As Trials Report Cardiovascular Outcomes Data, What About Microvascular Results?

LARGE CARDIOVASCULAR OUTCOMES trials (CVOTs), designed to show how new diabetes medications afect the incidences of cardiovascular (CV) death, heart attacks, and strokes, also provide limited insight into another area: microvascular complications, such as renal neuropathy and retinopathy.

The data, however, do not tell a consistent story. Glucagon-like peptide 1 (GLP-1) receptor agonists may reduce the overall risk of kidney problems, but at least 1 medication in the class was associated with proliferative retinopathy progression in trial patients. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, on the other hand, appear to reduce the overall risk of kidney problems more than any of the GLP-1 agonists, all without any reported short-term efect on retinopathy. However, the SGLT2 inhibitor, canaglifozin—but no other drug from this class to date—is associated with a higher risk of amputation compared with placebo, although overall rates were small. As for dipeptidyl peptidase-4 (DPP-4) inhibitors, there’s no evidence that they have any particular infuence on any microvascular outcome (although these outcomes were not rigorously evaluated with these agents in CVOTs).

The strength for all of these vascular fndings is far from conclusive, but according to John B. Buse, MD, PhD, there’s more evidence of renal protection, particularly for the SGLT2 inhibitors, than damage elsewhere. The ease of measuring creatinine levels ensures that most CVOTs collect regular data on every patient’s kidney function, but no CVOT has regularly measured circulation to the eyes and extremities, so the outcome data have come from the very few patients whose adverse events required surgical procedures.

“The CVOTs to date haven’t made any efort to systematically measure neuropathy or retinopathy in all patients, and there just aren’t enough surgeries to use them as proxies. I suspect the association between some drugs and increased surgeries may stem from the suddenness with which they lower blood sugar,” said Buse, a distinguished professor at the University of North Carolina (UNC) School of Medicine who has participated in several CVOTs. “Previous work has shown that fasting blood sugar reductions can exacerbate preexisting eye problems, even though lower blood sugar reduces long-term complications, so doctors might want to take the precaution of starting small and gradually increasing the dose, particularly in poorly controlled patients who already have eye damage. For patients with clinical CV disease, the benefts on heart attack, stroke, and CV death far exceeds these small risks.

“The evidence on kidney function is much more robust, and it shows that both GLP-1 agonists and SGLT2 inhibitors tend to improve outcomes. That said, the fndings are not yet strong enough that they should be a major consideration in drug selection,” said Buse, who is also the chief of UNC Health Care’s Division of Endocrinology and head of its diabetes center. “The main consideration is still what it has always been: getting the patient’s A1C [glycated hemoglobin] to target levels of blood sugar control with whatever combination of medications works best for each patient.”

GLP-1 Agonists:

• The LEADER trial, which randomized 9340 patients between liraglutide (Victoza) and placebo and followed them for a median period of 3.8 years, made headlines by finding that the GLP-1 analogue was associated with lower rates of stroke, myocardial infarction, and CV death. Less publicized was the fact that liraglutide use was associated with a signifcant reduction in nephropathy events, which were defned as “a new onset of persistent macroalbuminuria or persistent doubling of serum creatinine level and creatinine clearance per MDRD<45 mL/min/1.73m² [Modifcation of Diet in Renal Disease Study equation] or the need for continuous renal-replacement therapy (in the absence of an acute reversible cause) or death due to renal disease.” There were 1.5 such events per 100 patient-years in the liraglutide group and 1.9 per 100 patient-years in the placebo group (HR, 0.78; 95% CI, 0.67-0.92; P = .003). There was no signifcant diference in retinopathy between the 2 groups and no specifc attempt to measure neuropathy by amputations or other vascular outcomes.¹
• The SUSTAIN-6 trial, which randomized 3297 patients among placebo and 2 doses of semaglutide (a longer-acting version of liraglutide), found that the GLP-1 agonist resulted in signifcantly less nephropathy than placebo (defned as in the LEADER trial) and signifcantly more proliferative retinopathy progression (defined as “the need for retinal photocoagulation or treatment with intravitreal agents or vitreous hemorrhage or diabetes-related blindness). Neuropathy events were detected in 62 semaglutide patients and 100 placebo patients (HR, 0.64; 95% CI, 0.46-0.88; P = .005). Retinopathy was detected in 50 semaglutide patients and 26 placebo patients (HR, 1.76; 95% CI, 1.11-2.78; P = .02).²
• The ELIXA trial, which randomized 6068 patients between lixisenatide (Adlyxin) and placebo, found that the albumin/creatine ratio in urine samples rose 26% in lixisenatide users (to 11.9 mg/g) and 32% in placebo users (to 13.4 mg/g). Renal and urinary adverse events were also found in fewer lixisenatide patients (12) than placebo patients (20). Neither result rose to the level of signifcance, however, and there were no data on retinopathy or neuropathy.³
• The EXSCEL trial, which randomized 14,752 patients between weekly exenatide (Byetta) and placebo, did not report any microvascular data in the main paper.⁴

