Glomerular Filtration Rate and Associated Risks of
Cardiovascular Events, Mortality, and Severe Hypoglycemia in Patients with Type 2 Diabetes:
Secondary Analysis (DEVOTE 11)
verfasst von:
Aslam Amod, John B. Buse, Darren K. McGuire, Thomas R. Pieber, Rodica Pop-Busui, Richard E. Pratley, Bernard Zinman, Marco Bo Hansen, Ting Jia, Thomas Mark, Neil R. Poulter, the DEVOTE Study Group
The associations of chronic kidney disease (CKD) severity, cardiovascular
disease (CVD), and insulin with the risks of major adverse cardiovascular events (MACE),
mortality, and severe hypoglycemia in patients with type 2 diabetes (T2D) at high
cardiovascular (CV) risk are not known. This secondary, pooled analysis of data from the DEVOTE
trial examined whether baseline glomerular filtration rate (GFR) categories were associated
with a higher risk of these outcomes.
Methods
DEVOTE was a treat-to-target, double-blind trial involving 7637 patients with
T2D at high CV risk who were randomized to once-daily treatment with either insulin degludec
(degludec) or insulin glargine 100 units/mL (glargine U100). Patients with estimated GFR data
at baseline (n = 7522) were analyzed following
stratification into four GFR categories.
Results
The risks of MACE, CV death, and all-cause mortality increased with worsening
baseline GFR category (P < 0.05), with a trend towards
higher rates of severe hypoglycemia. Patients with prior CVD, CKD (estimated
GFR < 60 mL/min/m2), or both were at higher risk of MACE, CV
death, and all-cause mortality. Only CKD was associated with a higher rate of severe
hypoglycemia, and the risk of MACE was higher in patients with CVD than in those with CKD
(P = 0.0003). There were no significant interactions
between randomized treatment and GFR category.
Conclusion
The risks of MACE, CV death, and all-cause mortality were higher with lower
baseline GFR and with prior CVD, CKD, or both. The relative effects of degludec versus glargine
U100 on outcomes were consistent across baseline GFR categories, suggesting that the lower rate
of severe hypoglycemia associated with degludec use versus glargine U100 use was independent of
baseline GFR category.
There is limited evidence regarding the associations of severity of chronic
kidney disease (CKD) with the risks of various outcomes in patients with type 2 diabetes
(T2D).
Data are particularly limited for older individuals with multiple
comorbidities, where the associations of coexisting CKD, established cardiovascular
disease (CVD), and basal insulin with the risks of outcomes are not clear.
Our secondary analysis from the DEVOTE cardiovascular outcomes trial examined
whether baseline glomerular filtration rate (GFR) categories or a prior medical history of
CKD, CVD, or both were associated with higher risks of the above outcomes.
What was learned from the study?
In the DEVOTE cohort of patients at high cardiovascular risk, worsening
baseline GFR categories were associated with progressively higher risks of cardiovascular
events and death, with a trend towards higher rates of severe hypoglycemia. There were no
significant interactions between randomized treatment and GFR category, although
consistently lower rates of severe hypoglycemia were observed with degludec compared with
glargine U100, regardless of prior CVD or prior CKD (there was no significant difference
for those without prior CVD).
The relative effects of degludec and glargine U100 on cardiovascular outcomes
were consistent across the baseline GFR categories, suggesting that the lower rates of
severe hypoglycemia observed with degludec versus glargine U100 were independent of
baseline GFR category (there were only significant differences for GFR categories G2 and
G3).
Considering that there was an observed association between baseline GFR
category and risk of death regardless of randomized basal insulin assignment, a better
understanding of this association and methods to mitigate the incremental risk associated
with declining GFR remain important clinical objectives.
Introduction
Cardiovascular disease (CVD) and chronic kidney disease (CKD) are highly
prevalent comorbidities in patients with type 2 diabetes (T2D) [1, 2]. Both are associated with an
increased risk of death [3‐6].
