Newer diabetes drugs: Surprising shared benefits and unique side effects

Over the past decade or so there has been a daunting increase in the number and pharmacologic breadth of medications available to treat patients with diabetes mellitus. There are innumerable new insulin preparations. Some medications, like the glucagon-like peptide-1 (GLP-1) receptor agonists, stimulate endogenous insulin release, while the sodium-glucose cotransporter-2 (SGLT2) inhibitors decrease blood glucose levels independently of any direct effect on insulin. It is difficult to keep up with all these new drugs, but as we learn more about these 2 classes of drugs in particular, we are pushed to think about the pathobiology of diabetes and the interrelationships between diabetes and the comorbidities that are not completely dependent on the blood glucose level.

There has always been a glucocentric emphasis with diabetes treatment; no surprise, as the disease is defined by hyperglycemia. But we have learned that diabetes complications are variably abrogated by tight glycemic control—think micro- vs macrovascular complications. A striking heuristic reminder of a hyperglycemia-independent metabolic consequence of insulin deficiency is the rare occurrence of euglycemic ketoacidosis in patients with diabetes treated with SGLT2 inhibitors.¹

Because tight glucose control in earlier studies did not demonstrate a marked reduction in total cardiovascular events, the beneficial effect of both the SGLT2 inhibitors and the GLP-1 receptor agonists on reducing cardiovascular events suggests a mechanism other than glucose control alone. Both classes of drugs also reduce proteinuria and the progression of chronic kidney disease in patients with type 2 diabetes.

The search for a common mechanism of action to account for these shared effects by totally distinct drugs can begin (and may end) with the ever-popular hunt for an anti-inflammatory explanation. Their shared anti-inflammatory mechanism of action may involve effects on a known metabolic pathway that links glucose and intracellular energy metabolism to the synthesis and secretion of proinflammatory cytokines. Both the SGLT2 inhibitors and the GLP-1 receptor agonists can increase intracellular levels of adenosine monophosphate–activated protein kinase (AMPK), which is a key metabolic regulator connecting cellular energy status to the control of inflammation.^2–4 AMPK is a critical sensor of intracellular energy stores. Increased levels of AMPK decrease the activity of the proinflammatory transcription factor nuclear factor (NF)-kappa beta. Reducing NF-kappa beta decreases the downstream synthesis and release of many proinflammatory cytokines, including tumor necrosis factor and interleukin-1, and favors the polarization of macrophages to their M2 (anti-inflammatory) state. Notably, interleukin-1 plays a major role in the control of the level of circulating CRP (C-reactive protein).

Further understanding of the mechanism by which these drugs are able to disrupt this metabolic inflammatory pathway may result in the development of therapies that can affect the incompletely explained connection between systemic inflammation and cardiac events, as is known to exist in patients with gout, rheumatoid arthritis, psoriasis, and other systemic inflammatory disorders.

Given their distinct mechanisms of action, despite sharing some anti-inflammatory effects, these 2 classes of drugs not surprisingly exhibit distinct side-effect profiles. Kodur et al⁵ in this issue of the Journal discuss the management of the more common side effects of the SGLT2 inhibitors, while Mehta et al⁶ discuss the occurrence of pancreatitis in patients receiving GLP-1 receptor agonists and whether it is indeed a side effect of this therapy.

It is becoming increasingly evident that we all need to become facile with the use of these drugs, whether or not we primarily manage patients’ diabetes.

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