efficacy to individual monotherapies

• Provides more significant reduction of HbA1c levels as compared to other OADs

34
 Sample size: A total of 318 patients were screened and 270 patients were randomized
into 3 groups.

 Primary Objective: Evaluation of the efficacy of fixed dose combination of Dapagliflozin

plus Vildagliptin Sustained Release Tablets in patients with type 2 diabetes mellitus
inadequately controlled on Metformin monotherapy.

 Secondary Objective: Evaluation of the safety of fixed dose combination of

Dapagliflozin plus Vildagliptin Sustained Release Tablets in patients with type 2 diabetes
mellitus inadequately controlled on Metformin monotherapy.

Data on file
EFFICACY OF VILDAGLIPTIN & DAPAGLIFLOZIN

Data on file
 ADVERSE EVENT PROFILE
ADVERSE EVENT VILDA SR 100 + DAPA 5 VILDA SR 100 + DAPA 10 SAXA 5 + DAPA 10
Nervous system disorder 03 (3.33%) 02 (2.22%) 02 (2.22%)

Gastrointestinal disorder 05 (5.55%) 04 (4.44%) 03 (3.33%)

Infections and infestations 03 (3.33%) 07 (7.77%) 04 (4.44%)
Musculoskeletal and 02 (2.22%) 01 (1.11%) 02 (2.22%)
connective tissue
disorders
Metabolic disorders 04 (4.44%) 08 (8.88%) 07 (7.77%)
General disorder 01 (1.11%) 02 (2.22%) 03 (3.33%)
Investigations 00 (00.00%) 01 (1.11%) 00 (00.00%)

There were no serious adverse events in the study.

Data on file
PATIENTS ACHIEVING GLYCEMIC TARGET

Data on file
 PHARMACOKINETIC PROFILE
PK PARAMETER VILDAGLIPTIN DAPAGLIFLOZIN

Cmax (ng/ml) 229.16 152.42

AUC0-t (ng.hr/ml) 1649.74 666.29

tmax (hr) 5.00 1.5

t1/2 (hr) 4.64 6.12

The 90% confidence intervals for pharmacokinetic parameters Cmax and AUC0-t
were within the bioequivalence limits of 80.00 to 125.00%.
Data on file
BIOEQUIVALENCE STUDY

Data on file
 SUMMARY
Vildagliptin and Metformin provides better reduction of HbA1c levels as compared to glimepiride-
metformin combination without causing weight gain

Vildagliptin and Dapagliflozin with background Metformin was non-inferior to FDC of Saxagliptin and
Dapagliflozin tablets.

Vildagliptin and Dapagliflozin with background Metformin was found to be safe and well tolerated in
patients with T2DM.

54.44% patients achieved an ADA glycemic target in 16 week duration.

Data on file