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Historically, cardiovascular outcomes trials (CVOTs) have excluded patients with
CKD [7], while standard trials of antihyperglycemic
therapies have typically enrolled cohorts of younger patients at a lower risk of cardiovascular
events [8]. However, as a result of industry
guidance, CVOTs for new antihyperglycemic therapies now include patients at high risk of
cardiovascular events (including those with CVD or CKD) [9, 10]. Recently, results from a
number of CVOTs (and secondary analyses) of patients with T2D have been published that
demonstrate the potential for some antihyperglycemic therapies to improve cardiovascular and/or
renal outcomes [11‐15]. Some of these CVOTs have
also compared the effects of treatment on cardiovascular outcomes in patients with T2D
stratified by baseline estimated glomerular filtration rate (eGFR) [11, 14,
16].
Antihyperglycemic medications in patients with differing levels of renal function
can affect treatment efficacy and safety; for instance, they can lead to an increased risk of
hypoglycemia [11] and/or increased risks of
cardiovascular events and mortality [17‐23], resulting in product-label cautions, warnings, and
contraindications [11, 24]. As patients with a lower glomerular filtration rate (GFR)
tend to have a higher burden of CVD, a longer duration of T2D, and more commonly require insulin
therapy [11, 14], there is a need to better understand the relationships between CKD and CVD
risk factors, outcomes, and the use of medications in this population (particularly those with
severe CKD who have been excluded from most trials) [11].
DEVOTE, a CVOT comparing insulin degludec (degludec) and insulin glargine 100
units/mL (glargine U100) in a population at high cardiovascular risk and renal risk, presents an
opportunity to evaluate cardiovascular outcomes in insulin-treated patients with T2D along with
CVD and/or CKD [25]. Thus, the present analyses
evaluated the associations of baseline GFR category, prior CVD, and/or prior CKD with the risks
of major adverse cardiovascular events (MACE), cardiovascular death, all-cause mortality, and
severe hypoglycemia. They also examined whether randomized treatment had an impact on these
outcomes stratified by baseline GFR category.
Methods
Trial Design
The secondary analyses described below utilized data from the DEVOTE CVOT.
Detailed descriptions of the protocol, methods, and primary results have been published
previously [25, 26]. In brief, DEVOTE was a multicenter, prospective, treat-to-target,
randomized, double-blind, active comparator CVOT that was designed to continue until at least
633 MACE (as confirmed by a central, blinded Event Adjudication Committee, EAC) had accrued.
DEVOTE is registered with ClinicalTrials.gov (NCT01959529) and was conducted in accordance with
the Declaration of Helsinki and the Good Clinical Practice Guideline of the International
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
[27, 28]. The protocol was approved by an independent ethics committee or
institutional review board for each center; written informed consent was obtained from each
patient before any trial-related activities were performed.
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Patients and Treatments
Patients eligible for inclusion in DEVOTE were those who had T2D treated with
at least one oral or injectable antihyperglycemic agent and had glycated hemoglobin (HbA1c)
levels ≥ 7.0% (53 mmol/mol) or < 7.0% and treated with ≥ 20 units/day of basal insulin. In
the present analyses comparing patients by baseline renal function, only patients with eGFR
data at baseline/time of randomization were included. In DEVOTE, patients were randomized 1:1
to receive either degludec or glargine U100 (both in identical 100-U/mL, 10-mL vials) blinded,
administered by subcutaneous injection once daily between the evening meal and bedtime, in
addition to the standard of care. Patients were eligible if they had a medical history of
either at least one coexisting cardiovascular or renal condition and were aged ≥ 50 years, or
if they had at least one among a range of pre-specified cardiovascular risk factors
(microalbuminuria or proteinuria; hypertension and left ventricular hypertrophy identified by
electrocardiogram or imaging; or left ventricular systolic and diastolic dysfunction identified
by imaging or ankle/brachial index < 0.9) and were aged ≥ 60 years [26]. All patients were allowed to continue their pre-trial
antihyperglycemic therapy with the exception of basal and premix insulins, which were
discontinued.