SGLT2 Inhibitors:

• The EMPA-REG OUTCOME trial, which randomized 7020 patients among 2 doses of the SGLT2 inhibitor, empaglifozin (Jardiance), and placebo, also found evidence of CV beneft, but the initial write-up provided no signifcant microvascular data. The rate of kidney failure was lower in empaglifozin users than in the placebo group (5.2% vs 6.6%, respectively), but the diference was not signifcant. The study did not publish any comparative data related to neuropathy or retinopathy.⁵
• The CANVAS program, which followed 10,142 patients who were randomized between canaglifozin (Invokana) and placebo for a mean period of more than 3 years, also found better renal outcomes in the canaglifozin group than in the placebo group. There was a 40% reduction in combined endpoint of estimated glomerular fltration rate, the need for renal-replacement therapy, or death from renal causes (HR of canaglifozin was signifcantly associated with increased risk of lower extremity amputation. There were 6.3 amputations (mostly toes or metatarsals) per 1000 patient-years in the canaglifozin group and 3.4 amputations per 1000 patient-years in the placebo group (HR, 1.97; 95% CI, 1.41-2.75).⁶

DPP-4 Inhibitors:

• The EXAMINE trial, which followed 5380 patients randomized between alogliptin (Nesina) and placebo, tracked kidney function over a median period of 18 months and found no signifcant diference between the 2 arms. The study paper did not disclose any data about retinopathy or neuropathy.⁷
• The SAVOR-TIMI-53 trial, which randomized 16,492 patients between saxagliptin and placebo, did not reveal meaningful diferences in signifcant renal events. The study authors did not disclose data on less serious kidney problems or on neuropathy or retinopathy.⁸
• The TECOS trial, which randomized 14,671 patients between sitagliptin (Januvia) and placebo, reported on several types of microvascular outcomes but found little diference between the medication and placebo. Renal failure occurred in 1.4% (100) of sitagliptin patients and 1.5% (111) of placebo patients, which was not a signifcant diference. Similar numbers of sitagliptin and placebo patients also experienced peripheral arterial disease (2.7% [197] vs 2.9% [209]), amputation (0.8% [60] vs 0.9% [66]), diabetic neuropathy (4.1% [303 vs 3.8% [281]), diabetic blindness (0.3% [24] vs 0.3% [25]), and retinopathy (2.8% [205] vs 2.2% [158]).⁹

Physicians should have more microvascular outcome data to guide their decisions. Another major CVOT, the DECLARE-TIMI-58 trial of dapaglifozin (Farxiga), is expected to report results in 2019. Researchers, moreover, are mining the huge amounts of data generated by existing CVOTs to find additional results. All of the initial papers focused very heavily on the CV outcomes such trials are designed to measure.)

Researchers have already mined data from the EMPA-REG trial for more information about empaglifozin and renal function, and they have found that SGLT2 inhibitor use is associated with slower progression of kidney disease and fewer renal events. New or worsening nephropathy occurred in 525 of 4124 (12.7%) empaglifozin patients and 388 of 2061 (18.8%) placebo patients (HR, 0.61; 95% CI, 0.53-0.70; P <.001).¹⁰

“The renal outcomes analysis from EMPA-REG evaluated several measures of renal disease progression and found that empaglifozin use was consistently associated with relative risk reduction in important renal events of approximately 40%. Analysis of canaglifozin data from the CANVAS program produced similar fndings. Although these studies were not specifcally designed to evaluate chronic kidney disease [CKD] progression as a primary outcome (most patients in these trials did not have signifcant CKD at baseline), these results are still pretty compelling,” said Mikhail Kosiborod, MD, a professor of medicine at Saint Luke’s Mid America Heart Institute and University of Missouri-Kansas City School of Medicine, who was not involved in either EMPA-REG or CANVAS, but is participating in other CVOTs of antidiabetic agents.

