News & Perspective

It’s not about better HbA1c in the medical record, it’s about survival and QoL improvement

8 months ago, OP Editor

The completed cardiovascular outcomes trials (CVOTs) for the sodium-glucose cotransporter 2 (SGLT2) inhibitors have yielded important information regarding the potential CV benefits of the drug class. At the 23rd Hong Kong Medical Forum (HKMF), Dr. Mikhail Kosiborod of Saint Luke’s Mid America Heart Institute and University of Missouri-Kansas City, US, argued that the time may have arrived for a paradigm shift in the management of patients with type 2 diabetes.

Current approaches to the treatment of type 2 diabetes tend to focus on blood glucose control. However, findings from the CVOTs, particularly in those that investigated SGLT2 inhibitors, have shown that the remarkable reductions in CV risk may not be entirely due to the glucose-lowering effect.1 In fact, other mechanisms activated by SGLT2 inhibition have been proposed, but remains unclear.1

“There was a hypothesis for a long time – just by simply controlling blood glucose and lowering HbA1c, we can significantly reduce all complications of diabetes, including CV complications,” Dr. Kosiborod explained. “When you put all the results together (findings from large randomized controlled trials [RCTs]), the story is pretty clear, the surrogates of microvascular complications are improved with more aggressive HbA1c lowering… But the strategy of driving hemoglobin A1c (HbA1c) levels as low as possible, as fast as possible, really has not convincingly reduce the risk of CV events.”

Dr. Kosiborod also stressed on the importance of real-world evidence that are derived from actual clinical practice, considering that the Asian population is underrepresented in clinical trials. “RCTs controls biases, known and unknown, therefore provide very high level of confidence in the results and internal validity. However, it is important to not just look at the RCTs, but also the real-world studies with data coming from clinical practice. The reason for that is, as we all know, Asians in clinical trials represent a sliver of overall patient population,” he said.

CVD-REAL 2, a real-world study that found consistent CV benefits with SGLT2 inhibitors regardless of the CV disease at baseline,2 was previously covered in the article ‘CVD-REAL 2 adds the evidence that the CV benefits of SGLT2 inhibitors are consistent’ in the Issue 09 (May 2018) of Omnihealth Practice. Considering the huge number of patients included (~470,000) as well as the low proportion of them having an established cardiovascular disease (~27%),2 the findings carry important implications to the paradigm of diabetes management.

“[In the CVD-REAL 2], there were huge differences in the distribution of specific compounds in the US and Europe, with canagliflozin being the predominant type of agent used in the US, and dapagliflozin predominated in Europe… These are just market dynamics, there is no selection bias in terms of specific SGLT2 inhibitor agent,” Dr. Kosiborod said.

Moreover, it’s not just about SGLT2 inhibitors, as there are also several other classes of glucose-lowering medicine that have shown CV benefits. A meta-analysis on the CVOTs of glucagon-like peptide-1 (GLP-1) receptor agonists, namely ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN 6 (semaglutide), and EXSCEL (extended-release exenatide), summarized the large quantity of evidence for this class of medication, and found an overall relative risk reduction CV mortality and all-cause mortality, albeit to varying degrees for individual drugs.3

“Recently, we have some additional data indicating CV benefits with pioglitazone as well,” Dr. Kosiborod added, referring to the findings from the Insulin Resistance Intervention after Stroke (IRIS) trial.4

“You have to ask yourself a question: What is the primary goal of management in people with type 2 diabetes? I would argue that the primary goal of management is not to make HbA1c look better in the medical record, but it’s actually to prolong life and improve the quality of life (QoL),” Dr. Kosiborod said.

“Since CV disease is the number one cause of death in this patient population, one of the surest ways is preventing CV complications,” he said. “However, if you look at the typical algorithm of diabetes management that we’ve been practicing for many years… It’s really all based on HbA1c.”

“If your goal of treatment is to improve survival and QoL… I would argue that a new paradigm is in order, where you actually think about initiating therapy not just based on HbA1c, but also based on where the patient is in the spectrum of CV disease,” he concluded. “These emerging data should shift our focus of type 2 diabetes therapy from glycemic management to comprehensive CV risk reduction.”

  1. Cefalu WT, Kaul S, Gerstein HC, et al. Cardiovascular Outcomes Trials in Type 2 Diabetes: Where Do We Go From Here? Reflections From a Diabetes Care Editors’ Expert Forum. Diabetes Care. 2018;41(1):14-31.
  2. Kosiborod M, Lam CSP, Kohsaka S, et al. Lower Cardiovascular Risk Associated with SGLT-2i in >400,000 Patients: The CVD-REAL 2 Study. J Am Coll Cardiol. 2018 [Epub ahead of print].
  3. Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018;6(2):105-113.
  4. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med. 2016;374(14):1321-31.


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