Outcomes
The main outcomes in the present analyses were as per the primary analysis in
DEVOTE [26]. The primary composite MACE outcome
was time to first occurrence of EAC-confirmed cardiovascular death, nonfatal myocardial
infarction, or nonfatal stroke. Secondary outcomes included time to EAC-confirmed all-cause
mortality and the number of EAC-confirmed severe hypoglycemic events. Severe hypoglycemia was
defined in accordance with the American Diabetes Association criteria as an episode requiring
the assistance of another person to actively administer carbohydrate or glucagon or to take
other corrective actions [29]. Other secondary
outcomes included the HbA1c level achieved, the fasting plasma glucose (FPG), and the
self-measured blood glucose (SMBG).
Statistical Analysis
In a set of pre-planned analyses, patients were grouped by baseline GFR
category according to their baseline renal function as defined by the Kidney Disease: Improving
Global Outcomes guidelines [30]:
GFR category G1 (≥ 90 mL/min/1.73 m2, normal
function)
GFR category G2 (60– < 90 ml/min/1.73 m2, mild
impairment)
GFR category G3 (30– < 60 mL/min/1.73 m2,
moderate impairment)
GFR category G4–5 (< 30 mL/min/1.73 m2, severe
impairment).
Patients with a baseline GFR category of G4 (n = 207) or G5 (n = 7) were combined to ensure
a sufficient number of patients and events in these categories were included for comparison
with other categories. The reference group for comparison of outcomes was G1, as these patients
were those with a normal baseline eGFR. Patient outcomes were also evaluated according to
randomized treatment by baseline GFR category.
Comparisons between GFR categories, treatment differences within each GFR
category, and the interaction between treatment and GFR category were investigated for all
outcomes. Analyses of outcomes were all pre-specified except for the evaluation of the
interaction between treatment and prior CKD (defined as
eGFR < 60 mL/min/1.73 m2 at baseline) [30] and/or prior CVD at baseline (according to medical
history) as well as the analyses of outcomes as a function of baseline eGFR (as a continuous
measure). Analyses investigating the associations of prior CVD and/or prior CKD with outcomes
utilized a pooled population (i.e., independent of the randomized treatment) of all patients
with CVD (with and without CKD) or with CKD (with and without CVD). In addition, supplementary
analyses compared the associations with outcomes in patients with prior CVD only to those with
prior CKD only.
Time from randomization to first MACE, cardiovascular death, and all-cause
mortality were analyzed using Cox proportional hazard regression models with treatment,
baseline GFR category, and interaction between treatment and baseline GFR category as fixed
factors. The number of severe hypoglycemic events was analyzed using a negative binomial
regression model with log-link function and the logarithm of the observation time (100 patient
years) as offset in addition to randomized treatment, baseline GFR category, and their
interactions. Additionally, for all the endpoints mentioned above, the interaction effect was
dropped from the corresponding models to obtain pooled contrasts for baseline GFR category. In
the analysis of the cardiovascular component of the MACE outcome, any patient whose first event
was death from noncardiovascular causes was censored at their time of death.
Sensitivity analyses of all the pre-specified analyses were conducted following
adjustment for the following additional baseline covariates: sex, geographical region, age,
diabetes duration, cardiovascular risk stratum, insulin use, and smoking status.
The relationship between baseline GFR and the proportion of events during
1 year was modeled by polynomials of up to five degrees, with the best model selected using
Akaike’s information criterion [31].
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Changes in HbA1c and FPG from baseline to 24 months by baseline GFR category
were analyzed with a mixed-effects model for repeated measures (MMRM) within participants,
using an unstructured residual covariance matrix among visits. Besides randomized treatment and
baseline GFR category, the MMRM included a fixed effect for the baseline measure of the given
outcome.
