List of therapies that reduce cardiovascular mortality in diabetes

I’m giving grand rounds on Tuesday on SGLT2 inhibitors and I’m trying to come up with a list of therapies that lower CV death in diabetes.

Here is my list:

  • Blood pressure control
    • UKPDS
    • ADVANCE All-cause mortality was reduced with a near miss on CV mortality (P=0.041)
  • Empagliflozen
  • Canagliflozin
    • CANVAS Only partial credit here. CV death was part of the composite outcome, but CVD was not significant on its own
  • Semaglutide
    • SUSTAIN-6 Weak. Hit the primary outcome but CV death was explicitly identical between groups
  • Liraglutide

Drugs that have run the FDA CV disease gauntlet and that are non-inferior to standard of care:

  • Exanatide
  • Rosiglitazone
  • Pioglitazone
  • Alogliptin
    • EXAMINE (This is a secondary prevention trial. As far as I can tell it is the only FDA mandated outcome trial that is specifically designed as a secondary prevention. Not sure why.)
  • Saxagliptin
  • Degludec


I’m sure I’m missing some. There must be a statin trial of diabetics. Right?


Swapnil was first with the statin answer:

And Edgar came up with a great visual from a review paper:

And Szymon came up with the Steno trial. I can’t believe I forgot about that one.


AASK: a cautionary tale for bardoxolone?

Robert Leversee had some questions regarding my presentation on diabetic nephropathy. You can see his concerns in the comments after the post. he was specifically concerned about this slide.

Robert felt it minimized the GFR gains found with bardoxolone. What is not clear from the deck is that 56 weeks, represents the GFR one month after stopping the drug. In the lecture, I pointed out that patients that were on bardoxolone all had a higher GFR than at baseline, while patients randomized to placebo had a lower GFR.

As a reminder, the primary end-point of the study was the change in GFR at 24 weeks and that was dramatic.

The reason I included the slide showing the 56 week data was my concern that bardoxolone may be pulling a creatinine slight of hand. My personal concern is that the changes in GFR are due to simple hemodynamic changes like were seen with amlodipine in AASK.

AASK was a trial of hypertension therapy in African Americans with a renal end-point rather than a cardiovascular end-point that are more common in hypertension trials. The trial is a two by three design with two blood pressure targets (MAP 102-107 vs <92) and three blood pressure medications (amlodipine, ramipril, metoprolol).

The data is difficult to interpret because the amlodipine caused an acute hemodynamic-related bump in the GFR, but after 12 months the loss of GFR in the amlodipine group was faster than with ramipril. The study designers designated co-primary end points, a total change in GFR and a chronic change in GFR that ignored the initial 3 months.

Ramipril was superior to amlodipine in the chronic phase but not in the total change in GFR. Though this ambiguity was not represented in the conclusions of the trial:

The fact that amlodipine improved renal function for one year makes me nervous about the one year duration of the bardoxolone study. Thankfully BEACON is in full swing enrolling patients so a definitive answer is just ahead.

And the data keeps rolling in…

I am a believer in Richard Johnson’s theory regarding fructose uric acid and hypertension/CKD. So I love it when I see another study adding to the foundation. This from Diabetes Care. The investigators looked at 1500 patients with diabetes and normal renal function and no proteinuria. Over 5 years they tracked who developed CKD (either GFR<60 or proteinuria):

During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD.

The problem with numbers, the curse of intermediate end-points

The curse of treating chronic kidney disease is that one is always treating patients to the numbers:

  • Blood pressure. I need to get my patients below 130/80
  • Cholesterol. I need to get their LDL below 100
  • Metabolic bone disease. I need to keep their PTH
    • KDOQI 
      • Stage 3: 35-70
      • Stage 4: 70-110
      • Stage 5: 150-300
    • KDIGO
      • In patients with CKD stages 3–5 not on dialysis, in whom serum PTH is progressively rising and remains persistently above the upper limit of normal for the assay despite correction of modifiable factors, treatment with calcitriol or vitamin D analogs is suggested. (hey KDIGO, thanks for the guideline)
  • Diabetes. I need to keep their Hgb A1c less than 7
  • Anemia. I need to keep their hemoglobin
But these numbers are all intermediate, and from a patient perspective, pretty abstract. Patients don’t get PTH angina. Targetting the numbers is a way to shift the odds toward better patient outcomes, to load the dice in the patient’s favor. However we cannot allow the numbers to substitute for the real goals of care. I don’t really care about your blood pressure, I just want to prevent the heart failure, dementia, kidney failure, stroke and erectile dysfunction that result from the high blood pressure. If you give me a pill that magically improves the blood pressure but doesn’t avoid those end-points I’m not interested.
But as the number game has become a larger part of medicine we are getting medications that are pursued and approved only for their ability to fix the numbers. Some have been super successful, statins have repeatedly and reliably shown their ability to reduce events in lockstep with reducing the cholesterol. Lately however, it is feeling like success of the statins to reduce LDL and also reduce cardiovascular events maybe more the exception than the rule.
The recent experience with ESAs and hemoglobin have been beat to death in the nephrology community. See this post for a deep dive. The core issue, is that low hemoglobins are bad for patients, but using ESAs to improve the hemoglobin does not mitigate the risk. And not only does it not mitigate the risk, it appears that the current agents bring with them novel arterial and venous thrombotic risks.
The experience with A1c seems to be playing out using a similar script. Glitazones were approved based on their ability to reduce blood sugars. They effectively lower blood sugar but Rosiglitazone increased the risk of cardiovascular death by 64% and was associated with increased composite outcome of stroke, heart failure and total mortality compared to pioglitazone.
And June 9th pioglitazone was pulled from the shelves in France for increased risk of bladder cancer. A position validated by the FDA on June 15th.
This comes on the heals of three studies in 2008 and 2009 that question the notion of very tight (less than 7%) hemoglobin a1c targets to improve patient outcomes.
In cardiology, following the stunning success of statins and LDL we have a string of failures, Ezetimibe (Zetia/Vytorin) for LDL and niacin/torcetripib for HDL
I often feel the only reason we still treat PTH is that no one has done the study to show that it helps and when we get around to that trial, I’m looking at you Abbott, we will find that it too, has been a waste of money and attention.

