SGLT2 inhibitors

The 33% risk increase for DCCB users

For millions of patients managing type 2 diabetes, hypertension is an almost inevitable complication. Controlling that blood pressure is the primary way to slow the slide toward kidney failure, but a new analysis suggests that not all blood pressure medications are created equal. According to Medical News Today, the use of dihydropyridine calcium-channel blockers (DCCBs) was associated with a 33% higher risk of major adverse kidney events compared to alternative hypertension treatments.

The study tracked a massive cohort of roughly 31,031 adults with type 2 diabetes between 2016 and 2021. The researchers utilized retrospective data from electronic health records, specifically drawing from the Clalit Health Services database in Israel, to monitor patient outcomes over time. To ensure the results weren’t skewed by a lack of basic care, every patient in the group was already receiving the current gold standard of kidney protection: renin-angiotensin system (RAS) inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors. Despite this protective foundation, those who added a DCCB to their regimen faced significantly worse outcomes.

The researchers didn’t just look at general “kidney health,” but focused on specific, high-stakes markers. As reported by DocWire News, the study utilized a composite endpoint known as Major Adverse Kidney Events (MAKE). This composite measure allowed researchers to capture a broader spectrum of renal decline rather than relying on a single metric. The MAKE endpoint included:

• A decline of 40% or more in the estimated glomerular filtration rate (eGFR), the primary measure of how well kidneys filter waste.
• Progression to end-stage kidney disease, requiring either a transplant or dialysis.

Over a median follow-up of 3.5 years, the data showed a clear divergence. The hazard ratio for those taking DCCBs was 1.33, indicating that these patients were 33% more likely to experience one of the MAKE endpoints than those not using the drug class. While DCCBs are highly effective at lowering systemic blood pressure, that success may come at a steep cost to the internal architecture of the kidney.

How DCCBs may increase intraglomerular pressure

The danger isn’t that the drugs fail to lower blood pressure, but rather how they do it. The kidneys filter blood through tiny units called glomeruli. In diabetic kidney disease, these units are already under immense strain, often experiencing “hyperfiltration,” where they work too hard under excessive pressure.

According to EMJ, the researchers believe DCCBs disrupt the delicate balance of blood flow within the kidney. Specifically, these drugs preferentially relax the blood vessels that carry blood into the filtering units (the afferent arterioles) without having the same effect on the vessels carrying blood out (the efferent arterioles).

This creates a “bottleneck” effect. By opening the intake valve but leaving the exhaust valve unchanged, DCCBs may inadvertently increase the pressure inside the glomeruli. This sustained internal pressure can accelerate the damage to the filtering system, effectively neutralizing some of the benefits of other kidney-protective drugs. The study highlights that while RAS inhibitors typically work by dilating the efferent arteriole to reduce this pressure, the powerful afferent dilation caused by DCCBs may override this protective mechanism.

Why SGLT2 inhibitors didn’t stop the progression

The most concerning aspect of this data is that it persisted even in patients taking SGLT2 inhibitors. These drugs have fundamentally changed the treatment of diabetic kidney disease by reducing the risk of kidney failure. The research team expected these modern therapies to act as a shield against any potential harm caused by DCCBs, as SGLT2 inhibitors are known to reduce intraglomerular pressure through tubuloglomerular feedback.

“We initially thought the kidney-protective effects of SGLT2 inhibitors might counterbalance the potential harms associated with DCCBs. However, the increased risk of kidney disease progression appeared to persist even in this group.”
Dr. Timna Agur, nephrologist at Rabin Medical Center, via U.S. News & World Report.

This suggests a fundamental incompatibility in how these drugs interact with kidney hemodynamics. While SGLT2 inhibitors work to protect the kidney, the mechanical pressure increase caused by DCCBs may be powerful enough to override those protections. For clinicians, this creates a difficult balancing act: using a drug that is excellent for overall blood pressure control but potentially toxic to the specific organ they are trying to save. The findings indicate that the combination of SGLT2i and RAS inhibitors—previously thought to be an impenetrable defense against progression—is still vulnerable when DCCBs are introduced into the regimen.

The limitations of observational data and next steps

Before patients panic or stop their medication, there is a critical caveat: this was an observational study. It identifies a strong association—a correlation—but it does not prove a direct cause-and-effect link. There may be “confounders,” such as other health conditions, differences in baseline kidney function, or medication interactions, that influenced the results. The researchers noted that patients prescribed DCCBs might have had more severe hypertension or other comorbidities that independently increased their risk of kidney decline.

Because of this, the research team has been explicit that current medical guidelines should not be changed based on this data alone. Patients are warned not to quit their medications without consulting a physician, as uncontrolled hypertension is itself a primary driver of kidney failure. The current standard of care, supported by organizations like KDIGO (Kidney Disease: Improving Global Outcomes), continues to emphasize the necessity of strict blood pressure control.

“Further prospective studies and randomized controlled trials are needed to confirm these observations and better define the safest blood pressure treatment strategies for patients with DKD. However, given how commonly these medications are prescribed, any increase in kidney risk could have important implications for large numbers of patients with DKD.”
Dr. Timna Agur, nephrologist at Rabin Medical Center, via U.S. News & World Report.

The next 30 to 90 days will likely see a push for randomized controlled trials (RCTs) to determine if switching from DCCBs to alternative second-line antihypertensives—such as non-dihydropyridine calcium channel blockers or other classes—can actually lower the rate of kidney failure. For now, the findings serve as a high-priority warning for nephrologists to scrutinize the choice of blood pressure medications in diabetic patients, especially those already on a regimen of RAS and SGLT2 inhibitors. The presentation at the ERA Congress has prompted a wider discussion among the international nephrology community regarding the “hemodynamic clash” between different antihypertensive classes.

<!– /wp:paragraph The study focused on key markers of kidney health, including measures of renal function and urinary protein levels, which are essential for assessing disease progression.