The CAROLINA trial: Make or break for sulfonylureas?
The recent joint consensus statement from the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) favors dipeptidyl peptidase-4 (DPP-4) inhibitors over sulfonylureas as second- or third-line therapy in type 2 diabetes management. Conversely, The World Health Organization categorically supports the use of sulfonylureas in type 2 diabetes patients whose glucose is inadequately controlled with metformin. Meanwhile, current guidance from the national professional organizations of India and South Africa splits the difference by suggesting both as options.
When compared in a cursory manner, DPP-4 inhibitors and sulfonylureas seem to be totally different classes of drugs. However, we should be mindful of two important aspects here:
- Both DPP-4 inhibitors and sulfonylureas are insulin secretagogues; the key difference is that DPP-4 inhibitors act indirectly on the beta cell, via the incretin pathway, while sulfonylureas act directly to increase insulin secretion.
- Not all sulfonylureas are alike. Modern sulfonylureas, such as gliclazide modified release (MR) and glimepiride, have different molecular structures, binding sites and pharmacokinetics to the older formulations, which allow for much safer glucose control.
DPP-4 inhibitors vs modern sulfonylureas: Not so different?
When DPP-4 inhibitors are compared with modern sulfonylureas alone, multiple similarities become more obvious, as highlighted in the table below:
Affected by weight
Weight-neutral and cause less hypoglycemia.
Weight-neutral, have low risk of hypoglycemia.
Can be used in the elderly and those who fast.
Can be used safely in prolonged fasting such as during Ramadan.
Cardio-renal benefit and safety
Linagliptin, sitagliptin, and alogliptin have proven cardiovascular safety; however, saxagliptin is associated with an increased risk of hospitalization for heart failure. Linagliptin has been shown to have renal benefits in terms of albuminuria reduction.
Dose adjustment requirement
Linagliptin does not require dose adjustment.
Require dose titration.
Thus, we need to be equipped to make a choice between DPP-4 inhibitors and modern sulfonylureas in an objective, unbiased and patient-centered manner. That said, significant debate remains regarding the cardiovascular safety of older sulfonylureas, most of which are not in common use. It may interest global readers to know that tolbutamide continues to be used in Sri Lanka, and gliquidone in Indonesia, as they are extremely economical drugs. Most of the controversy related to sulfonylureas’ safety stems from the results of the University Group Diabetes Program (UGDP).
Older sulfonylureas: Why the controversy?
Launched in 1960, the UGDP was a placebo-controlled, multi-centered, efficacy trial. The trial design included two oral arms (tolbutamide and phenformin) as well as two insulin arms. While the UGDP has been as criticized on many counts, its method of randomization was associated with an extremely low risk of error, and stood out as a seminal case in that era. However, the UGDP did not allow titration of tolbutamide doses (though the protocol did so for insulin), and did not use glycated hemoglobin (HbA1c) as a marker of glucose control, owing to this metric becoming the standard for trials much later.
It should also be noted that the UGDP did not demonstrate any improvement in outcomes, even within its insulin intervention arms. This was demonstrated by later research such as the United Kingdom Prospective Diabetes Study (UKPDS) and the Steno-2 trial. The Steno-2 trial, in fact, used gliclazide MR, a modern sulfonylurea, as part of a multifactorial intervention to achieve healthier micro- and macrovascular outcomes, as well as reduce mortality.
The CAROLINA study
It is critical that we view sulfonylurea-related cardiovascular outcome data objectively, keeping in mind the nature of the sulfonylurea studied, and the limitations of the trial design used. The CAROLINA study, which compares cardiovascular outcomes with linagliptin versus glimepiride, is a welcome attempt to settle the cardiovascular safety controversy of sulfonylureas. While, at the time of writing, the top-line results had been released, detailed data was shared at the ADA Scientific Sessions on 10 June 2019, during which the speakers presented the study design, statistical plan, and baseline characteristics of the study cohort, followed by metabolic, bodyweight, cardiovascular, mortality, and hospitalization outcomes. Adverse events and hypoglycemia will be analyzed separately, and clinical implications discussed from a cardiology and diabetology perspective.
For a clinician who works to achieve optimal outcomes, glucose-lowering therapies form part of a multifactorial intervention package. The top-line results of the CAROLINA trial indicate that linagliptin is non-inferior to glimepiride. From the detailed results, once presented, I hope to be able to understand how to “type” my patients so that I can choose either linagliptin or glimepiride in an accurate, patient-centric manner. If dissected properly, the CAROLINA results should be able to help me practice precision medicine. By identifying patient characteristics related to effective and safe usage of the drugs, I should be able to choose either DPP-4 inhibitors or modern sulfonylureas for a particular patient.
Whatever the fine print may be, the CAROLINA trial has done great service to diabetes care. It has provided robust proof that two commonly prescribed drugs, linagliptin and glimepiride, can continue to be used for the benefit of persons with diabetes. This news must be welcomed by stakeholders in diabetes care.
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