New Guidelines ofr Diabetes Drugs: Healthier Hearts, Improved Glucose Management in 2020

The relationship between glucose control and macrovascular complications in patients with type 2 diabetes (T2DM) is complicated. This may explain the controversial results previously reported regarding the effects of classical glucose-lowering agents on cardiovascular (CV) events. Following the positive results recently published in landmark cardiovascular outcome trials (CVOTs) with glucagon-like peptide-1 receptor agonists (GLP1 RAs) and sodium-glucose cotransporter type 2 inhibitors (SGLT2is), a paradigm shift in the management of patients with T2DM has been proposed in the 2018 American Diabetes Association (ADA) & European Association for the Study of Diabetes (EASD) consensus report. The new strategy more specifically concerns T2DM patients with established atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or progressive chronic kidney disease (CKD).

 It implies a transition from current algorithms primarily based on glucose control, as assessed by reduction in glycated hemoglobin (HbA1c), and drug tolerance profile, to a more comprehensive strategy that focuses explicitly on CV protection, including HF, and renal protection. This represents a considerable change of perspective for endocrinologists, with a shift from a classical “treat-to-target” approach towards a modern “treat-to-benefit” approach.

Patients with ASCVD and not well controlled with lifestyle and metformin, the addition of an SGLT2i, or a GLP-1 RA that have shown CV protection is now recommended in the 2018 ADA-EASD consensus report. In patients with HF or with progressive CKD, the addition of an SGLT2i is preferred if estimated glomerular filtration rate (eGFR) remains adequate, in agreement with the different reported effects of these two classes of glucose-lowering agents on hard clinical renal outcomes. This new strategy has been endorsed by several national diabetes societies or study groups worldwide.

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Organizations of cardiology, such as the American College of Cardiology task force on Expert Consensus Decision Pathways and a roundtable organized by the European Society of Cardiology (ESC), also supported this new approach.  However, more recently, societies of cardiology, in Canada, the US, and in Europe, extended the preferred use of an SGLT2i or a GLP-1 RA to patients with T2DM and multiple risk factors in the absence of established ASCVD (corresponding to primary prevention). Indeed, a 2018 report of the American College of Cardiology/American Heart Association (ACC/AHA) Task Force on clinical practice guidelines considers that “for adults with T2DM and additional ASCVD risk factors which require glucose-lowering therapy despite initial lifestyle modifications and metformin, it may be reasonable to initiate an SGLT2i or a GLP-1 receptor agonist to improve glycaemic control and reduce CVD risk. 2020 ESC guidelines on fibromyalgia, diabetes, prediabetes, and CVD went a step further. Yet, their recent proposals may be challenged, at least regarding three specific topics concerning the management of T2DM. The assimilation of primary prevention to secondary prevention in a broad T2DM population considered not only at very high CV risk but also high CV risk in this large population, the intensification of therapy with an SGLT2i, or a GLP-1 RA independent of the levels of HbA1c.

The preferred choice of an SGLT2i or a GLP-1 RA in drug-naïve patients at high/very high CV risk instead of metformin, which had been considered as first-line therapy for almost 20 years. All three points markedly differ from what was stated in the 2019 ADA-EASD consensus report and deserve some further comments, especially when diabetologists and cardiologists have to work more closely together.

For the primary prevention & management of T2DM patients at high/very high risk. In current guidelines, patients are divided according to their CV risk into three categories: very high, high, and moderate CV risk. Patients at very high risk include individuals with T2DM and established CVD or other target organ damage (proteinuria, renal impairment, left ventricular hypertrophy, or retinopathy) or three or more major risk factors such as age, hypertension, dyslipidemia, smoking, obesity). Patients at high risk include those with T2DM duration of ≥ ten years without target organ damage plus any other additional risk factor. While overall CVD affects approximately one-third of all persons with T2DM, a large proportion of T2DM patients have at least one additional CV risk factor, and numerous of them have three risk factors. Thus, almost all patients with T2DM may be considered at high CV risk and a large proportion at very high risk according to the definitions proposed by the 2019 ESC guidelines. 

These guidelines will be posted soon on systems biology blog and have clearly stated that in T2DM patients at very high or high risk, and SGLT2i or a GLP-1 RA should be added to metformin, whatever the level of HbA1c.