Top 5 Diabetes Highlights From 2019

Ever since the US Food and Drug Administration (FDA) mandated cardiovascular outcome trials (CVOTs) for all diabetes medications, these trials have hogged the limelight in diabetes-related news. No doubt, they have provided much-needed safety and efficacy evidence and shifted the focus from just A1c lowering to reducing diabetes complications.

But now, for the first time in several years, an FDA-mandated CVOT is not leading the list of the year's top diabetes news!

Here are my top 5 diabetes highlights of 2019—let's see if you agree.

1. CREDENCE

In April 2019, at the International Society of Nephrology World Congress, we got to see for ourselves why this visionary trial (not the typical FDA-mandated CVOT) was stopped prematurely after a planned interim analysis. A wide array of hard nephropathy outcomes—including the clinically meaningful composite of dialysis, kidney transplantation, or renal death—were substantially reduced.

And the subsequent data analyses from CREDENCE just kept getting better. An analysis presented at the American Diabetes Association (ADA) Scientific Sessions suggested major adverse cardiovascular event (MACE) reduction in the primary prevention diabetic kidney disease subgroup. More recent presentations at Kidney Week and the International Diabetes Federation (IDF) Congress suggest that the nephropathy benefits with canagliflozin extend to the lower end of eGFR (possibly to those with eGFR < 30 mL/min/1.73 m²) and A1c scales (< 7%).

Further questions about whether these benefits observed in an overt diabetic nephropathy patient population apply to those with lesser magnitude of proteinuria, or even nondiabetic nephropathy, may be answered by Dapa-CKD (possibly reporting in 2020) and EMPA-KIDNEY.

2. REWIND

Although CREDENCE was halted early (median follow-up of 2.6 years), REWIND ran its full course (median follow-up of 5.4 years), making it the longest-running diabetes medication CVOT published to date. Overall, the primary outcome showed a reduction in MACE, with no new safety signals for dulaglutide.

REWIND's claim to fame is that it extends the MACE benefits with GLP-1 receptor agonists—previously reported mostly in secondary prevention (LEADER, SUSTAIN-6, and Harmony Outcomes)—to primary prevention in high-risk patients. REWIND participants with and without history of cardiovascular disease (CVD) had a similar 12% relative risk reduction on MACE. A separate analysis showed a hint of renal protection, which will need to be investigated further in dedicated nephropathy trials.

Even though REWIND had the most generalizable population of all the CVOTs to date, the primary prevention population in this trial also included patients with cardiovascular risk factors (participants aged ≥ 55 years had left ventricular hypertrophy, nephropathy, or subclinical CVD; those aged ≥ 60 years also had at least two additional risk factors, such as tobacco use, dyslipidemia, hypertension, or abdominal obesity). So keep in mind that these results do not necessarily apply to every lower-risk patient who walks into your clinic.

3. European Society of Cardiology (ESC) Guidelines

My third pick is the somewhat controversial guideline from the ESC, developed in collaboration with the European Association for the Study of Diabetes (EASD). As if buoyed by the exciting results of CREDENCE and REWIND, this new guideline, focusing entirely on macrovascular risk reduction in people with diabetes (or those at risk for diabetes), accentuates these findings with a brand-new cardiovascular risk classification.

There are three patient factors that lead to a patient being categorized as "very high risk" in this new classification system:

Established CVD;
Target organ damage (nephropathy, left ventricular hypertrophy, or retinopathy); and
The presence of three or more major risk factors (age, hypertension, dyslipidemia, smoking, or obesity).

The guideline offers several new recommendations for this eclectic "very high risk" group. These include consideration of a GLP-1 receptor agonist or an SGLT2 inhibitor as first-line therapy (ie, even before metformin), an LDL target of < 54 mg/dL (< 1.4 mmol/L), and a consideration for aspirin even without history of established CVD.

Watch for my next Sugar Beat column on the topic of metformin (the holy grail of type 2 diabetes management for several decades) being sidetracked to second-line status for very high-risk individuals in the ESC guidelines.

