With recent developments in medications and their clinical implications, the worlds of both diabetes and cardiology were focussed on the American Diabetes Association (ADA) Scientific Sessions, held in San Francisco, USA, from 7th – 12th June 2019. Key trials included REWIND, the PIONEER programme, and CAROLINA, as well as updates from DECLARE-TIMI and CREDENCE. In addition to major cardiovascular outcome trials, other highlights included studies with vitamin D, type 1 diabetes prevention and type 2 diabetes in youth. Dr Amar Puttanna reports.
One of the highlights of the conference and, for many, the main event was the presentation of results from REWIND (Researching CV Events with a Weekly Incretin in Diabetes), a cardiovascular outcome trial (CVOT) for the GLP-1 receptor agonist (GLP-1RA) dulaglutide.1 Prior to this trial, the majority of CVOTs (and all prior CVOTs with GLP-1 RAs) were conducted in a predominantly secondary prevention population. Thus any positive cardiovascular (CV) outcomes were only shown in those with established atherosclerotic cardiovascular disease (ASCVD). The baseline population characteristics in REWIND, however, included only 31.5% with prior CV disease, a predominantly primary prevention group, which potentially would be more applicable to patients seen in primary care.
In the study, 9,901 patients were randomly assigned to dulaglutide (n = 4,949) or placebo (n=4,952). Over a median follow up of 5.4 years, 12% of participants in the dulaglutide group (2.4 per 100 person years) and 13.4% in the placebo group (2.7 per 100 person years) reached the study‘s primary composite end point, the three-point major adverse cardiovascular event (3P MACE), defined as non-fatal stroke, non-fatal myocardial infarction (MI) and death from CV or unkown causes (hazard ratio [HR] 0.88, confidence interval [CI] 0.79–0.99, p=0.026). This result was predominantly driven by the differences in stroke – 3.2% (0.61 per 100 person years) in the dulaglutide group versus 4.1% (0.81 per 100 person years) in the placebo group (HR 0.76, CI 0.62–0.94, p = 0.01).
A further exploratory analysis of the data revealed a reduction in a composite of renal outcomes (the first occurrence of new macroalbuminuria, a sustained decline in estimated glomerular filtration rate (eGFR) of 30% or more from baseline, or chronic renal replacement therapy). Some 17.1% (3.47 per 100 patient years) of patients in the dulaglutide group versus 19.6% (4.07 per 100 patient years) in the placebo group reached the renal composite outcome (HR 0.85, CI 0.77–0.93, p = 0.0004).
Thus REWIND reinforced the positive CV outcomes seen with previous GLP-1 RAs but showed benefits in a predominantly primary prevention population, with benefit being driven mainly by a reduction in stroke.
With the recent multitude of CVOTs, some of the ‘older’ medications used in patients with diabetes were being questioned, none more so than sulphonylureas, whose use has been questioned with the positive CV findings of the SGLT-2 inhibitors and GLP-1 RAs. Hence results from the CAROLINA (Cardiovascular Outcome Trial of Linagliptin Versus Glimepiride in Type 2 Diabetes) study2 posed an interesting consideration – would sulphonylureas still be relevant?
CAROLINA pitted two specific medications against each other – specifically the DPP-4 agent linagliptin to the sulphonylurea glimepiride. The study randomised 6,033 patients with type 2 diabetes and either established CV disease or at increased (58%) CV risk to either medication. Over a median follow up of 6.3 years, the 3P MACE end point occurred in 11.8% of the linagliptin group versus 12% in the glimepiride group (HR 0.98, p = 0.76) indicating no difference between groups.
This result may reinforce the CV safety of glimepiride as CV safety was already known from the previous CARMELINA trial with linagliptin. The CAROLINA trial did, however, highlight the higher hypoglycaemic risks with sulphonylureas as there was roughly a four-times increased risk of hypoglycaemia with glimepiride compared to linagliptin (37.7% vs. 10.6%, respectively, p<0.0001) and this was irrespective of various factors including age, baseline Hba1c or eGFR.
We could conclude that CAROLINA was perhaps more of a sulphonylurea CV safety study than one for DPP4s … but it did highlight the increased risk sulphonylureas have with regard to hypoglycaemia, which may be an important consideration in vulnerable groups.
Results from the DECLARE-TIMI (Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes) trail,3 the CVOT for the SGLT2 inhibitor dapagliflozin, had already been presented at last year’s American Heart Association meeting. Whilst it did not show 3P MACE benefit in this predominantly primary prevention population (only 40.6% had established ASCVD), the co-primary end point of CV death/hospitalisation for heart failure was met, driven by reduction in hospitalisation for heart failure.
Further data presented at the ADA looked at secondary subgroup analyses and renal benefits. With both empagliflozin (EMPA-REG) and canagliflozin (CANVAS-R and CREDENCE4) already showing benefits on renal function, it would add to evidence that the renal benefits of SGLT2 inhibitors are a class effect. In the original DECLARE TIMI-58 study, 17,160 patients were randomly assigned to dapagliflozin or placebo. The baseline eGFR characteristics were of particular note, with 92.6% having an eGFR of > 60ml/min per 1.73 m2. Subgroup analysis revealed a 46% reduction in sustained eGFR decline (by at least 40%) to less than 60ml/min/1.73 m2 in the dapagliflozin group compared to placebo (1.4% vs. 2.6%, respectively, HR 0.54, CI 0.43–0.67, p<0.0001). The risk of end stage renal disease or renal death was also reduced in the dapagliflozin group compared to placebo (0.1% vs. 0.3%, respectively, HR 0.41, CI 0.2–0.82, p = 0.012).
