The last day of this year’s American Diabetes Association (ADA) conference in San Francisco is only a half day – but it is quite a half day! The results from three clinical trials are reporting. Normally on the last day of any conference, attendance has shrunk dramatically. But not today and I enter into a packed auditorium to hear the results of CREDENCE, CARMELINA and PIONEER 6.
The CREDENCE study showed that canagliflozin reduced the risk of kidney failure and prevented cardiovascular (CV) events in people with type 2 diabetes and chronic kidney disease (CKD).
In participants with type 2 diabetes and CKD, canagliflozin reduced major CV events and renal outcomes across a broad spectrum of subgroups including those without CV disease at baseline.
The overall safety profile was consistent with known side effects of canagliflozin, importantly with no increased risk of amputation. This finding suggests that canagliflozin can be effectively used for both primary and secondary prevention of major CV events in people with type 2 diabetes and CKD.
Subsequent to these findings, the ADA Standards of Care have been updated with renal guidance based on the results of CREDENCE. Professor William Cefalu, Chief Scientific, Medical and Mission Officer of the ADA said “ The CREDENCE trial was the first sodium-glucose cotransporter 2 (SGLT-2) inhibitor trial to assess renal-specific primary outcomes and ended early due to efficacy. Incorporating these findings into the (ADA) Standards of Care now gives providers the latest evidence-based recommendations to treat people with type 2 diabetes and diabetes-related chronic kidney disease”.
Based on the Grade A evidence from the CREDENCE trial, the ADA living guidelines (updated on the 3rd June 2019) propose the following:
“For patients with type 2 diabetes and diabetic kidney disease, consider use of an SGLT-2 inhibitor in patients with an eGFR ≥ 30mL/min/ 1.73m2 and particularly in those with > 300 mg/g albuminuria to reduce risk in CKD progression, cardiovascular events, or both”.
In the CARMELINA study, the aim of the study was to investigate the long term impact on cardiovascular (CV) morbidity, mortality and renal function of treatment with the DPP-4 inhibitor, linagliptin, in a selected population of patients with type 2 diabetes and to compare outcomes against placebo, on a background of standard of care.
Additional insights or questions that the researchers wanted to address were:
- Is linagliptin safe in people with type 2 diabetes who are at very high risk CV risk including the elderly?
- What is the effect on kidney function in people with type 2 diabetes, especially in those with CKD?
- Does linagliptin impact heart failure risk in people with type 2 diabetes and CKD who are at very high risk of developing heart failure
The trial showed that, in participants with type 2 diabetes and concomitant atherosclerotic cardiovascular disease and/or CKD, linagliptin did not affect risk for hypertensive heart failure or other associated heart failure-related complications.
These findings were consistent across pre-specified analyses comprising individual and composite heart failure-related outcomes and subgroup analyses by renal function and age.
In a patient population at very high risk for heart failure and its complications, linagliptin can be used without increasing the risk of hypertensive heart failure.
The investigators concluded that linagliptin significantly reduced the urine albumin-to-creatinine ratio (UACR) over time, including across UACR and renal function categories. It also increased the likelihood for improving albuminuria for most outcomes assessed.
In CARMELINA, linagliptin demonstrated a long term CV safety profile in participants with type 2 diabetes and/or kidney disease, including across renal function and age groups. The drug showed no increase in risk of hospitalisation for heart failure in participants at high risk of heart failure, including across renal function and age groups. Linagliptin demonstrated an assuring long-term kidney safety profile, with a reduction in progression of albuminuria, as before, including across renal function and age groups. The investigators concluded that CARMELINA provides unique clinical evidence for a patient population that is highly relevant in clinical practice.
And, finally, the results of some of the continuing suite of PIONEER trials were announced.
The medical rationale for an oral GLP-1 receptor agonist (GLP-1RA) is that it might improve acceptance and adherence for some patients compared with injectable formulations. Such drugs have already been demonstrated to provide effective glycaemic control, weight reduction, low risk of hypoglycaemia and CV benefits in patients with CV disease.
PIONEER 6 achieved its primary objective by confirming non-inferiority for oral semaglutide versus placebo and a non-significant 21% reduction in 3-point MACE over a median follow up of 15.9 months. The primary CV endpoints of a 3-point MACE were the time from randomisation to first occurrence of a MACE composite endpoint i.e. CV death, non-fatal myocardial infarction or non-fatal stroke.
Although numbers of events were small and duration of follow up short, patients randomised to oral semaglutide had a ~50% reduction in CV death and all-cause mortality.
Oral semaglutide is currently under review by the US Food and Drug Administration and other regulatory agencies. By eliminating the barrier of injection, oral semaglutide has the potential for wide use to improve the lives of patients with type 2 diabetes.
Oral semaglutide provides pathophysiologic-based treatment and targets both fasting and postprandial glucose. As a single pill, it may improve adherence and the glycaemia and CV benefits are similar to injectable formulations. However, data is needed vis-a-vis adherence in the real world and we still need a longer, better powered study to determine equivalence to other GLP-1RAs on efficacy of CV event reduction.
The number of drug trials reporting over the past few months has given us sometimes conflicting evidence as to what you should be recommending for your patients. Over the next few months, the EASD e-Learning team will be working to build new courses and the EASD e-Learning platform is considering a number of new modules on drug actions and advice on how and when to use them – including a “Tips and Tricks to Prescribing SGLT-2 Inhibitors” module – so please click here to leave any feedback about this that you may have for the team. We’d be interested to hear from you as to what you would like to see on our e-learning platform as it continues to grow and to provide you with the learning that you want!