Interactions between visit and treatment, visit and GFR category, and visit and
first dose were also included as fixed effects, as was the three-way interaction
(treatment × GFR × visit). The pooled treatment population differences in change from baseline
HbA1c and FPG were analyzed by baseline GFR category using the same model with interactions
between visit and treatment, visit and GFR category, and visit and baseline included as fixed
effects, but without the three-way interaction effect. Total insulin dose (U/kg) at 24 months
was analyzed by GFR category using the same MMRM as above, but using an unstructured residual
covariance matrix among visits at 3, 6, 9, 12, 15, 18, 21, and 24 months, with log(first dose)
included as a fixed effect.
A two-sided P value of less than 0.05 was
considered statistically significant, although it was not multiplicity adjusted (SAS version
9.4, SAS Institute, Cary, NC, USA). All statistical analyses by randomized treatment assignment
followed the intention-to-treat principle.
Results
Patients
The median observation time in DEVOTE was 2.0 years for both treatments. In the
pre-planned analyses from DEVOTE (n = 7637), data on
baseline eGFR were available for 98% of patients (n = 7522).
Similar to the overall DEVOTE cohort, this population consisted of approximately equal numbers
of patients randomized to treatment with degludec (n = 3765)
or glargine U100 (n = 3757). In the total population
(n = 7637), established CVD (72%) was more common than CKD
(38%) at baseline. Furthermore, the presence of both prior CVD and prior CKD (25%) was more
common than the absence of both (15%).
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Comparing baseline characteristics and demographics across baseline GFR
categories, patients with worse GFR categories were older, had a longer diabetes duration,
included a lower proportion of males, had lower HbA1c levels, had higher body mass index (BMI)
values, and were more likely to have established CVD/CKD (Table 1). Patients with worse GFR categories were also more likely to use insulin,
angiotensin-receptor blockers, diuretics, and lipid-modifying drugs. In contrast, metformin and
angiotensin-converting enzyme inhibitor use was more common in patients with less advanced GFR
categories. Detailed comparisons of these data are provided in the supplementary results in the
Electronic supplementary material (ESM), as are descriptions of baseline blood pressure and
potassium levels.
*GFR categories G1–5 were defined according to the Kidney Disease: Improving
Global Outcomes (KDIGO) guidelines [30]
†Six patients had missing drug initiation dates; they
were assumed to be on treatment at baseline
‡Pre-trial insulin treatment
§Nine patients had missing drug initiation dates; they
were assumed to be on treatment at baseline
¶Conversion factor for serum creatinine in mg/dL to
μmol/L, × 88.4. A total of 115 patients had missing baseline eGFR data and were removed from
the analysis
Cardiovascular and Mortality Outcomes
Worse baseline GFR categories were associated with numerically higher risks of
MACE, cardiovascular death, and all-cause mortality. Compared with patients with normal
baseline eGFR (G1), risks were significantly higher for MACE (G3–5), cardiovascular death
(G2–5), and all-cause mortality (G2–5) (Figs. 1,
2). Cardiovascular death accounted for 66% of
all-cause mortality (n = 277/422), with similar
contributions seen for all baseline GFR categories (63–69%). Cardiovascular death accounted for
41% of all MACE (n = 277/671); this increased from 27% in
patients with GFR category G1 to 36, 50, and 53% in patients with GFR categories G2, G3, and
G4–5, respectively. When evaluating outcomes using baseline eGFR as a continuous variable, the
risks of MACE, all-cause mortality, and cardiovascular death were higher in patients with lower
eGFR, but the relationship was nonlinear (Fig. S1 in the ESM).
Fig. 1
Risks of various outcomes by baseline GFR category relative to GFR category G1.
