Summary | Changing focus in diabetes: From glucose to CV risk management
Prof. Jacob focused on the shift from glucose regulation to CV risk management in patients with diabetes. It is widely known that diabetes is a major problem worldwide and that the costs are exploding. In diabetes, there is not only a doubling of CVD, but also a tremendous increase in microvascular complications. In the past, diabetes was defined as a hyperglycemic condition and this was assessed by HbA1c as a measure of mean glycemia. Looking at the mean HbA1c and all the different (co)morbidities, there is always a close association between higher HbA1c levels and higher event rates, including mortality rates. For instance, the UK Prospective Diabetes Study (UKPDS) demonstrated a clear association between higher HbA1c levels and a higher rate of complications . The event curve based on HbA1c concentration is a straight line, which hints at that reduction of HbA1c levels would lead to fewer events. Focusing on the events, a study has demonstrated that per 1% reduction of HbA1c there is a 14% reduction of fatal MI, 43% reduction of peripheral vascular disease (PVD), 16% reduction of HF and 12% reduction of stroke . Thus, it seems effective to lower HbA1c, but it should be noted that these data only show the association, but there was no intervention.
For a long time it was thought that correction of hyperglycemia would automatically improve the fate of patients. A consequence was that the main focus was on HbA1c. But is that really successful?
What would one expect from an HbA1c difference of 1.5%, which is the maximum HbA1c decrease seen in major trials? The article of Stratton et al. suggests that in the Veterans Affairs Diabetes Trial (VADT), in which 1.5% lowering of HbA1c was maintained over 6.5 years, further reductions would be expected in MI (21%), PVD (~~64%), stroke (80%) and HF (~~24%) . However, in the VADT trial the primary outcome was not reduced, nor were mortality or microvascular events. In UKPDS, a significant reduction in events was finally reported ten years after the end of the trial [16,17]. However, this legacy effect has to be questioned a bit, because in the second part of the observation only questionnaires were used to follow patients remotely, due to funding constraints. Furthermore, when interpreting these findings, it should be kept in mind that the used co-medication was not the medication that is used nowadays, with 12% of the subjects on anti-hypertensive and almost nobody on lipid-lowering agents. The VADT trial had also reported a legacy effect, however, after 15 years the investigators did not find a legacy effect either. A Cochrane meta-analysis focusing on intensive versus conventional glycemic control showed no reduction in MACE, with even increased mortality in some studies . Although some reduction in macrovascular disease was found, hypoglycemia and weight gain were also observed more often.
The last 25 years a lot of new agents have been developed for the treatment of diabetes. Nowadays different types of studies have to be conducted with anti-diabetic agents, because the FDA guidance for industry requests that companies show safety of novel anti-diabetes medications. This has led to many CV outcome trials in diabetes, mainly aiming at non-inferiority to prove safety.
The dipeptidylpeptidase-4 (DPP-4) agents have been proven to be safe with regard to CV outcomes, but no superiority was shown. Then good news came from the EMPA-REG OUTCOME trial and the CANVAS program, evaluating SGLT2 inhibitors, and LEADER and SUSTAIN-6 trials, evaluating GLP-1 receptor agonists (GLP-1RAs), which showed CV benefit [19-21]. Empagliflozin in the EMPA-REG OUTCOME, for instance, showed a significant reduction in the primary endpoint of CV death, non-fatal MI or non-fatal stroke, and even in mortality. Moreover, EMPA-REG OUTCOME demonstrated a marked reduction in hospitalization for HF, which was confirmed in the CANVAS program. GLP1-RAs were also proven to reduce MACE in optimally CV managed patients .
But what is this effect driven by? Results showed a significant difference in HbA1c levels, body weight, BP (albeit small), and some improvements in lipid levels . However, all these changes probably cannot explain the major benefit - reduction of MACE. Jacob expects multi-factorial effects, because. ‘GLP1-RAs and SGLT2 inhibitors have additional effects besides lowering glucose, which would also improve CV outcome’.
For a long time it was thought that the aim of diabetes management was just glucose control, but to reduce complications more should be done. That already became clear from the Steno-2 trial, which showed beneficial effects of multiple risk factor management. Over the years, diabetes management has evolved. Before 2008 it was thought that only HbA1c levels should be lowered, but then we learned from the negative trials about importance of preventing hypoglycemia and weight gain. With all the new data, we now know that CV risk can be reduced by controlling BP, controlling lipids and by using glucose-lowering agents with safety and superiority as proven in the trials. This is also reflected by the new recommendations, such as the Standards of Medical Care and the American Diabetes Association/ European Association for the Study of Diabetes (ADA/EASD) statement.
Jacob concluded that bad glycemic control as assessed by HbA1c is clearly associated with CV complications in epidemiology; however, intervention studies have failed to improve outcome. Maybe because treatment-induced adverse events have played an important role, or HbA1c may be the wrong target, because it does not inform us on hypoglycemia and fluctuations in glucose. However, the new treatments with GLP1-RAs and SGLT2 inhibitors can reduce CV events and even mortality in high-risk patients. Although this seems to be independent of improved glycemic control, the underlying mechanism is still being discussed. New treatment recommendations now target CV effects, which should be translated to the patients. Jacob: ‘There is a change of paradigm: treat the patient, not the sugar, and reduce CV risk, and not only HbA1c’.
This is a summary of the presentation given by prof. Stephan Jacob, during the PACE symposium entitled 'Targeting SGLT2 in clinical cardiology: Exploring the benefits in CV risk, diabetes & heart failure', held during ESC in Munich, Germany, on August 27, 2018.