iPhone: the ultimate tool for patient empowerment.

I walk into a patient’s encounter today and he is reading Twitter on his iPhone 4. We exchanged Twitter handles and began discussing his diabetic nephropathy.

I ask how his blood sugars have been and he fires up Glucose Buddy and proceeds to show me all of his blood sugar reading since March of 2010. Then he e-mails me the data.

When we discuss blood pressure, he fires up the iPhone again and shows me iBP. When he sends me his home blood pressure readings I get the choice of receiving them as text, html or CSV. Awesome.

Glucose Buddy for the iPhone
iBP for the iPhone

Here’s is what the e-mail output looks like:

This was the first patient I have met who is using his phone to document his health. I hope this is a trend because I am sick of patients telling me that they wrote down all of their blood pressures but left the notebook at home. It’s nice to see a cell phone do something other than interrupt a clinical encounter.

I just gave the world’s greatest lecture on diabetic nephroapthy

It was incredible. The residents, who usually sleep through the second half of noon conference, were completely charged up and by the end of the lecture were holding up lighters and chanting my name. I dove from the stage and was passed around like a Rock God.
Here is the lecture in powerpoint format to download. You can also see the Slideshare but they mangle the animations so if you want to really feel the educational frenzy download the .ppt.

Hemoglobin A1c of 18.6

That corresponds to an average blood sugar of 486!
Six months and 1,500 mg of metformin later it is down to 8.4% corresponding to an average of 194. That 18.6 has got to be an error. Right? Right?
Unfortunately for her GFR is 30 mL/min.
No metformin for you.

Journal Club: Aggrenox and AVG for TZDs in HD

Dixon et al. Effect of dipyridamole plus aspirin on hemodialysis graft patency. N Engl J Med (2009) vol. 360 (21) pp. 2191-201 (PDF)

Randomized placebo controlled double blind trial of patients on hemodialysis or to start hemodialysis in the next 6 months with a new AVG.

Primary outcome was loss of primary unassisted graft patency. thrombosis, 50% stenosis. Patients underwent regular site monitoring and referred for angiography if qB was less than 600 or less than 1000 and a greater than 25% reduction of qB.

Power analysis required 1054 patients.

results: 321 randomized to Aggrenox
328 assigned to placebo

No difference in bleeding or cardiovascular events.

Take home message: modest benefit from expensive drug in underpowered but well designed and executed study.

Brunelli et al. Thiazolidinedione use is associated with better survival in hemodialysis patients with non-insulin dependent diabetes. Kidney Int (2009) vol. 75 (9) pp. 961-8 (pdf)

Thiazolidinediones (TZDs)

  • bind peroxisome proliferator-activated receptor gamma
  • increase insulin sensitivity in peripheral tissues
  • increase HDL
  • decrease triglycerides
  • decrease visceral fat
  • improve endothelial function

This study is a retrospective analysis of hemodialysis patients in the ArMORR cohort.
ArMORR is a cohort of incident dialysis patients at FMC units. The total cohort includes 10,044 patients.

This analysis restricted to patients with diabetes surviving at least 30 days on dialysis.

Patients on pioglitazone (Actos) or rosiglitazone (Avandia) were placed in the TZD group. Primary outcome was time to death from any cause. Maximum follow-up was one year.

Results: 5,290 patientss were eligible for inclusion.
9.6% were treated with a TZD

Improved survival was seen among patients on TZDs, especially patients not also on insulin. Interestingly the survival benefit came from a reduction of non-CV end-points.

Hey my diabetic nephropathy lecture is in the spotlight

This morning I woke to find this in my in-box:

Hi nephron!

Your presentation Diabetic Nephropathy is currently being showcased on the ‘Health & Medicine’ page by our editorial team.

It’s likely to be there for the next 16-20 hours…


– the SlideShare team

And here it is:

Here is the actual lecture. I would recommend going to the SlideShare website and downloading the lecture as it looks a lot better in PowerPoint than in the online presentation. You will need to establish a SlideShare account to download the presentation.