Cardios, Nephros, PCPs -- We're All Diabetologists Now

A surgeon once said to me, "I wish I had your job. All you do is adjust medications here and there to control blood sugars."

"I'm a diabetologist, not a glucologist," I said, to which she replied, "To-may-to, to-mah-to."

Until about a decade ago, most major diabetes studies looked at outcomes associated with intensive versus conventional glycemic control. Some trials showed that better control of blood sugar levels led to a lower risk of developing microvascular complications, but many cynics countered that the effort-to-benefit ratio didn't seem worth the trouble, as reduction of hard outcomes, such as death and cardiovascular (CV) events, remained elusive.

Sure, diabetes was christened a CV risk factor, but no study had conclusively shown at that time that controlling diabetes actually made a difference in CV outcomes. Even though landmark trials such as Steno-2 showed impressive outcomes in dyslipidemia, blood pressure, and microalbuminuria with intensive control of blood sugars, the treatment of diabetes continued to be relegated to achieving a certain A1c target.

Studying CV Outcomes

This began to change gradually in 2008, when the US Food and Drug Administration mandated that all new diabetes medications undergo dedicated CV outcomes trials to establish that they don't increase the risk for CV mortality, nonfatal myocardial infarction, and nonfatal stroke compared with placebo. For the first time, CV outcomes were studied for individual medications—essentially independent of glycemic control, as the placebo group received standard of care with other medications to achieve established glycemic targets.

The initial crop of studies showed that such agents as dipeptidyl peptidase 4 inhibitors didn't increase major adverse cardiovascular events (MACEs) and seemed safe. But the much-needed shot in the arm was when the EMPA-REG outcomes trial showed that a diabetes medication could help reduce MACEs, hospitalizations for heart failure, and even death. In quick succession, trials with other sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists echoed these results. For the first time, we had conclusive proof that use of certain diabetes medications mitigated the occurrence of debilitating vascular events, even when these agents were started many years after the diagnosis of diabetes.

What speaks to the profound impact of these trials is that healthcare professionals outside primary care and endocrinology started looking at the outcomes trials with growing interest. Colleagues in cardiology noted that the reduction in hospitalizations for heart failure with SGLT2 inhibitors surpassed results of some outcomes trials of medications that were specifically developed to treat heart failure.

GLP-1 receptor agonists showed remarkable MACE reductions regardless of the dose and even when the starting A1c was not very high; therefore, it was thought that the CV effects were independent of the blood sugar-lowering effects.

The Lines Get Blurred

So then, the boundaries of "jurisdiction" started getting blurred, as cardiologists began recommending and even actively prescribing diabetes medications for reasons other than blood sugar control.

Patients with diabetes are three times more likely to see a cardiologist than an endocrinologist. With the support of our cardiology colleagues, more patients with diabetes were initiated on these medications and began receiving better metabolic care.

By this time, we thought we had achieved the Holy Grail of diabetes care, with CV protection to boot. Things couldn't get any better.

But then came the CREDENCE trial.

One cause of mortality in patients with diabetes that has not shown any decline in the past few decades is end-stage renal disease. After the remarkable results seen with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), there was little breakthrough in the care of diabetic kidney disease for more than 20 years.

This changed when the CREDENCE trial was stopped prematurely because of the significant reduction of events noted in the canagliflozin group compared with placebo in patients with established chronic kidney disease and estimated glomerular filtration rates (eGFRs) as low as 30 mL/min/1.73 m² at baseline. Nephrologists noted that the 30% reduction in the composite outcome of doubling of creatinine, progression to dialysis, or occurrence of renal death was unprecedented, and hailed this trial as a practice-changing phenomenon.

The medication was working to protect the kidneys at ultra-low eGFRs, at which point its blood sugar reduction potential is at nadir. This suggested that similar to the cardioprotection, the renal protection was also independent of the drug's blood sugar-lowering effects.

The cherry on top was when the DAPA-HF trial recently showed reduced hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF). These were sick patients who were already on current gold-standard care with beta-blockade, ACEIs/ARBs, mineralocorticoid receptor antagonists, and even ACEI plus an angiotensin receptor-neprilysin inhibitor. What was perhaps most surprising was that the effects were similar whether patients had dysglycemia or not. Who would have imagined that a diabetes medication could save the lives of patients without diabetes?

What will follow in the next several years are studies looking at the renoprotective effects of other medications in the SGLT2 inhibitor class, even in patients without diabetes, as well as those with type 1 diabetes. Large-scale CV studies are looking at every aspect of this class of drugs, including its effects in the population with heart failure with preserved ejection fraction and those admitted to the hospital with acute exacerbation of heart failure, some of whom do not have diabetes. Other trials that are under way include those looking at MACE outcomes with GLP-1 receptor agonists in people with obesity, including those without diabetes.

We need to be cautiously optimistic and wait for the data to emerge in their entirety before incorporating these drugs for other indications, because we still don't fully understand why these medications are so good at what they do. Nonetheless, what these medications can do remains undebatable.

So Where Do These Medications Belong?

For the first time, a cardiology society (the European Society of Cardiology, in conjunction with the European Association for the Study of Diabetes) has developed guidelines for treating patients with diabetes. The Canadian Cardiovascular Society guidelines have incorporated the use of dapagliflozin for patients with HFrEF, including those without diabetes. I'm hearing nephrologists advocating the use of canagliflozin in patients with ultra-low eGFRs. We've reached a point where cardiologists joke that these are actually cardiac medications with a side effect of controlling sugars, and nephrologists claim that these are "antidialysis" medications.

This is the best time to be caring for patients with diabetes. There is, of course, the consideration of short-term costs of the newer medications versus the long-term benefits that they might offer. Nevertheless, we are now able to control blood sugar without the risk for hypoglycemia. We are able to help patients with diabetes in their battle against ongoing weight gain and insulin resistance. We have conclusively seen a decline in microvascular complications of diabetes. We are able to help reduce the risk for heart attacks, strokes, hospitalizations for heart failure, and even progression to dialysis in the sickest of our patients.

Will the endocrinologists, cardiologists, or nephrologists stake their individual claims to the newer diabetes medications? In my humble opinion, the home of these medications should be the family physician's office, where for the appropriate patient, we can help prevent many of the previously untouchable complications in the cardiometabolic-renal domain. And yes, we are all diabetologists now!

Akshay B. Jain, MD, is a clinical endocrinologist who has practiced in three countries, focusing on mitigating the complications of diabetes and obesity. He is fluent in six languages and has spoken at more than 500 programs internationally.

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