*Rate of events/100 patient years of exposure. GFR category G1 (solid circle) was used as
the reference for GFR categories G2, G3, and G4–5 (open circles). Time from randomization
to first MACE, cardiovascular death, and all-cause mortality were analyzed using Cox
proportional hazard regression models with treatment, baseline GFR category, and
interaction between treatment and baseline GFR category as fixed factors. The number of
severe hypoglycemic events was analyzed using a negative binomial regression model with
log-link function and the logarithm of the duration of observation time (100 patient years)
as offset in addition to randomized treatment, baseline GFR category, and their
interactions. Data on the proportion of patients with events and the rate of severe
hypoglycemic events are based on observed numbers. CI
confidence interval, CV cardiovascular, GFR glomerular filtration rate, MACE major adverse cardiovascular events
Fig. 2
Kaplan–Meier plots for a time to first MACE,b time to cardiovascular death, c time to all-cause mortality, and d number
of severe hypoglycemic events by baseline GFR category. GFR glomerular filtration rate, MACE major
adverse cardiovascular events
×
×
There were no significant interactions between randomized treatment (degludec
versus glargine U100) and baseline GFR category for MACE, cardiovascular death, or all-cause
mortality (Fig. 3).
Fig. 3
Comparisons of associations of treatment with degludec or glargine U100 with the
risks of MACE, cardiovascular death, and all-cause mortality and the rate of severe
hypoglycemia by baseline GFR category. *P value for the
interaction between treatment and baseline GFR category;†rate of
events/100 patient years of exposure. Time from randomization to first MACE, cardiovascular
death, and all-cause mortality were analyzed using Cox proportional hazard regression
models with treatment, baseline GFR category, and interaction between treatment and
baseline GFR category as fixed factors. The number of severe hypoglycemic events was
analyzed using a negative binomial regression model with log-link function and the
logarithm of the duration of observation time (100 patient years) as offset in addition to
randomized treatment, baseline GFR category, and their interactions. Data on the proportion
of patients with events and the rate of severe hypoglycemic events are based on observed
numbers. The MACE and severe hypoglycemia analyses have already been published
[25]. CI
confidence interval, GFR glomerular filtration rate,glargine U100 insulin glargine 100 units/mL, MACE major adverse cardiovascular events
×
Severe Hypoglycemia
There was a nonsignificant trend towards higher rates of severe hypoglycemia
with more advanced baseline GFR category (Figs. 1,
2), with the risk of severe hypoglycemia increasing
with decreasing baseline eGFR (Fig. S1 in the ESM). There was no evidence of heterogeneity
regarding the association between randomized treatment and baseline GFR category for severe
hypoglycemia, as illustrated by the nonsignificant interaction (P = 0.9; Fig. 3).
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Sensitivity Analyses of MACE, All-Cause Mortality, and Severe Hypoglycemia
The sensitivity analyses adjusting for baseline covariates were broadly
consistent with the results of the primary analyses (Table S1 in the ESM). However, after
adjustment, compared with patients with GFR category G1, patients with GFR category G2 no
longer had significantly higher risks of cardiovascular death or all-cause mortality, and
patients with GFR category G3 no longer had a significantly higher rate of severe
hypoglycemia.
Associations of Prior CVD and Prior CKD with the Risks of MACE, Cardiovascular Death,
All-Cause Mortality, and Severe Hypoglycemia
Patients with either prior CVD or prior CKD were at higher associated risk of
MACE, cardiovascular death, and all-cause mortality than those without a history of either of
these conditions (Fig. 4). In contrast, only prior CKD
was associated with a significantly higher rate of severe hypoglycemia (Fig. 4).
Fig. 4
Comparison of associations of prior CVD/CKD and no prior CVD/CKD with the risks
of MACE, cardiovascular death, and all-cause mortality and the rate of severe hypoglycemia.