“All other things being equal, these fndings suggest that, clinically, one might consider an SGLT2 inhibitor for a patient with evidence of early diabetic nephropathy. More data will be generated on this very topic in the next few years, with several dedicated large clinical trial programs currently evaluating the efects of various SGLT2 [inhibitors] on renal outcomes in patients with CKD, regardless of diabetes status.”

Other research teams are working to combine data from various trials to perform meta-analyses. The hope, as always, is that truly giant patient populations will create the statistical power needed to reach fndings that go beyond the scope of the individual studies.

Better still, the makers of empaglifozin and dapaglifozin have already begun new trials in patients with CKD. The frst of the trials will have 5000 patients¹¹ and the second will have 4000 patients.¹² The CREDENCE trial of canaglifozin’s renal outcomes, moreover, has already been going on for several years.¹³

There will be limits, however, to the ability of all of this research to answer questions about microvascular outcomes. Many of the trials that are available for researchers to analyze simply did not collect much data on neuropathy or retinopathy, and CVOT patients, depending on the trial, may not be refective of patients with type 2 diabetes as a whole. Most of them have longstanding and poorly controlled disease that has already led to a CV event, and although their microvascular profles may be more representative, there’s no guarantee that their outcomes will mirror those of other patients.

Despite these limitations, physicians have little reason to expect more robust microvascular data anytime soon. Trials specifcally designed to discover how new drugs afect neuropathy and retinopathy seem unlikely. The Diabetes Control and Complications Trial took 10 years to demonstrate the microvascular benefts of a 2 percentage point reduction of A1C levels (in patients with type 1 diabetes).¹⁴ Establishing the beneft, if any, of lesser reductions associated with the use of new medications would likely take longer and cost more, even if the specifc effects of those medications improved outcomes by means other than blood sugar reduction, Buse said.

Efforts to mine real-world data can help, but have their own limitations. Coding errors can occur with microvascular outcomes, which may impact the findings. If patients switch medications frequently, as patients with diabetes do, this may complicate interpretation of the results. Even in places like the United Kingdom or Denmark, where most citizens are publicly insured and limited formularies minimize drug switching, it’s hard for retrospective analyses to provide a high degree of certainty for microvascular events.REFERENCES

1. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi: 10.1056/ NEJMoa1603827.

2. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844. doi: 10.1056/NEJMoa1607141.

3. Pfeffer MA, Claggett B, Diaz R, et al; ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247-2257. doi: 10.1056/NEJMoa1509225.

4. Holman RR, Bethel MA, Mentz RJ, et al; EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228-1239. doi: 10.1056/NEJMoa1612917.

5. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.

6. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925.

7. White WB, Cannon CP, Heller SR, et al; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-1335. doi: 10.1056/NEJMoa1305889.

8. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI-53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326. doi: 10.1056/NEJMoa1307684.

9. Green JB, Bethel MA, Armstrong PW, et al; TECOS Study Group. Effects of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232-242. doi: 10.1056/NEJMoa1501352.

10. Wanner C, Inzucchi SE, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323-334. doi: 10.1056/NEJMoa1515920.

11. AstraZeneca announces two new phase IIIb trials for Farxiga in chronic kidney disease and chronic heart failure [press release]. Cambridge, UK: AstraZeneca; September 12, 2016. astrazeneca.com/media-centre/press-releases/2016/astrazeneca-announces-two-new-phase-IIIb-trials-for-Forxiga-in-chronic-kidney-disease-and-chronic-heart-failure-120920161.html. Accessed November 27, 2017.

12. Empagliflozin (Jardiance) to be studied in chronic kidney disease [press release]. Ingelheim, Germany, and Indianapolis, IN: Boehringer Ingelheim; June 12, 2017.

https://www.boehringer-ingelheim.com/press-release/empagliflozin-be-studied-chronic-kidney-disease. Accessed November 27, 2017.

13. Evaluation of the effects of canagliflozin on renal and cardiovascular outcomes in participants with diabetic nephropathy (CREDENCE). clinicaltrials. gov/ct2/show/NCT02065791. Updated August 28, 2017. Accessed November 27, 2017.

14. Nathan DM; DCCT/EDIC Research Group. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care. 2014;37(1):9-16. doi: 10.2337/dc13-2112.

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