Does Dapagliflozin Regress Left Ventricular Hypertrophy In Patients With Type 2 Diabetes?

Left ventricular hypertrophy (LVH) is present in the majority of patients with type 2 diabetes, since it affects 70%. It is a strong independent predictor of cardiovascular deaths and events and is even worse than triple vessel coronary disease. The reason why LVH is so adverse is because it predates so many different cardiovascular events i.e. LVH is intrinsically arrhythmogenic and causes sudden death, it impedes left ventricular (LV) filling and leads to diastolic heart failure, it reduces coronary perfusion reserve and causes ischaemia and it causes left atrial enlargement, atrial fibrillation (AF), and cardio-embolic strokes. Controlling blood pressure (BP) and using a drug that blocks the renin-angiotensin system (RAS) are the standard approaches to the management of LVH but this approach is only partially effective since 44% of all patients with type 2 diabetes are normotensive patients with LVH. Thus "normotensive LVH" is very common. Indeed, BP only contributes 25% to the variability in LV mass seen in a population. (This is important since LVH is the same thing as a high level of LV mass). Despite a "normal" BP, normotensive LVH is just as risky as is hypertensive LVH. Nevertheless, we do know that regressing LVH irrespective of BP changes is an effective way to reduce the incidence of all major cardiovascular (CV) events including specifically sudden deaths, heart failure hospitalisations, new onset AF and strokes. The Losartan Intervention For Endpoint reduction in hypertension study (LIFE) provides conclusive proof that in diabetes, LVH regression per se reduces future cardiovascular events (by 24%), reduces CV deaths (by 37%) and reduces total deaths (by 41%) irrespective of BP.

Since controlling BP and using an angiotensin enzyme inhibitor or angiotensin receptor blocker is only partially effective at regressing LVH, additional ways of regressing LVH are now required. Insulin resistance is another mediator of LVH. The literature is awash with observational studies linking insulin resistance to LVH. Pub Med identifies 67 such papers, 5 of which are inconclusive. In the remaining 62 papers, 46 identify a significant relationship between LVH and some measure of insulin resistance while 16 found no such relationship. The large studies are mostly positive which includes Framingham, the Whitehall trial, the Strong Heart trial and the Women's Health Initiative trial while the Hypertension Genetic Epidemiology Network (HyperGEN) trial is the one large negative trial. There are a multitude of mechanisms whereby hyperinsulinaemia should produce LVH e.g. through signalling pathways such as Akt, transforming growth factor and peroxisome proliferator-activated receptors, through increased myocardial free fatty acid oxidation and through RAS activation causing sodium retention and thus increased cardiac preload. Therefore, it is likely that glycaemia contributes to LVH. However, reducing glycaemia per se appears to be insufficient to reduce CV events and key ancillary properties of each anti-glycaemic drug will be necessary to deliver the CV benefits we so badly need in diabetes.

A separate albeit related factor mediating LVH is obesity. Importantly, dapagliflozin has been shown to reduce weight. Thus the ideal treatment to regress LVH might be one that not only improves glycaemia but one that also aids weight loss. Dapagliflozin is the obvious option here since it has been shown to reduce both glycaemia and weight. Metformin is the only other anti-glycaemic which reduces both glycaemia and weight. Indeed the reason metformin reduces CV events in diabetes while other anti-glycaemic agents do not could well be in part because metformin reduces both glycaemia and weight which then reduce LVH (in fact we already have a separate British Heart Foundation grant to see if metformin really does reduce LV mass).

However dapagliflozin has other unique effects on the CV system which will impact on LVH. Dapagliflozin reduces blood pressure (LV afterload) and this by itself should also further reduce LVH. Further reducing BP even in normotensive patients has been shown to definitely regress LVH. Dapagliflozin also has diuretic effects which should reduce preload on the heart (this will be measured preload in this trial by MRI assessed end diastolic volume). The fact that dapagliflozin reduces both preload and afterload on the heart makes it uniquely promising as a way to reducing future CV events in patients with diabetes and, here, in reducing LV hypertrophy. Thus, dapagliflozin should regress LVH in patients with diabetes because it is unique in reducing the four main causes of LVH: glycaemia/insulin resistance, weight, preload and blood pressure. No other anti-diabetic medication alters even three of these. Even metformin only alters two since it does not change blood pressure. All other diabetic medications only reduce one (glycaemia) of these mediators of LVH. This may be why other new anti-glycaemic agents have failed to reduce CV events. In this trial, it is proposed to trial whether dapagliflozin causes regression of the independent cardiac risk factor of LVH in diabetic participants on optimal current evidence based therapy.

Original Hypothesis

Dapagliflozin will regress LVH in normotensive participants with type 2 diabetes.

RATIONALE FOR TRIAL

Cardiac MRI will be used to assess whether Dapagliflozin regresses LV mass more than placebo does over a one year treatment period. If it does, this would strongly suggest that Dapagliflozin will reduce CV events especially in the 44% of patients with type 2 diabetes who have LVH despite a controlled blood pressure.

All studies examining LVH regression require to be parallel group studies as effects on LV mass take 6-12 months to occur. Hence this is a parallel group, one year trial of the active drug vs. placebo.

The issue of what dapagliflozin does to CV events in diabetes is a hot topic. Most new antidiabetic drugs have been neutral or harmful but, judging by its pharmacological effects, it is quite possible that dapagliflozin might reduce CV events. A large ongoing trial (Dapagliflozin Effect on CardiovascuLAR Events - Thrombolysis in Myocardial Infarction (DECLARE - TIMI)) is just beginning to look at this. Why therefore do we also need to trial the effects of dapagliflozin on LV mass in those with LVH? If DECLARE-TIMI shows clearly that dapagliflozin reduces CV events, then our trial will have revealed a possible contributing mechanism to the reduced CV events i.e. LVH regression (patients in DECLARE-TIMI will not receive echocardiography so that subgroup analysis will not be able to answer this question and electrocardiograms are useless at identifying LVH. Furthermore, the accuracy of MRI over echo is so great that echo studies of LVH regression should no longer be considered reliable).

In other words, large mega-trials like DECLARE-TIMI are very valuable, but parallel smaller mechanistic studies like this can enhance their value by helping to explain the mechanisms producing the mega-trial results and/or helping to identify a subgroup who get a particular benefit meaning that the drug becomes more cost effective in that subgroup. Overall, this trial might, in conjunction with a mega-trial, help decide the course of future research (should LVH be a favoured target?) and help decide how to apply the results of a mega-trial in clinical practice.