Empagliflozin for Diabetic Kidney Failure

When it comes to treating diabetic kidney disease and reducing the risk of kidney failure (requiring dialysis or kidney transplantation), it's not every day that we hear about medications that justify terms like, "Holy Grail," "game-changer," "major breakthrough," and so on. Well, we might really be at one of those rare moments in medicine where a drug has shown results promising enough to justify those labels.

The cause of enthusiasm: a medication for control of diabetes called Jardiance (empagliflozin). In order to understand empagliflozin's potential role in preventing kidney failure, it is essential to know a bit of a background.

Why Diabetes Is So Damaging to the Kidneys

Diabetes mellitus is, hands down, the single biggest reason for kidney disease and kidney failure in most of the developed world. Its prevalence continues to rise, while its implications continue to pose a public-health nightmare. It is a silent disease—all too easy to ignore until a patient begins to develop complications.

Kidneys are not the only organs wrecked by this malady. Since diabetes damages the blood vessels, technically, every organ is fair game. Depending on the size of the blood vessels involved, blood vessel disease induced by diabetes has traditionally been divided into microvascular (e.g., diabetic retinopathy in the eyes, kidney disease, etc.), and macrovascular complications (e.g., coronary heart disease leading to increased risk of heart attacks, cerebrovascular disease in the brain's blood vessels increasing the risk of stroke, etc.). 

Given the above, it's understandable that any time a breakthrough is made in the field of diabetes management, the world pays attention. Physicians and patients await good news with bated breath. Is the new drug going to reduce the risk of diabetes-related death? How about heart attacks or strokes? Or will it potentially reduce the risk of diabetic kidney failure? 

Or, as is often the case, will it be a frustrating situation where improved diabetes control does not translate into better clinical outcomes for patients? In fact, there have been studies reporting a higher risk of death or disease with certain diabetes medications. It is because of this seeming dichotomy that the FDA now requires all oral diabetic drug manufacturers to prove that their new medications will not worsen the risk of heart and vascular disease.

Could Medications Improve Diabetes and Related Kidney Disease?

The past decade has seen some entirely new categories of medications approved for control of diabetes. A few examples:

• GLP-1 agonists increase insulin release by the pancreas.
• DPP-4 inhibitors prolong the action of GLP-1, and therefore indirectly lead to the same action as above.
• SGLT-2 inhibitors prevent glucose (sugar) reabsorption in the kidney. These drugs are the focus of discussion in this article.

How Do SGLT-2 Inhibitors Affect the Kidneys?

SGLT stands for sodium-glucose cotransporter. To put it in simple terms, it is a protein involved in transporting two kinds of substances within the kidney, from the urine into blood. One of these is sodium, and the other one is glucose, which essentially "piggybacks" on sodium's transportation. The number "2" refers to the specific type of protein found in the kidneys' drainage system, a part called the "proximal tubule." (There is also an SGLT-1, but that is responsible only for a small fraction of this transport).

This background in molecular biology is helpful to understand why the endocrinology and nephrology universe is going gaga over these new SGLT-2 inhibitors.

Now that we know the role of SGLT-2, it might be a bit easier to understand what would happen if you were to "block" the action of this protein. The kidney would no longer be able to absorb the glucose already filtered into the urine (which is what it typically does), so essentially it pees that sugar/glucose out all the way into the toilet. Which means less glucose retained in your blood, and perhaps better diabetes control.

Empagliflozin is an SGLT-2 inhibitor approved by the FDA for treatment of type 2 diabetes. While some of the newer diabetes medications have been accompanied by slick marketing extolling their benefits, many trials have failed to show a reduced risk of hard clinical outcomes (like improvement in heart attack or stroke risk) with these new medications, as compared to traditional drugs for controlling diabetes. For a change, however, when a new medication actually shows strong promise of reducing heart attacks, strokes, or kidney failure, it is bound to be the center of attention.

Traditional Treatment of Diabetic Kidney Disease

Unfortunately, over the last two decades, we have not made any major strides in improving the treatment of patients with diabetic kidney disease. The current standard of treatment basically rests on generic interventions like controlling blood pressure or reducing protein loss in the urine (using medications called ACE-inhibitors or angiotensin receptor blockers). We might couple these interventions with other goals, such as increasing the alkali levels in the blood, good diabetes control, and reducing uric acid levels. However, in many instances, these interventions might not be enough to make a meaningful difference in the chances of a patient developing kidney failure.

Could Empagliflozin Be the Miracle Cure for Diabetic Nephropathy?

There are reasons to believe that empagliflozin might break the frustrating "therapeutic inertia" of the last 20 years. Empagliflozin first burst on the diabetes management scene in late 2015, when the results of the so-called EMPA-REG trial showed it had a significant effect on reducing cardiovascular death, nonfatal heart attacks, and strokes. The results were later published in the New England Journal of Medicine.

The study itself was a huge trial involving over 7,000 diabetic patients in 42 countries at multiple centers. It is important to note that over 80 percent of the participants were already on standard treatment for diabetic kidney disease (with more than 80 percent being on ACE inhibitors or angiotensin receptor blockers). Almost all patients were high risk for cardiovascular disease. The size of the trial was one of the factors that added credibility to its conclusions.

Given these heartening results, further analysis of the effects of empagliflozin on the rate of development and worsening of kidney disease was performed. This led to a second article, published in June 2016, which focused on what the drug does to the kidneys. Specifically, the analysis looked at worsening kidney function (in patients on vs. not on the drug). This was done by measuring the worsening of creatinine level or protein loss in the urine. The final results indicate that diabetic kidney disease patients who are high risk for cardiovascular disease, and who take empagliflozin (added to "standard care") could perhaps see a significantly slower decline in kidney function than those who don't. Patients taking this medication also had better blood sugar control as well as lower blood pressure, waist circumference, weight, and uric acid levels.

Adverse Effects and Unanswered Questions

Any time a drug is called a game-changer, it is usually a good idea to step back and look at it with a healthy dose of scientific skepticism, and there remain questions about empagliflozin's efficacy. Here are some questions that still need to be reliably answered at this time:

• Are the purported benefits in fact a result of the lower blood pressure or weight that were seen in patients who took empagliflozin?
• Could better blood sugar control explain the superiority of empagliflozin?

The issues above do raise the specter of over-promise and hype. What if we could shoot for better blood sugar/blood pressure control using existing medications and lifestyle adjustments (think something like metformin + lisinopril + diet/exercise)? Would that give us the same bang for the buck, perhaps at a much lower cost? These and more questions will be subjects of research for years to come.

Finally, keep in mind empagliflozin's adverse effects, reported in the trial, some of which were:

• Genital infections
• Urosepsis
• While the empagliflozin trial did not report this, the FDA recently issued a warning about the risk of kidney damage from use of its "cousins" (canagliflozin, dapagliflozin).

The Take-Home Message

1. The results of these two trials on the effects of empagliflozin on risk of heart, vascular, and kidney disease are undoubtedly impressive, but will likely need future verification.
2. The studies suggest empagliflozin can lower risk of heart attacks, strokes, and death when added to standard diabetes management in patients with type 2 diabetes who are at high risk for cardiovascular disease.
3. Empagliflozin can perhaps slow down the often-inevitable decline in kidney function that is seen in high-risk diabetics. We still do not fully know if this is due to a protective effect on the kidney over and above glycemic (blood sugar) control.
4. If the results are proven in further trials, for the first time perhaps, we might be able to move past generic interventions that are currently used to treat diabetic kidney disease (like blood pressure and sugar control). This could actually offer patients something that can realistically reduce the chance of them ending up on dialysis.