Which Diabetes Drugs Are Best for the Heart and Kidneys?

A new study shows that GLP-1 and SGLT2i drug classes have protective effects

With Ali Al-Khazaali MD and Jinnie J. Rhee ScD

Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) can reduce adverse impacts.

There have been studies that show there are heart and kidney benefits to using certain classes of drugs for patients with type 2 diabetes beyond controlling of blood sugar (1-10), but a paper released at the virtual ENDO-2020 conference has confirmed on a larger scale glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) can reduce adverse impacts (11).

GLP-1 drugs include brand names such as Trulicity, Ozempic, and Victoza, while some of the best-selling SGLT2i drugs are Invokana, Jardiance, and Farxiga.

Both classes of drugs improved cardiovascular outcomes

The authors of the paper combed through 10 clinical trials to see if either class of medication provided a significantly better protection or fewer negative outcomes for patients’ kidney and cardiovascular health.

The main endpoints studied by the various papers reviewed included cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke, as well as hospitalization for heart failure. Secondary considerations were total mortality and hospitalization for heart failure.

Renal outcomes were more varied among the papers examined: most looked at doubling of creatinine and decrease in glomerular filtration rate, progression to macroalbuminuria, starting renal replacement therapy, serious adverse events, and death from kidney disease.

SGLT2i drugs had a significantly better effect on the heart failure hospitalization rate

Both classes of drugs improved cardiovascular outcomes, but the SGLT2i drugs had a significantly better effect on the heart failure hospitalization rate. For patients with underlying heart disease, major adverse cardiovascular events, death, and heart failure hospitalization rates were significantly better with that class of drugs.

Adverse impacts confirmed in the review for SGLT2i drugs included yeast infections among women – which are common enough that the authors said they should be expected – and diabetic ketoacidosis, which is a rare, but more severe effect that should be considered when prescribing.

For the GLP-1 agonist class of drugs, the major adverse impact found was gastrointestinal discomfort that led to discontinuation of their use. However, it is possible that titration could ameliorate such affects, the authors noted. There was also a “weak” confirmation of adverse impact on liver function.

Author Ali Al-Khazaali, MD, an internal medicine physician and a fellow in endocrinology at St. Louis University, says he was not surprised by the findings, but was pleased that “it showed the benefits and adverse event profile in larger scale to what was known to us from the individual clinical trials.”

The data was “compelling in terms of heart and kidney benefits,” he adds, while noting that the renal outcomes varied depending on the study. “It provides more clarification on perhaps choosing one class or the other.”

SGLT2i use is limited in advanced kidney failure

Al-Khazaali notes that although both classes of drugs have benefits for kidney and heart health, due to the adverse event profile, SGLT2i use is limited in advanced kidney failure. GLP-1 agonists, on the other hand, may offer improved patient compliance as some of them are only used weekly. “These things make both classes of drugs essential in our armamentarium when thinking of managing patients with type 2 diabetes.”

Neither class is “better” or “worse”, says Jinnie J. Rhee, MS, ScD, an instructor in the Division of Nephrology at Stanford University. “The findings of this particular manuscript showed that while GLP1a and SGLT2i both reduce major adverse cardiovascular events and cardiovascular deaths, neither class was superior to the other.” Patients who have more severe heart disease benefit even more.

The confirmation of previous studies is great additional information, she says, but it is not enough to change prescription practice at this time. For that to happen, there needs to be more standardized definitions of what constitutes renal outcomes, as they varied according to study.

In addition, Rhee says these are newer drugs on the market, and there are many barriers to prescription and use that have to be overcome – both by physicians and their patients. For example, they are higher cost than older drugs.

SGLT2i drugs can cost upward of $500 for a 30-day supply, and GLP-1 agonists can be more than double that, with some reaching $1300 per month. Metformin, by contrast, can be as little as $4 for a one-month supply. For many insurance companies, doctors need to get prior approval for these more expensive drugs.

The findings on prescriptions among type 2 diabetes patients who also have chronic kidney disease were published in another recent paper that looked at some of the reasons why specific drugs go unused for patients who might benefit.

Among the results of the study was that some drugs are prescribed for patients with kidney disease even when there are clear contraindications for them. Metformin, an older, cheaper drug isn’t prescribed nearly as often as researchers thought it would be. Only half of the cohort studied were on it. The use of the newer GLP-1 agonist drugs was much less than it could be based on the potential benefits for patients who suffer from both kidney disease and type 2 diabetes.

Rhee notes that depending on the physician, knowledge of newer classes of drugs may be limited. While an endocrinologist may be well aware of them, a primary care physician may not, so the prescribing patterns of one specialty versus another can be very different.

There are limitations to the work. It was based on retrospective data and individual patients were not compared to each other. The trials also varied in length, and for kidney disease, the longer the trial, the more able researchers would be to observe doubling of creatine levels. Further work needs to be done.

Next up, Al-Khazaali would like to see researchers determine the mechanisms behind the risks and benefits of these drugs. There also need to be head-to-head studies of the drug classes to determine if there are some patients who clearly benefit from one type over another.

For now, he thinks doctors should consider the added benefits and potential risks of GLP-1 agonists and SLGT2i drugs, and to consider whether patients who have heart or kidney disease might benefit from opting for one of these prescriptions rather than others. He believes the American Diabetes Association should also consider amending their guidelines to point providers to these drugs for patients with heart and kidney issues.

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