13 responses to “What are the CV risks of TZDs: have the safety questions been answered?”

  1. I think this gives us guidance in the use of TZDs with all the differing opinions floating out there. It is a balanced, cautious approach until more confirmatory evidence comes to light which is quite helpful.

  2. Good summary of the evidence and good decision support for practice. Are you aware of any existing (well designed, specific to this question) study to clarify the cardiovascular risk?

  3. A major trial is underway, sponsored by GlaxoSmithKline (manufacturers of Avandia), called the Thiazolidinedione Intervention With Vitamin D Evaluation (TIDE) trial.

    This study will test the cardiovascular effects of long-term treatment with rosiglitazone or pioglitazone compared to standard of care in patients with type 2 diabetes with a history or risk of cardiovascular disease.

    The second question will compare the effects of long-term supplementation of vitamin D on death and cancer.

    The enrollment will be 16,000 subjects (large trial), but the expected completion date is not until 2015. So, the question will remain open until that time.

  4. I have definitely seen Avandia associated with worsened macular edema in my patients. Most of my patients are no longer on this drug for diabetes.

  5. A clear summary of an approach. Everyone agrees to start with metformin. Are sulfonylureas not the most commonly used second agents? I have tended to use these two agents and then go to insulin.

  6. A clear summary of an approach. Everyone agrees to start with metformin. Are sulfonylureas not the most commonly used second agents? I have tended to use these two agents and then go to insulin.

  7. There are lots of benefits of using TZDs in patients with T2DM. What I do?
    Although not fully conclusive, but once there are reports of increased CV events and controversies regarding rosiglitazone since 2007, I have deleted rosiglitazone from my prescription list but continuing pioglitazone.
    Pio acts as a PPAR-gamma agonist and in addition to this it has also PPAR-alpha stimulating activity to a lesser extent.
    Pio leads to weight gain but this weight gain mainly due to increase in subcutaneous fat (not visceral) having high adiponectin activity.
    Of course I categorically avoid pio to patients with heart failure having II, III, IV stages according to NYHA classification.
    Once mono-therapy is required, if patient can not tolerate metformin (it must be the first line) why not to go for pio before going to SU to preserve residual beta cells?

  8. It’s a real shame there is only one agent with benefits on hard clinical endpoints – metformin. It’s one thing to lower the a1c, but unless there’s benefits on CV, renal, eye and neuropathy, we are fooling ourselves we are making a meaningful difference. Sulfonylureas, TZDs, insulin – all have very shaky evidence for benefit and some evidence of harm (wt gain, increased insulin resistance, CHF), despite the improvements in a1c.

  9. The benefits of improved glycemic control on microvascular complications of diabetes, such as retinopathy, nephropathy and neuropathy, have been confirmed in several large studies (DCCT, UKPDS, ADVANCE). The cardiovascular benefits are less well established, but appear to be evident if good glycemic control is started at a younger age, before the duration of diabetes is > 15 years. Trials, such as VADT and UKPDS 10-year follow-up suggest that patients with better glycemic control early in the course of their disease have lower rates of CV events in the future. However, once CVD is estastablished, the clear benefits of tight glycemic control become less evident.

    I recommend using any and all appropriate agents (including TZDs) in younger patients, to reduce the long-term risk of CV complications. However, once CV disease or CV risk factors are established, more caution is needed in selecting agents and establishing glucose targets.

  10. In the poll section at the end of the article, you should maybe think of putting tick box for “I already do this”, because in this case, well, I already do this! :)

  11. In July 2010, the United States FDA held Avisory Committee hearings on the cardiovascular safety of Rosiglitazone (Avandia). The conclusions were mixed and no firm consensus was reached about the overall CV risk of Avandia or of TZDs in general.

    On July 21st, the TIDE trial was placed on partial clinical hold, so that no new patients could be enrolled, but patients already enrolled would be allowed to continue in the trial. This would allow time for the participating IRBs to review the FDA findings and update consent forms as needed. It is not yet clear whether the trial will be halted entirely.

    Overall, no fundamentally new data arose from the FDA hearings. The evidence was not sufficient to draw a firm conclusion about the CV risks of Avandia or TZDs in general.

    It is up to each individual practitioner to make his/her own decision regarding the safety of TZDs. One could argue that, since there are other ways to treat diabetes, we can avoid TZDs altogether. However, although I am cautious about the use of TZDs, I continue to feel that these agents have a role to play in certain diabetic patients (mostly young (<50), obese men). Also, there is growing evidence for benefit of TZDs in non-diabetes settings, such as non-alcoholic steato-hepatitis (NASH).

    Unfortunately, until we have more evidence, practitioners will have to manage with uncertainty.

  12. Hmmn- maybe ‘normalizing’ blood sugar in this fashion doesn’t correct the underlying issues- we need to understand what they are. Maybe this makes cells ‘sicker’.
    I had great response with Actos in a number of very ill type 2 diabetic patients with CHF and renal failure. I saw them almost weekly and worked very hard together to manage BP/ glucose/ diet/ weight and all the metabolic abnormalities that arise in this group PLUS the CHF component.
    I wonder – many things. Were these patients adequately managed for BP. cholesterol!!! etc/
    And again the underlying deficit in type 2 diabetes is obesity/ glucose intolerance ( I have met skinny elderly type 2 diabetics) That is what really needs correction- bariatric surgery is more effective than anything. —
    Be simpler if people could just stop eating-eh?

  13. The benefits of TZDs are modest as far as I can tell. As some of the previous commentators have suggested, using metformin, salphonylureas and insulin seems a tried and trusted approach.

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