*Rate of events/100 patient years of exposure. A more detailed exploration of the impact of
a history of CVD or CKD on these outcomes is available in the ESM. Time from randomization
to first MACE, cardiovascular death, and all-cause mortality were analyzed using Cox
proportional hazard regression models with treatment, baseline GFR category, and
interaction between treatment and baseline GFR category as fixed factors. The number of
severe hypoglycemic events was analyzed using a negative binomial regression model with
log-link function and the logarithm of the duration of observation time (100 patient years)
as offset in addition to randomized treatment, baseline GFR category, and their
interactions. Data on the proportion of patients with events and the rate of severe
hypoglycemic events are based on observed numbers. CI
confidence interval, CVD cardiovascular disease,CKD chronic kidney disease, glargine U100 insulin glargine 100 units/mL, MACE major adverse cardiovascular events
×
Upon comparing outcomes in patients with CVD only to those with CKD only, prior
CVD was found to be associated with a higher risk of MACE than prior CKD (P = 0.0003), but there were no significant differences between
patients with prior CVD and patients with prior CKD in the risks of cardiovascular death
(P = 0.6), all-cause mortality (P = 0.2), and severe hypoglycemia (P = 0.1;
Fig. S2 in the ESM).
A significantly higher risk of each outcome was consistently observed in
patients with both prior CVD and prior CKD as compared with patients with neither of these
conditions or with prior CVD alone (MACE, cardiovascular death, all-cause mortality: allP < 0.0001; severe hypoglycemia: P = 0.04 and P = 0.002,
respectively; Fig. S2 in the ESM).
There were no significant interactions between randomized treatment and the
association of prior CVD or prior CKD with MACE (P = 0.6
and 0.8, respectively), cardiovascular death (P = 0.2 and
0.9, respectively), all-cause mortality (both P = 0.2), or
severe hypoglycemia (P = 0.09 and 0.6, respectively;
Fig. 5). In addition to an absence of significant
interactions, there were also no significant associations between randomized treatment and
prior CVD status or prior CKD groups for MACE, cardiovascular death, and all-cause mortality.
Regardless of whether patients had prior CVD or prior CKD, the rate of severe hypoglycemia was
consistently lower with degludec than with glargine U100 except in patients with no prior CVD
(Fig. 5). A more detailed exploration of the
associations between a history of CVD or CKD and these outcomes is provided in Figs. S2 and S3
of the ESM.
Fig. 5
Comparison of the associations of prior CVD/CKD/no prior CVD/CKD and treatment
with degludec/glargine U100 with the risks of MACE, cardiovascular death, all-cause
mortality and the rate of severe hypoglycemia. *P value
for interaction between treatment and baseline CVD and CKD
status;†rate of events/100 patient years of exposure. Times
from randomization to first MACE, cardiovascular death, and all-cause mortality were
analyzed using Cox proportional hazard regression models with treatment, baseline GFR
category, and interaction between treatment and baseline GFR category as fixed factors. The
number of severe hypoglycemic events was analyzed using a negative binomial regression
model with log-link function and the logarithm of the duration of observation time (100
patient years) as offset in addition to randomized treatment, baseline GFR category, and
their interactions. Data on the proportion of patients with events and the rate of severe
hypoglycemic events are based on observed numbers. CI
confidence interval, CVD cardiovascular disease,CKD chronic kidney disease, glargine U100 insulin glargine 100 units/mL, MACE major adverse cardiovascular events
×
Efficacy Measures
In general, differences in SMBG and changes in HbA1c and FPG were absent
between baseline GFR categories G2–G5, with the exception of a lower total insulin dose (U/kg)
in patients with a more advanced baseline GFR category (G1: 0.85, 95% confidence interval [CI]
0.82–0.89; G2: 0.76, 95% CI 0.74–0.78; G3: 0.69, 95% CI 0.67–0.71; G4–5: 0.61, 95% CI
0.54–0.68; see the supplementary results and Fig. S4 in the ESM).
Discussion
These secondary analyses from DEVOTE demonstrate that patients with a more
advanced baseline GFR category were at greater risk of MACE, cardiovascular death, and all-cause
mortality as compared with those in the normal baseline GFR category. In addition, severe
hypoglycemia tended to be more common, albeit not significantly so, in patients with a more
advanced baseline GFR category.