4. DAPA-HF

The results of this first bona fide trial of heart failure treatment with an SGLT2 inhibitor in patients with reduced ejection fraction were released at the ESC World Congress in August 2019.

Clear-cut benefits, including a reduction in all-cause mortality, with no new adverse effects (specifically no increase in volume depletion adverse effects), were reported. During the trial period (median, 18 months), the number needed to treat with dapagliflozin to prevent one primary event (worsening heart failure or cardiovascular death) was 21.

Of interest, data released at the 2019 American Heart Association Scientific Sessions suggest that the primary outcome benefit is consistent across age groups and the range of baseline health status, and in diabetes and normoglycemia/prediabetes.

The obvious outstanding question of whether these benefits are observed in truly normoglycemic individuals (ie, those without prediabetes) remains to be answered.

Additionally, we need more data analysis and further trials to determine whether the same benefits apply to those with high New York Heart Association (NYHA) Class heart failure or those with preserved ejection fraction. Note that there was significant heterogeneity in DAPA-HF, with no apparent reduction in the primary endpoint seen in those with NYHA Class III-IV HF at baseline.

5. DECLARE-TIMI 58

Though the original trial published in early 2019 showed a significant reduction in the primary outcome of cardiovascular death/hospitalization for HF (CVD/HHF) but not MACE, further analyses released at the American College of Cardiology, ADA, EASD, and IDF congresses in 2019 provided new insights into the benefits of dapagliflozin:

MACE reduction in addition to CVD/HHF in those with a history of myocardial infarction, with an apparent greater benefit for MACE within 2 years after the last acute event;
Reduced progression of kidney disease in those with and without established CVD;
Consistent reduction in CVD/HHF regardless of preserved or reduced ejection fraction or age subgroups at baseline; and
Significant heterogeneity in diabetes duration with reductions in MACE, myocardial infarction, and stroke suggested for participants with longer-standing diabetes (> 20 years), even in those without a history of established CVD.

Many of these later analyses are post-hoc or depend on subgroups, and hence should be considered as hypothesis generating.

The clinically important question of whether the combination of an SGLT2 inhibitor and a GLP-1 receptor agonist had additive cardiovascular benefits could not be addressed in DECLARE. This will need to be evaluated in future SGLT2-inhibitor trials with a higher proportional use of GLP-1 receptor agonists, or trials of a GLP-1 receptor agonist with a higher proportional use of SGLT2 inhibitors.

And Not to Be Dismissed...

Among the honorable mentions for this year's top highlights:

The CAROLINA CVOT, which showed neutral MACE results (and lower rates of hypoglycemia, as expected), with linagliptin versus glimeperide in patients with relatively early type 2 diabetes and elevated cardiovascular risk. This should be taken as the final CVOT verdict for DPP-4 inhibitors and, more importantly, sulfonylureas. Both are safe to prescribe from a cardiovascular perspective.
The PIONEER 6 trial, which showed safety (neutral MACE) of oral semaglutide in a small, preapproval CVOT. A much larger CVOT named SOUL, with a superiority objective, is ongoing. Meanwhile, oral semaglutide became the first ever oral GLP-1 receptor agonist to get the FDA nod.

Overall, 2019 will be remembered as the year SGLT2s and GLP-1s delivered important cardio- and nephroprotection data, along with expanding indications.

As before, however, those prescribing any of these diabetes agents must continue to take into consideration clinical scenarios, patient preferences, adverse effects/intolerances, cost and coverage, etc.

Here's to good evidence in diabetes continuing in 2020! I wish you all a happy new year.

Harpreet S. Bajaj, MD, MPH, is a community endocrinologist in Brampton, Ontario, and vice chair of the Diabetes Canada Guidelines. His clinical and research interests are the prevention and management of diabetes and its related complications. He is the founder of STOP Diabetes Foundation and volunteers with numerous community public health organizations to raise awareness of diabetes prevention and treatment.

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