Does Dapagliflozin Regress Left Ventricular Hypertrophy In Patients With Type 2 Diabetes?
Condition: Type 2 Diabetes; Left Ventricular Hypertrophy
MeSH terms: Hypertrophy, Left Ventricular; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypertrophy
Study type: Interventional
Phase: Phase 4

Summary: 
      Left ventricular hypertrophy (LVH) is common in people with type 2 diabetes (70%) and is the
      strongest independent risk factor for cardiovascular events and all-cause mortality that
      there is. It is worse than triple vessel coronary disease. LVH often occurs in patients with
      "normal" blood pressures (BP). Apart from BP, the other three main factors causing LVH are
      insulin resistance, obesity and cardiac preload. Dapagliflozin reduces ALL four factors known
      to promote LVH i.e. Dapagliflozin reduces weight, glycaemia, preload and blood pressure and
      is therefore the ideal agent to reduce LVH since it uniquely attacks all four known mediators
      of LVH. This trial will investigate the ability of dapagliflozin to regress LVH in 64
      participants with normotensive diabetes. This will be done by seeing if dapagliflozin reduces
      left ventricular mass as measured by cardiac magnetic resonance imaging (MRI). This trial may
      identify a novel way to reduce the strong independent risk factor of LVH which often persists
      despite optimum medical therapy in patients with diabetes. If dapagliflozin does reduce LVH,
      this would be a key sign of which subgroup of patients with diabetes (those with LVH) should
      be especially targeted with dapagliflozin.

      64 participants with type 2 diabetes and LVH will be recruited through the Scottish Diabetes
      Research Network (SDRN), Scottish Primary Care Research Network (SPCRN) and other routes, in
      this single centre study. Participants will be randomised to receive either 10mg
      dapagliflozin or placebo daily for 12 months. Cardiac MRI will be performed at baseline and
      at 12 months, this will be assessed for the primary outcome of change in left ventricular
      mass. Secondary outcomes will examine change in 24 hour blood pressure and weight.
    

Detailed description: 
      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.
    

Intervention name(s): Dapagliflozin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): SGLT2 inhibitor; Matching Placebo
Other intervention name(s): Forxiga
Intervention MeSH terms: Dapagliflozin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Type 2 Diabetes; Left Ventricular Hypertrophy; Dapagliflozin