Patients with either prior CVD or prior CKD had higher risks of MACE,
cardiovascular death, and all-cause mortality than those without these conditions, while those
with both had the highest risks of these outcomes compared with those without prior CVD and
prior CKD or those with only prior CVD. Patients with prior CVD had a significantly higher risk
of MACE compared with those with prior CKD, and only prior CKD was associated with a
significantly higher rate of severe hypoglycemia. When patients with prior CVD only were
compared to those with prior CKD only, the risks of cardiovascular death and all-cause mortality
were similar in both groups, despite the presence of a stronger association with CKD than with
CVD.
The similar effects of randomized treatment across the GFR categories, together
with the lack of significant interactions of baseline GFR category with randomized treatment for
MACE, cardiovascular death, or all-cause mortality suggest that the type of basal insulin
treatment applied did not affect the associations between GFR severity and outcomes. That is,
regardless of the baseline GFR category, the results are consistent with those from the primary
DEVOTE analyses [25], where the risks of MACE,
cardiovascular death, and all-cause mortality were not found to differ significantly between the
degludec and glargine U100 groups. Likewise, the similar estimated reduction in the rate of
severe hypoglycemia with degludec versus glargine U100 (rate ratios: 0.62–0.77; significant
differences were only observed for GFR categories G2 and G3) and the absence of a significant
interaction between baseline GFR categories and randomized treatment for severe hypoglycemia
suggest that degludec use resulted in a lower rate of hypoglycemia (as indicated by the present
analyses and the primary DEVOTE analyses [25])
independently of the baseline GFR. The higher risks of MACE and all-cause mortality in patients
with more advanced baseline GFR categories were driven by higher rates of cardiovascular death,
which accounted for 44% of MACE and 66% of all-cause mortality.
These results are consistent with previous findings that patients with a lower
baseline GFR are at high risk of MACE [22],
all-cause mortality [32], and cardiovascular death
[33]. While many studies have not found a higher
risk of all-cause mortality in patients without CKD versus those with CKD [18, 20‐22], the present study found
that even mild CKD (category G2) is associated with a higher risk (hazard ratio 1.57, 95% CI
1.11–2.22) of all-cause mortality compared with normal GFR. This finding might be explained by
the high burden of CVD in this population (71.7%) and the persistently high risk of
cardiovascular death, accounting for 63–69% of all deaths across baseline GFR categories G2–G5.
Indeed, a prior study of the contributions of CVD and CKD to all-cause mortality in patients
with T2D found that CVD had the strongest association with risk of all-cause mortality in
patients with and without CKD [23]. However,
results in the present study demonstrate that prior CVD and prior CKD were similarly associated
with risk of all-cause mortality and, if anything, prior CKD had the strongest
association.
Risk factors predisposing patients with CKD to a greater risk of cardiovascular
death include age, diabetes prevalence, diabetes duration, and hypertension, along with other
risk factors associated with the development of atherosclerotic vascular disease [34]. In the present study, patients with CKD (G3–5) had a
higher prevalence of established CVD/CKD and associated risk factors (e.g., longer diabetes
duration, older age, and higher BMI) [35] than
patients without CKD (G1–2). Other differences in terms of baseline antihyperglycemic and
cardiovascular medications may reflect the longer duration and more advanced state of diabetes
in patients with CKD.
If any aspect of the observed association between baseline GFR and risk of
all-cause mortality (as reported in the present and previous studies [17, 18,
20, 21, 23, 36]) are causally connected (in other words, not an
epiphenomenon), efforts to identify and limit the progression of CKD need to be pushed to the
forefront of clinical care. The treatment of patients with T2D and at high risk of developing
CVD or CKD is complex. Glycemic control and blood pressure management may limit the progression
of CKD, but the effects of intensive glycemic control on cardiovascular outcomes have been
inconsistent [37‐40]. While glycemic control and
blockade of the renin–angiotensin–aldosterone system remain paramount in the treatment of
patients with T2D and CKD [41], the potential for
antihyperglycemic medications to have favorable effects on cardiovascular and renal outcomes are
being investigated [42]. For example, canagliflozin
[11, 43, 44], empagliflozin
[12, 45], liraglutide [15, 46], albiglutide [47], semaglutide [13],
dapagliflozin [48], and dulaglutide [49] all have favorable effects on cardiovascular outcomes,
while some of these also slow the progression of CKD compared with placebo [50].
