GLP-1 dulaglutide dec renal and cardiovasc events

Another industry-sponsored study found benefit for a GLP-1 agonist on renal and cardiovascular outcomes, this time with dulaglutide in the REWIND study.

RENAL BENEFITS: (see dm dulaglutide dec renal events lancet2019 in dropbox, or doi.org/10.1016/S0140-6736(19)31150-X

Details:

-- 9901 participants from 371 sites in 24 countries in this randomized double-blind trial, comparing dulaglutide injections of 1.5 mg vs placebo

-- mean age 66, 46% women, 76% white, duration of diabetes 11 years, median A1c 7.2%, BMI 32, blood pressure 137/78,

-- meds: metformin 81%, sulfonylureas 46%, insulin 24%, ACE inhibitors 50%, ARB’s 34%, ACE-I or ARB 81%

-- baseline: 8% had macroalbuminuria, 27% microalbuminuria, mean urinary albumin/creatinine ratio UACR, 2 mg/g, mean eGFR 77 (22% had eGFR <60), creatinine 0.95 mg/dL

-- primary composite outcome: 1^st occurrence of nonfatal MI, nonfatal stroke, or death from cardiovascular causes

-- secondary outcome composite of microvascular outcomes (eye and renal) and safety outcomes

-- participants took the dulaglutide 82% of the follow-up time

-- this was an exploratory analysis assessing the renal component of the composite microvascular outcomes: 1^st occurrence of new macroalbuminuria (UACR, >30 mg/g), sustained decline of eGFR > 30% from baseline, or chronic renal replacement therapy

-- UACR and eGFR were measured every 12 months

-- follow-up 5.4 years

Results:

-- over 51,820 person-years, renal outcome developed in:

    -- dulaglutide group: 848 (17.1%), incidence rate of 3.5 per 100 person-years

    -- placebo : 970 (19.6%), incidence rate of 4.1 per 100 person-years

        -- 15% lower with dulaglutide, HR 0.85 (0.77-0.93), p=0.0004

-- clearest effect was for new macroalbuminuria, at 23% lower rate, HR 0.77 (0.68-0.87), p<0.0001. The graph showed a decrease over the 1^st year of treatment, then the curves paralleled each other

-- sustained decline of eGFR>30%: almost clinically significant 11% decrease, HR 0.89 (0.78-1.01), p=0.066. This reflected decreases of 4.32 ml/min/1.73 m² for dulaglutide and 4.75 for placebo over the course of the study. The graphs show pretty linear decrease continuing over time

-- chronic renal replacement therapy: nonsignificant difference (all 3 of these outcomes had similar 25% decreases, though for chronic renal replacement it was far from statistically significant, not surprisingly given how renally-healthy this cohort was)

-- at the final visit, fewer people on dulaglutide were taking drugs that are known to improve renal outcomes, including SGLT2 inhibitors (5.3% vs 7.3%), or ACE inhibitors/ ARBs (75.8% vs 77.6%)

-- subgroup analysis: very similar dulaglutide benefits if eGFR <60 or >60, normo- vs micro- or macroalbuminuria, or ACE inhibitor/ARB use, as well as subgroups defined by age, sex, duration of diabetes, and baseline A1c.

-- Dulaglutide was also associated with 25% reduced incidence of sustained eGFR of >40% or >50%

-- the overall absolute risk difference: 1 composite renal outcome would be prevented for every 31 similar people with diabetes treated with dulaglutide for median of 5.4 years

Commentary:

-- in general, diabetic kidney disease (as defined by an eGFR <90) affects 40% of people with diabetes; and this is an independent risk factor for cardiovascular disease, hypertension, retinal disease, and premature death

-- and, diabetes is responsible for 45% of people who develop end-stage renal disease

-- current medical interventions to decrease the rate of diabetic kidney disease are primarily through intensive glucose control and blood pressure lowering. In addition, use of ACE inhibitors or ARBs and SGLT2 inhibitors help.

-- Other studies have found that the GLP-1’s liraglutide in semaglutide decrease predefined composite renal outcomes overall, as well as in people with an already reduced eGFR.