The take home message from this study was that dapagliflozin reduced deterioration in renal function and progression to end stage renal disease. This was seen regardless of the presence of established ASCVD and also in those with preserved renal function.
Further subgroup analyses presented at the meeting also highlighted the possibility of renal benefits beyond CV outcomes. CREDENCE (Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy),4 was the first renal outcome trial for the newer SGLT2 medications, with results presented earlier this year highlighting renal benefit with canagliflozin.
The analysis presented at the ADA focussed on the differences between those with (49.6%) and without (50.4%) established ASCVD. Renal end points (end stage renal failure and cardiovascular or renal death) were reduced regardless of whether patients on canaglifozin were in the primary or secondary prevention group (HR 0.69 vs. 0.70, respectively). Additionally, reductions in CV death or hospitalisation for heart failure (HR 0.74 and 0.66 in primary and secondary prevention, respectively) and a composite of CV death, MI and stroke (HR 0.68 and 0.85, respectively) were reduced in both groups.
This new analysis highlighted that the benefits of canagliflozin were seen in a population with and without established ASCVD.
Whilst SGLT2 inhibitors have captured the imagination with their recent trials, the GLP-1 RAs have not been far behind in proving their worth with liraglutide, albiglutide and now dulaglutide all showing reduction in 3P MACE.
Semaglutide, a once-weekly GLP-1 RA, had a CVOT for its injectable form, which was powered for non-inferiority. Perhaps the most significant aspect of this molecule is that it has also been developed as an oral medication, which is the first for this class. An update on the PIONEER programme5 (PIONEER 1-8), consisting of several studies designed to test the efficacy and safety of oral semaglutide, was presented.
New data were presented around PIONEER 6, a CVOT for semaglutide looking at non-inferiority, which randomised 3,183 patients (84.9% having presence of CV disease) to oral semaglutide or placebo. Results showed 2.9 events per 100 patient years occurred in the semaglutide group compared to 3.7 events per 100 patient years in the placebo group (HR 0.79, CI 0.57–1.11, p<0.001 for non-inferiority but p = 0.17 for superiority). Despite not meeting superiority, additional analysis showed semaglutide reduced all-cause mortality and CV death by about half.
Thus, oral semaglutide reached its primary outcome of non-inferiority in 3P-MACE over a 15.9 month median follow up. Whilst the study was not powered for superiority, the results provides an initial look at the CV profile of this exciting first of its kind oral GLP-1 RA. A further CVOT, SOUL (Cardiovascular Safety of Oral Semaglutide in Subjects with Type 2 Diabetes), is currently in progress.
Best of the rest
Many other studies were presented at the meeting. We report a small selection.
Type 1 diabetes prevention
An interesting trial6 assessed whether teplizumab (an Fc receptor–nonbinding anti-CD3 monoclonal antibody) could delay the onset of type 1 diabetes in those at higher risk of developing the condition. Results showed teplizumab delayrf progression to clinical type 1 diabetes in high-risk participants. The median time to the diagnosis of type 1 diabetes was 48.4 compared to 24.4 months in the teplizumab and placebo groups, respectively; the disease was diagnosed in 19 (43%). HR for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (CI 0.22– 0.78, p = 0.006). The annualised rates of the diagnosis of diabetes were 14.9% per year in the teplizumab group compared to 35.9% per year in the placebo group.
This study7 was designed to assess whether vitamin D can prevent progression to diabetes in patients with prediabetes. Participants who met criteria for ‘pre-diabetes’ were given 4,000 IU of vitamin D and followed up for time to onset of type 2 diabetes. At the median follow up of 2.5 years, there was no difference between groups (HR 0.88, CI 0.75–1.04, p = 0.12) indicating that vitamin D supplementation did not affect progression to type 2 diabetes.
TODAY 2 study
This observational study was a second phase follow-up of a cohort of young people (mean age 21.2 years) with type 2 diabetes to assess the progression of their disease. Significantly, complications occurred at a high rate over the six-year follow up, with evidence of peripheral neuropathy, retinopathy, renal and cardiovascular complications in a young cohort. This indicates the significant burden diabetes has in a younger age group and its implications for clinical management. Results are awaiting formal publication.
Conflicts of interest
AP has received honoraria or participated in advisory boards for Astra Zeneca, Eli Lilly, Janssen, Menarini, MSD, Napp, Novo Nordisk, and Sanofi.
AP’s attendance at ADA 2019 was made possible through sponsorship from Napp Pharmaceuticals.
Consultant in Diabetes and Endocrinology
Good Hope Hospital, Rectory Road, Sutton Coldfield, West Midlands
1. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121–30. https://doi.org/10.1016/S0140-6736(19)31149-3 [Epub ahead of print]
2. https://www.boehringer-ingelheim.com/press-release/CAROLINA-full-data [accessed 10/07/2019]
3. Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol. 2019;7(8):606–17. https://doi.org/10.1016/S2213-8587(19)30180-9 [Epub ahead of print]
4. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–306. https://doi.org/10.1056/NEJMoa1811744
5. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019 Jun 11. https://doi.org/10.1056/NEJMoa1901118 [Epub ahead of print]
6. Herold KC, Bundy BN, Long SA, et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N Engl J Med 2019 Jun 9. https://doi.org/10.1056/NEJMoa1902226 [Epub ahead of print]
7. Pittas AG, Dawson-Hughes B, Sheehan P, et al. Vitamin D supplementation and prevention of type 2 diabetes. N Engl J Med 2019 Jun 7. https://doi.org/10.1056/NEJMoa1900906 [Epub ahead of print]