2Dr. Bhavesh Lalan, Manager, Department of Medical Affairs, Lupin Ltd, Mumbai, India
3Dr. Amit Bhargava, VP and Head, Department of Medical Affairs, Lupin Ltd, Mumbai, India
Table 1 represents the data regarding the rates of mortality associated with CVD in persons with T2DM.
|Disease||Author (year)||Patients||n||CVD deaths||% Death rate||% CVD proportion of all deaths|
|CVD||Malik (2015) ||T2DM adults||121,523||3722||3.10%||21.10%|
|CVD||Salinero-Fort (2016) ||T2DM Adults||2442||96||3.90%||47.30%|
|CVD||Salinero-Fort (2016) ||T2DM adults + kidney disease||965||124||12.80%||56.10%|
|CAD||Carnethon (2010) ||T2DM only||659||132||20%||28.20%|
|CAD||Carnethon (2010) ||T2DM + CVD||260||111||42.70%||50.70%|
|CAD||Jackson (2012) ||Male diabetics||116,145||6000||5.20%||27.20%|
|CAD||Jackson (2012) ||Female diabetics||100,507||4554||4.50%||22.10%|
|CHF||Mazza (2007) ||Male diabetics||202||22||10.90%||------|
|CHF||Mazza (2007) ||Female diabetics||379||29||7.70%||------|
|MI||Shestakova (2016) ||T2DM adults||3,060,516||3393||0.10%||5.10%|
|SCD||Kucharska-Newton (2010) ||T2DM adults||1550||69||4.50%||----|
|Stroke||Jackson (2012) ||Male diabetics||116,145||1942||1.70%||8.80%|
|Stroke||Jackson (2012) ||Female diabetics||100,507||2436||2.40%||11.80%|
As demonstrated in table 1, T2DM increases the propensity of CVD. The current need is to find a therapeutic measure which is not only fast acting but also provides sustained beneficial effects on glycemic control thereby delaying the onset and progression of CVD.  Current trends suggest the use of fixed dose combinations comprising of agents having complementary actions to reduce macrovascular complications. One such combination is empagliflozin and linagliptin.  Linagliptin is known to enhance levels of postprandial insulin and decrease glucagon secretion following food intake. [9,10] Also, linagliptin elevates insulin secretion and reduces glucagon secretion in a glucose-dependent manner, thereby reducing the probability of hyperglycemia with minimal risk of hypoglycemia.  Additionally, current literature suggests that it is weight neutral. 
A reduction by 38%, 35%, 34% in CV mortality, HF hospitalization and a composite of CV mortality or HF hospitalization respectively was noted in T2DM patients with concomitant CVD in the EMPA-REG OUTCOME trial. These outcomes appeared identical in those with/without a pre-existing diagnosis of HF at the baseline.  These findings were in accordance with another analysis stating similar effects of empagliflozin on CV mortality and HF hospitalizations.  These analyses therefore further reinforce the recent ESC HF guideline, stating an important and indispensable role of empagliflozin in T2DM patients for preventing and delaying the onset of HF, thereby improving the life expectancy. 
P/O ratio indicates the number of ATP molecules produced per oxygen atom reduced by the mitochondrial electron transport chain.
It was demonstrated in a CV meta-analysis that linagliptin may either have a beneficial or a neutral effect on CV outcomes in a significant number of patients with T2DM compared with control treatments. Furthermore, the risk for CV events was unchanged, or lowered, across several pre-specified subgroups based on key demographic and clinical characteristics. These results include comparisons with placebo, as well as two active comparators, namely glimepiride and voglibose, either as monotherapy or in combination with common oral glucose-lowering drugs. 
Current evidence suggests that both empagliflozin and linagliptin have favorable cardiovascular data. Additionally, it has been reported that the combination treatment with empagliflozin and linagliptin in drug naïve patients,  where metformin therapy failed  and in patients where intensive glycemic control is indicated that cannot be achieved with dual therapy of metformin and empagliflozin or linagliptin [35,36] is efficacious and demonstrated significant reductions in HbA1c and FPG. Furthermore, treatment with this combination showed added benefit of BP and weight reduction which are established CVD risk factors. Also, the glycemic control with this combination was sustained for a period of 52 weeks indicating lesser chance of glycemic variability. [34-37] This may further support the CV safety of this combination.
Authors are employees of Lupin Ltd.
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