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.


I’m reading the January NephSAP on primary care for the working nephrologist

There is some great stuff in there. This line on the futility of cancer screening among dializers struck me as particularly interesting:

[Kajbaf et al.] calculated the maximum increase in life expectancy (for a 60-yr-old woman) from routine Papanicolaou (Pap) testing and mammography to be 3 and 2 days, respectively.

Wow. (Ref PDF)

I feel like dialysis is always geting beat up over the high yearly mortality rate, and admittedly it is high. So it was interesting to see this table of some other conditions and there associated mortality. I didn’t realize dialysis had such familiar company.

Happy July 1st, and don’t worry about the July phenomenon. All myth.

According to this article in Newsweek from last July:

the July medical-training period is associated with between 1,500 and 2,750 accelerated deaths every year. In a study of the July phenomenon from which initial findings were released in 2005 by the National Bureau of Economic Research, Harvard Business School health-care economists Robert Huckman and Jason Barro compared mortality rates in teaching and non-teaching hospitals around the country. They found that there are 4 percent more incidences of accelerated death in average-sized teaching hospitals in July and August.

They also found length of stay increased 2%. It is not clear from the above paragraph but the 1,500 to 2,750 deaths is also part of the same study by Huckman and Barro. A good review of the paper is found on this blog, A New Start. Here is a link to the abstract, full article costs $5.

A study done on hospitals in Ohio found no increase in mortality in ICU patients admitted in July through September. It looks like a massive study with rigorous methodology and it is more recent by nearly a decade.

In analyses of over 48,000 patients admitted to ICUs in 5 major teaching hospitals, using a validated method of adjusting for admission severity of illness, several important findings emerge. First, in-hospital mortality and LOS were similar in patients admitted to intensive care units from July through September and during later months of the academic year. Moreover, results were consistent when July, August, and September were analyzed separately, and there was no discernible pattern of variation when examining outcomes for individual months over the entire year. Furthermore, we were unable to detect differences when individual academic years, surgical and nonsurgical patients, and individual hospitals and ICUs were examined separately. These results were all similar in analyses of roughly 108,000 patients admitted to minor teaching and nonteaching hospitals.

With its unremarkable findings and disruption of the common wisdom is it any wonder that it is given short shift in the Newsweek article.

Journal Club: low protein diet

Effect of a very low protein diet on outcome: long-term follow-up.

This is the long-term follow-up of the B group from the original MDRD study.
Enrollment criteria:
  • Age: 18-70
  • Abnormal Cr 1.2-7 women 1.4-7 in men.
  • MAP of 125 or less (160/100)
  • Proteinuria less than 10g per day
  • No diabetics
GFR 13-24 mL/min for the B study (low protein versus very low protein diet). Higher GFR were enrolled in the A study (normal protein versus low protein diet).
Protein was restricted for 3 years.
9 months after the study every nutritional parameter was the same between the two groups.

The primary end-point was a composite of death or dialysis and just about every patient in both groups (95.7%) reached this end-point preventing a separation between the groups (p=0.5). Likewise there was no separation with regards to time to dialysis (p=0.4).

The surprising finding occurs when they looked at death after the initiation of dialysis. There were 34 deaths in the very low-protein group and 19 deaths in the low-protein group (p=0.01).

The separation begins around 15 months and grows over time. This difference was statistically significant and grew to a 2-fold increased risk of death after 6 years.

My take is this fits well with what I tell my patients when they ask me about protein restriction. I have always counseled patients against protein restriction. The two largest RCT were both negative trials (The Modification of Diet in Renal Disease and the Northern Italian Cooperative Study Group). Additionally my patients do not have the benefit of dedicated and repeated nutritional couseling that the patients in these trials receive. My fear is that with little therapeutic upside there is signifigent risk of malnutrition from overzealous protein restriction.

This study probably does not apply to my worry as I doubt patients would adhere to a very low-protein diet.

My other concearn regarding low-protein diets is patients need to get calories from somewhere. Calories can only come from protein, carbohydrates or fat. Considering that the vast majority of CKD patients are destined to die before dialysis I worry that my advice for protein restriction will result in increased carbohydrates (bad for diabetes and possibly CV disease, see Richard Johnson’s fructose hypertension research) and/or increased fats (bad for CV disease) and enhance the risk of death from the more likely outcome.