Summary | SGLT2 inhibition in cardiology: What is the profile of benefit?

In his presentation, prof. Marx discussed the beneficial effects of SGLT2 inhibition by addressing the mode of action of this drug class, and he presented clinical outcome data and potential mechanisms underlying the observed benefits.

In healthy subjects, glucose is filtered in the glomeruli of the kidneys and reabsorbed by the sodium glucose co-transporters 1 and 2 (SGLT1 and SGLT2) in the proximal tubuli, to avoid urinary glucose excretion [1]. Patients with diabetes, on the other hand, show an increase in glomerular filtration of glucose, and to avoid loss of energy, SGLT2 is upregulated, leading to increased reabsorption of glucose in the proximal tubuli. A new class of anti-diabetic treatment is SGLT2-inhibition, which prevents glucose reabsorption and results in increased excretion of glucose in the urine. In parallel, reabsorption of sodium is inhibited.

This concept has been tested in various clinical trials, with the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG) OUTCOME [2], evaluating empagliflozin versus placebo in a population of subjects with diabetes type 2 (T2DM) at high cardiovascular (CV) risk, and the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program [3], examining the effect of canagliflozin versus placebo, as main trials. Both SGLT2 inhibitors significantly reduced three-point MACE (combined endpoint of CV death, myocardial infarction [MI] and stroke) (HR: 0.86, 95%CI: 0.74-0.99, P-superiority=0.04 and HR: 0.86, 95%CI: 0.75-0.97, P-non-inferiority<0.001, P-superiority=0.02, respectively). In the EMPGA-REG OUTCOME trial, this effect was mainly driven by a highly significant reduction in CV death (HR: 0.62, 95%CI: 0.49-0.77, P<0.0001) and all-cause death (HR: 0.68, 95%CI: 0.57-0.82, P<0.0001), with a number needed to treat of 39 over three years to save one life. In addition, a surprising finding was the significant reduction of hospitalization for heart failure (HF) by the SGLT2 inhibitors (HR: 0.65, 95%CI: 0.50-0.85, P=0.0017), which already became evident after a couple of weeks of treatment. This result has been confirmed in the CANVAS program, in which canagliflozin significantly reduced hospitalization for HF compared to placebo (HR: 0.67, 95%CI: 0.52-0.87), again with a very early separation of the event curves. These data suggest that SGLT2 inhibitors reduce CV endpoints in T2DM patients at high CV risk, most likely through a reduction of HF-related events. Marx showed results of a subsequent analysis of the EMPA-REG OUTCOME trial that demonstrated that HF-related reduction in CV endpoints by empagliflozin was seen in T2DM subjects with or without HF at baseline [4].

Next, Marx focused on traditional risk factors that may be modulated by SGLT2 inhibitors. He started with the observation that there was some glucose-lowering effect in the EMPA-REG OUTCOME and CANVAS program. It is, however, very unlikely that glucose-lowering can explain the effect on CV events, given previous data on glucose-lowering in other trials. There was also some lowering of blood pressure (BP), which may have contributed to the reduction in CV endpoints, but it is unlikely that it solely explains the early separation of the curves. Weight loss was also seen with SGLT2 inhibition. Moreover, experimental data suggest that there is also a reduction in arterial stiffness in treated patients, which may also contribute to the reduction in events. However, even the combination of these effects is unlikely to explain the CV benefits seen in the EMPA-REG OUTCOME and CANVAS trials.

So, what is the underlying mechanism. Overall, there are many hypotheses [5-7], but the amount of data is limited. Recently, a couple of papers were published that addressed effects on hemodynamics and on cardiac metabolism.

Marx started with hemodynamic effects by discussing a study that examined the effect of empagliflozin on certain hemodynamic parameters in 76 T2DM patients and focused in particular on systolic BP as surrogate for afterload [8]. Arterial stiffness affects systolic BP, which has been linked to future CV events. The investigators found a significant reduction in systolic BP upon treatment with empagliflozin, as well as in other parameters. Their results suggest that treatment with empagliflozin for six weeks exerts beneficial effects on vascular function, as well as on central hemodynamics [8].

Marx and his co-workers looked at metabolic effects by using a very different unbiased approach. They treated 25 T2DM patients and CVD with empagliflozin for one month and performed an untargeted serum metabolomic approach [9], meaning that they looked for the pattern change as a result of empagliflozin. The population investigated in this study nicely mirrored the EMPA-REG OUTCOME population. The investigators detected about 1200 metabolites and using statistical analysis they looked for significant changes between before and after one month of treatment. Results showed 162 metabolites that were altered by treatment with empagliflozin, of which 112 were known metabolites. Pathway analysis suggested that SGLT2 inhibition led to increased branched chain amino acid (BCAA) catabolism and expanded ketone body utilization in T2DM patients [10].

But why may this be of importance in subjects with HF or in prevention of HF? Two years ago, data were published suggesting that catabolic defects in BCAA catabolism may promote HF [11]. In HF patients the catabolic activity is reduced, leading to an accumulation of BCAAs, as well as branched chain keto-acids [12]. This has direct effects in the heart, on the one hand by affecting electron transfer chain, leading to the generation of reactive oxygen species and thus oxidative stress, and at the same time these BCAAs can activate the mTOR pathway in the heart. Together, this contributes to heart hypertrophy as well as cardiac dysfunction. Thus, BCAA catabolism is diminished in HF and empagliflozin could potentially restore these defects in catabolism and provide, on the one hand, an optimal energy source for the heart, and on the other hand directly exhibit effects on cardiac function by influencing various signaling pathways.

Altogether, current hypotheses suggest that different processes may contribute to the effects on CV death and HF hospitalization in patients treated with SGLT2 inhibitors [4]. At a very early timepoint, effects on sodium content, volume and hemodynamics may explain the early separation of the curves, while later, mid and long-term effects on cardiac metabolism, cardiac function, cardiac oxygen demand, as well as oxidative stress may contribute to additional separation of the curves after one and two years.

References

Educational information

This is a summary of the presentation given by prof. Nikolaus Marx, during the PACE symposium entitled 'Targeting SGLT2 in clinical cardiology: Exploring the benefits in CV risk, diabetes & heart failure', held during ESC in Munich, Germany, on August 27, 2018.

View the slides