AUA 2019: John K. Lattimer Lecture: Diabetes and Urological Disease: No Sugar Coating

Chicago, IL ( Hunter Wessells gave an excellent Lattimer Lecture focusing on the impact of diabetes and urologic disease, an opus on his long-time work in this field. This was a very educational and enlightening lecture. The Diabetes Control & Complications Trial (DCCT) is a landmark clinical trial that assessed the impact of intensive insulin therapy in patients with diabetes compared to the standard of care (at that time). Based on this study, intensive insulin therapy has become the standard of care – as it demonstrated significant decrease in retinopathy, neuropathy and kidney disease. These are some serious long-term consequences of diabetes that were seen historically with poorly controlled diabetes. 

However, in the 21st century, with better diabetes control and intensive insulin therapy, the landscape has changed. Retinopathy, kidney disease and neuropathy are now less common – and as seen in the study by Jacobsen et al (Diab Care 2016), they have been superceded by erectile dysfunction and LUTS (in men) and female sexual dysfunction (FSF) and urinary incontinence (UI) (in females) as the main causes of lower quality of life in diabetic patients. As patients continue to do better, have better diabetic control and live longer, urologic effects of diabetes have become more prevalent and impactful.

As we all know diabetes has also been on the rise in the United States – fully 10% of Americans are now diabetic, per recent reports. The obesity epidemic has contributed to this rise – both in T2DM, but also an earlier presentation of T1DM. 

Diabetic related urologic disorders are prevalent and have known associations with neuropathy. However, Dr. Wessells’ main take-home point here is that these are currently just managed medically for symptoms – but have no impact on disease progression. 

In the above important diagram, he highlights the time course and physiologic impacts of diabetes on urologic symptoms. Importantly, there is an opportunity to start treatment early and hopefully prevent further progression – rather than treat after the “point of no return.” 

To that effect, he highlighted their work with the UroEDIC study. This work required an assembly of a multidisciplinary team (urology, epidemiology, psychology, diabetes medicine, neurology, genetics). Their goal was to determine burden of disease, develop risk models for specific urologic conditions, and provide information on importance to health care providers, family and patients on these traditionally embarrassing health problems.

In the DCCT, after 10 years (1993), the trial was stopped due to the clear benefits of intensive insulin therapy. At the end of the study, patients on the control arm were switched to intensive insulin therapy. More importantly, all these patients were followed prospectively with good retention of follow-up. So, the UroEDIC group completed two projects on these patients – one initial assessment (UroEDIC 1) followed by a serial second assessment (UroEDIC II). For both studies, there were able to capture between 550-580 women and 591-644 men – represents almost 80-90% of the entire 1441 patients in the study!

What is the extent of urologic complications from diabetes? Below is the breakdown for men and women:

Prevalence of urologic diseases ranged between 22% (LUTS) and 45% (FSD in women, ED in men). So, this is pretty common and quite significant. Remember, these are all younger ~40 year old patients with T1DM – compared to our usual 60-70 year old population with these conditions!

He then briefly focused on the work in the area of ED – as there is the most data in this area. This includes baseline data in DCCT. There is a 3 hit hypothesis for diabetes effect on ED – it hits the endothelium, smooth muscle and autonomic nerves! 

Evaluation of a priori predictors of ED were not entirely surprising: 

  1. Older age
  2. HbA1c at baseline (HR 1.36, p <0.001) – for every 1 point increase at baseline, 36% increased risk
  3. Treatment group – even though all patients were put on intensive insulin eventually, those on intensive insulin had significant benefit (HR 0.62, p = 0.027)
But diabetes duration was NOT associated with increased risk of ED.

That’s because it’s not always about glucose control – men with variable HbA1c developed ED. Other causes may explain the variation/onset of ED – including, testosterone deficiency, autonomic neuropathy, high blood pressure, and genetic factors. He touched a bit on each of these factors in the next few slides. Ultimately, they found the following as explaining onset/severity of ED:

  • Uncontrolled high glucose over long periods of time 
  • Autonomic neuropathy (measured indirectly through RR variation)
  • Hypertension (and prehypertension)
  • BMI, smoking, physical inactivity (from other studies and data)
On GWAS studies, no susceptibility genes were identified, however.

However, there is some signal from the longitudinal repeated assessments in UroEDIC2 that there are some patients have remissions in their ED – in fact, in all those urologic manifestations of diabetes, about 8-14% of patients (over a 7-year repeated assessment) reported some remission of their symptoms. 

Looking at a breakdown of all the patients below:

There is a subset of patients (~291 out of the cohort) in the middle who have intermittent ED (yellow) interspersed with periods of remission (blue). But what predicts this remission of ED? On MV analysis, longer ED durations (1-5 years), older age, obese patients (BMI >= 30) and higher HbA1c predict less remission. This slide above summarizes the interventions that can be made for T1DM patients to help prevent these complications and change the natural course, rather than just treat symptoms.

Naturally, there is still a lot of work left in this field. Currently, we make our decisions based on clinical phenotypic expression alone – eventually, however, as with cancers, we need to incorporate biomarkers based on biologic mechanisms to help better identify patients at risk and help prevent pathology development. This was a great presentation and represents excellent work by Dr. Wessels’ and his team!

Presented by: Hunter Wessells, University of Washington, Seattle, WA

Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology at the American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois
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