Empagliflozin reduces CV morbidity and mortality, nephropathy in T2DM patients
EMPA-REG OUTCOME trial
“The incidence of CV morbidity and mortality is about two- to three-fold higher in patients with T2DM compared with the background population,” said Ferrannini.
Empagliflozin reduces CV events, CV and all-cause mortality
In the randomized, double-blind, EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in T2DM Patients) of 7,020 patients with T2DM at high CV risk who were treated with either empagliflozin 10 mg, empagliflozin 25 mg or placebo, a significant 14 percent risk reduction in the primary composite endpoint of three-point major adverse CV events (MACE; CV mortality, nonfatal MI or nonfatal stroke) was seen in the combined empagliflozin group vs placebo (hazard ratio [HR], 0.86; p< 0.001). [N Engl J Med 2015;373:2117-2128]
Patients given empagliflozin were also noted to have significantly lower risks of death from a CV cause (HR, 0.62; p<0.001), all-cause mortality (HR, 0.68; p<0.001), and hospitalization for heart failure (HR, 0.65; p=0.002) compared with placebo. (Figure 1)
The reduction in heart failure hospitalization or CV death was consistent between patients treated with both empagliflozin doses. [Eur Heart J 2016;37:1526-1534]
“HbA1c levels in the empagliflozin group were lower as compared with the placebo group [adjusted mean difference vs placebo: empagliflozin 10 mg, −0.54; empagliflozin 25 mg, −0.60]. There were also reductions in body weight, systolic and diastolic blood pressure and serum uric acid levels over the course of the study,” Ferrannini added.
“What these results suggest is that empagliflozin treatment was actually impacting on case fatality rather than just the number of incident events. We can now modify the natural history of T2DM in terms of the most feared complication – CV disease – which has not been possible previously,” Ferrannini explained.
Mortality results of other landmark CV trials
To illustrate the magnitude of impact of empagliflozin treatment on all-cause mortality, Ferrannini compared the results of the EMPA-REG OUTCOME trial with several landmark CV studies.
The SOLVD trial (Studies of Left Ventricular Dysfunction) in patients with chronic heart failure with reduced ejection fraction showed a 16 percent reduction in all-cause mortality with enalapril vs placebo (p=0.0036). In the HOPE study (Heart Outcomes Prevention Evaluation Study), in patients with evidence of vascular disease or diabetes plus one other CV risk factor, ramipril reduced the rates of CV mortality by 26 percent and all-cause mortality by 16 percent vs placebo. (Figure 2) [N Engl J Med 1991;325:293-302; N Engl J Med 2000;342:145-153]
In the PARADIGM-HF study in patients with heart failure with reduced ejection fraction, the combination of sacubitril and valsartan reduced all-cause mortality by 16 percent vs enalapril. [N Engl J Med 2014;371:993-1004]
In the MERIT-HF study, treatment with metoprolol resulted in a 19 percent reduction in all-cause mortality vs placebo (p<0.001) among patients with symptomatic heart failure with reduced ejection fraction. [JAMA 2000;283:1295-1302]
In the 4S trial (Scandinavian Simvastatin Survival Study), simvastatin use decreased all-cause mortality by 30 percent in patients with coronary heart disease. [J Card Fail 1997;3:249-254]
“In terms of CV mortality, the strongest weapon in our hands is statins. But empagliflozin did just as well as statins, because it significantly reduced all-cause mortality by 32 percent in the EMPA-REG OUTCOME study,” said Ferrannini.
Empagliflozin’s CV protection: Metabolic, haemodynamic and intra-renal mechanisms
Inhibition of SGLT2 receptors will cause renal glucose excretion. The persistent glycosuria will cause a shift in preference from carbohydrate metabolism towards fat metabolism for energy production, similar to being in a fasting state. This shift is seen in both diabetics and nondiabetics. [Diabetes 2016;65:1190-1195]
The low fasting and postprandial plasma glucose concentrations cause a decrease in insulin levels, which then results in a concomitant increase in lipid oxidation and beta-hydroxybutyrate levels. [Cell Metab 2017;26:27-38] “This is important in cardiac physiology because these ketones are the preferred fuel of the heart, and are directly channelled into the mitochondria to be completely oxidized in an energetically efficient way. This means a higher cardiac output with lower oxygen consumption,” explained Ferrannini.
There is also an increase in tissue oxygen delivery because of a 3–5 percent increase in haematocrit in the empagliflozin group regardless of baseline estimated glomerular filtration rate (eGFR), which was evident from the 12th week of treatment and maintained throughout the 3.1-year observation period. This increase in haematocrit may be from haemoconcentration due to changes in circulating volume secondary to diuresis and natriuresis, but it may also be from an increase in erythropoietin concentration. [Diabetes Care 2016;39:1108-1114; J Clin Med Res 2016;8:844-847]
“This increase in haematocrit is the only factor with a more than 50 percent contribution to empagliflozin’s CV mortality benefit, according to an analysis to be published shortly,” said Ferrannini.
Because SGLT2-induced urinary glucose excretion is dependent on glomerular filtration, the magnitude of HbA1c decrease from baseline is lower in patients with poorer renal function compared with patients with a higher eGFR at the beginning of the trial. Despite this blunted effect on glycaemic control, baseline renal function did not have an effect on the magnitude of weight loss or the decrease in systolic blood pressure from empagliflozin therapy. [N Engl J Med 2015;373:2117-2128]
Empagliflozin also improves renal outcomes
Renal outcomes from the EMPA-REG OUTCOME trial, such as incident or worsening nephropathy (defined as progression to macroalbuminuria [ie, urinary albumin-to-creatinine ratio, >300 mg of albumin/gram of creatinine]), doubling of serum creatinine level, initiation of renal-replacement therapy, or death from renal disease, were also in favour of empagliflozin vs placebo. [N Engl J Med 2016;375:323-334]
Incident or worsening nephropathy was reduced in the empagliflozin group (both 10 mg and 25 mg doses) vs the placebo group (12.7 vs 18.8 percent; HR, 0.61; p<0.001). (Figure 3)
Treatment with empagliflozin also resulted in a 38 percent reduction in the risk of progression to macroalbuminuria vs placebo (HR, 0.62; p<0.001), along with a 44 percent reduction in the risk of doubling of serum creatinine level (HR, 0.56; p<0.001) and a 55 percent reduction in the risk of initiation of renal replacement therapy (HR, 0.45; p=0.04).
“There was an initial decrease of about 10 percent in eGFR in the empagliflozin vs placebo group, which gradually improved toward the first year of treatment. At the end of the trial, the eGFR values were stabilized and levelled off in the empagliflozin arm but a linear decrease was seen in the placebo arm. This shows that empagliflozin prevented renal damage and protected the kidney against further damage,” noted Ferrannini.
“It is also important to note that 80.7 percent of patients in the study were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers at baseline. These positive renal results were observed in a population of patients whose blood pressure was well managed with extensive use of renin-angiotensin-aldosterone system blockers – the recommended treatment for kidney disease in patients with T2DM,” he added.
Empagliflozin significantly decreased CV morbidity and mortality in patients with T2DM. Its long-term use also lowered the incidence of worsening nephropathy. “In the treatment of diabetes, it is not sufficient to lower HbA1c only. It is also important to reduce mortality and nephropathy and subsequently improve the quality of life of our patients,” Ferrannini concluded.