-- A recent report of the AWARD-7 study (see dm dulaglut vs insulin renal failure lancetdiabendo2018 in dropbox, or doi.org/10.1016/S2213-8587(18)30104-9) found that comparing dulaglutide vs insulin glargine in patients with stage III or IV CKD, and achieving similar A1c results, found a reduced decline in eGFR with dulaglutide in this one year trial. The REWIND study found a pretty-close-to statistically significant effect on eGFR, though the patients in this study had much less renal disease to begin with, and also had pretty well controlled diabetes at the start, so were at much lower risk of a renal decline

-- part of the explanation for renal protection is likely that the baseline A1c and systolic blood pressure decreased more in those on dulaglutide. Controlling for the likely contributions of these changes, the effect of dulaglutide on renal outcomes was attenuated by up to 26% after accounting for the effects of the A1c change and up to 15% after the effect on systolic blood pressure. This suggests that other factors are involved in the renal protection, and GLP-1 agonists are known to reduce inflammation, oxidative stress, and preserve endothelial function

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CARDIOVASCULAR BENEFITS: see dm dulaglutide dec cardiovasc lancet2019 in dropbox, or doi.org/10.1016/S0140-6736(19)31149-3

Details: as above with the following differences:

-- 32% had previous cardiovascular disease (ie 1/3 of the patients were assessed for secondary prevention; 2/3 primary prevention: a pretty healthy cohort since about 80% of diabetics die from cardiovascular disease)

-- primary outcome was 1^st occurrence of composite endpoint of nonfatal MI, nonfatal stroke, or death from cardiovascular causes

-- secondary outcomes: as in renal, but also hospital admission for unstable angina

Results:

--over the 5.4 years, primary composite outcome:

    -- dulaglutide: 594 people (12.0%), incidence rate of 2.4 per 100 person-years

    -- placebo: 663 people (13.4%), incidence rate of 2.7 per 100 person-years

        -- 12% decrease, HR 0.88 (0.79-0.99), p=0.026

-- consistent effect was found for all 3 components of the primary outcome, though the only one to reach statistical significance was for nonfatal stroke, with 24% decreased, HR 0.76 (0.61-0.95),p=0.017

-- subgroup analysis showed similar reductions in primary outcome for those with and without prior cardiovascular disease, those with A1c > vs <7.2%, and in those analyzed according to age, sex, duration of diabetes, and BMI. However I could find no specific analysis of those on vs off sulfonylurea/insulin therapy

-- for every 60 people with diabetes and additional cardiovascular risk factors treated for a 5.4 years with dulaglutide, one cardiovascular event was prevented; for those with a previous cardiovascular event (secondary prevention), it was one in 18

-- all-cause mortality did not differ between the groups, 10.8% in dulaglutide, 12% of placebo, HR 0.90 (0.80-1.01) ,p=0.67

-- no difference in hospitalizations for heart failure

Commentary: 

-- This trial also involved quite low risk patients, the average cardiovascular incidence of participants on placebo was 2.7%

-- it was notable that stroke reduction was the most significant of the cardiovascular outcomes assessed

-- one benefit of this trial is that its duration was significantly longer than that for the SGLT2 studies

-- One limitation is that about 25% of patients were not taking the study drug with a full 5.4 years

-- Given my evident preference for GLP-1 agonists over SGLT2’s (see multiple prior blogs, including http://gmodestmedblogs.blogspot.com/2019/06/diabetes-oral-semaglutide-better-than.html and https://gmodestmedblogs.blogspot.com/2019/06/diabetes-guideline-update-pushing-sglt.html), I should add that there seems to be a synergy with the combo: (see dm semaglut added to sglt2 lancet2019 in dropbox, or doi.org/10.1016/S2213-8587(19)30066-X), where adding semaglutide 1.0 mg vs placebo to an SGLT2 inhibitor led to an added 1.42 percentage point decrease in A1c.

so,

-- this REWIND trial did find a benefit for the GLP-1 dulaglutide for both renal and cardiovascular outcomes, even though these patients at baseline were at quite low risk of a significant complication

-- i bring these articles up because they are confirmatory of others suggesting benefit of GLP-1’s, but this time in a much healthier population with a longer life expectancy and therefore a likely increasingly improving benefit over their anticipated longer lifespans. 

-- Again, this supports the concept of starting with metformin and then adding a GLP-1 as a second medication, even in those with relatively well-controlled diabetes (this study started with mean A1c of 7.2%) and without pre-existing comorbidities.

geoff​

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