Denmark

Once dubbed the Danish Dynamite, the Denmark national soccer team has a wonderful football history (Audio 1). The decade between 1980 to 1990 established the Danish team as one of the most powerful in the football community. During the early years of that decade, the team impressed everyone during the early phases of the 1986 World Cup (Denmark's first appearance in the World Cup). Specifically, they crushed the Italians in the '82 Qualifying Matches. And after they defeated Uruguay 1-6 (no easy feat), they appeared to be one of the clear favorites for the '86 World Cup.


Alas they ultimately succumbed against Spain during the quarterfinals. Nevertheless their impressive performance launched the national team to football prominence and since then, they have fared very well in FIFA rankings (currently #9).


In the NephroWorldCup the Danes remain top contenders. The Dynamite return again with a powerful team that is a CVRM-fan favorite: SGLT2 inhibitors.

Figure 1: Content collected and analyzable from the Danish National Patient Register | Zoom in for details

Figure 3: Network map of various diabetic medication trials showing few comparisons between GLP1 RA and SGLT2 inhibitors (red arrow) | Courtesy of Dr. Giovanni Strippoli

Audio 1: 🎶 Danmarks Dynamite by Herrelandsholdet & Alphabeat

There are many similarities between The Dynamite and SGLT2 inhibitors. Both began their ascendancy in the early 1980s when NIH researchers performed seminal work to discover the presence of SGLT1 and, subsequently, SGLT2 receptors. Today, both continue to surprise believers and skeptics. SGLT2 inhibitors continue to amaze scientists as new applications for their use are discovered.

In the NephroWorldCup, Denmark is represented by "Sodium–glucose cotransporter 2 inhibitors and risk of nephrolithiasis" by Kristensen and collaborators. The authors performed a cohort-study using the Danish National Patient Register (another point of national pride) looking for patients starting SGLT2 inhibitors or glucagon-like peptide-1 receptor agonists (GLP1 RAs) (Figure 1). These patients were followed from treatment initiation until their first diagnosis of nephrolithiasis, death, emigration, or until the completion of the study.

Patients were matched 1:1 for a total of 12325 participants; the nephrolithiasis rate was 2.0/1000 person-years in the SGLT2i users versus 4.0/1000 for GLP1 RAs; the rate difference was 1.9/1000 person-years (95% CI -2.8, -1.0) and a HR of 0.51 (95%CI 0.37–0.71) (Figure 2).

Figure 2: Stone events based on treatment | Presented at the 2021 Kidney Week meeting by Dr. Lama Nazzal | Courtesy of Dr. David Goldfarb

The authors concluded that treatment with SGLT2i was associated with a clinically –and statistically significant– reduced risk for incident nephrolithiasis. With such an enormous win for this glycosuric class its no wonder that it is a strong contender for The Tournament.

Few trials have matched SGLT2 inhibitors against GLP1 RAs (Figure 3). As a result, we must all take notice of these findings and this team. Another note-worthy aspect of this team is that the authors offer a potential explanation of the perceived benefit of SGLT2 inhibitors. The investigators theorize the benefit of reduction in stone formation may arise from the osmotic diuresis seen in SGLT2 inhibitor use. This diuresis would causing an increased urinary flow and decrease the concentration of salts and other stone-promoter elements in the urine.

However questions still remain and cast a bit of a shadow over the Denmark team. It is unclear if the theory above is the only mechanism at play (unlikely); perhaps other mechanisms are also likely. For instance, patients using SGLT2 inhibitors are often advised to drink water to offset some of the diuresis of these agents: could the increase in water intake be the reason for decreased stone formation (Figure 4)? Is the use of SGLT2 inhibitors a confounder?

Figure 4: Reason to avoid SGLT2 inhibitor use | Presented at the 2021 ERA-EDTA meeting by Dr. David Wheeler

Alternatively what if the true benefits of SGLT2 inhibitor use reside with the osmotic diuresis? What if the theory above is correct? Does that mean we will see a return of osmotic nephropathy? (Carousel 1).

Carousel 1: Osmotic Nephropathy | Presented at the 2019 ERA-EDTA meeting and the 2019 NKF Spring Clinical Meeting | Courtesy of Drs. Hugo Diniz and Edgar Lerma

Breakthroughs in Nephrology come in peaks. Those peaks represent 'eras' and many would argue that we are in the era of SGLT2 inhibition (Figure 5). Something similar can be said about the Denmark National team which has matured through many eras as well: The Danish Dynamite, the Olsen Gang, the Hareide era, and today the Hjulmand era.

Figure 5: 30+ years in the CVRM space (specific attention to Nephrology) | Presented at the 2021 Global Trials Summit | Courtesy Dr. Carlos Santos-Gallego | Zoom in for details

While it is clear this team is loaded with history and tradition, something that fans across the globe appreciate in their teams, it is also clear that the future is bright for Denmark, CVRM science, and SGLT2 inhibitors.