While there is relatively little evidence that basal insulins differ in their
ability to reduce cardiovascular events or mortality, there is evidence that basal insulins
differ regarding the associated risk of severe hypoglycemia [25, 51, 52]. In the present study, the lack of significant interactions
between randomized treatment and baseline groups (CKD and prior CKD/CVD) indicate that, as was
the case for the overall DEVOTE cohort [25], the
rate of severe hypoglycemia was lower with degludec compared with glargine U100 regardless of
the baseline GFR. This finding is reassuring for clinicians, given that previous studies have
reported that patients with CKD are predisposed to a greater risk of these events [37] and are consequently also at a greater risk of death
[53].
While the DEVOTE CVOT has provided an ideal platform for exploring associations
between baseline GFR category and outcomes in a T2D cohort at high cardiovascular risk, these
post hoc analyses do have limitations. These include the likelihood that the DEVOTE eligibility
criteria may have resulted in a patient cohort that is unrepresentative of the wider population
of patients with T2D and CVD. An example of this that is relevant to the present study was the
exclusion of patients with severe renal impairment
(eGFR < 30 mL/min/1.73 m2 [G4–5]) at screening. Despite this, 214
had severe renal impairment at baseline, including seven patients with
eGFR < 15 mL/min/1.73 m2. An additional limitation is the lack of
data on microalbuminuria at follow-up; however, as illustrated by the baseline data, CKD with
microalbuminuria/proteinuria was not common in this cohort (37% of those with eGFR from 30
to < 60 mL/min/1.73 m2). Indeed, while the pathogenic role of
proteinuria in renal diseases is clear, nonalbuminuric pathways conducive to renal function loss
are more prevalent in patients with T2D and are the leading cause of end-stage renal disease
[54].
Conclusion
In this large cohort of patients with T2D at high cardiovascular risk, worsening
baseline GFR categories were associated with higher risks of MACE, cardiovascular death, and
all-cause mortality. Patients with prior CVD, CKD, or both were at higher risk of MACE,
cardiovascular death, and all-cause mortality. Only CKD was associated with a higher rate of
severe hypoglycemia, and the risk of MACE was higher in patients with only CVD than in those
with only CKD. The nonsignificant interactions between randomized treatment and study outcomes
were in agreement with the results from the overall DEVOTE CVOT analyses suggesting that the
lower rate of severe hypoglycemia with degludec than with glargine U100 (in the overall trial)
[25] were independent of the severity of baseline
CKD. Considering the observed association between baseline GFR category and risk of all-cause
mortality, regardless of randomized basal insulin assignment, efforts to better understand this
association and methods to mitigate the incremental risk associated with declining GFR remain
important clinical objectives.
Acknowledgements
We thank the trial investigators, trial staff, and trial participants for their
participation, and M. V. Bolten Jagd (Novo Nordisk) for insights that assisted in the
development of this article.
Funding
The trial, these secondary analyses and the Rapid Service Fee were funded by
Novo Nordisk. The sponsor contributed to data collection and statistical analyses. Novo Nordisk
was involved in obtaining the data and designing these secondary analyses, provided logistical
support, and ran all the statistical analyses, the results of which were evaluated jointly by
the authors and the sponsor. DEVOTE research activities were supported at numerous US centers
by Clinical and Translational Science Awards from the National Institutes of Health’s National
Center for Advancing Translational Science.
Medical Writing and Editorial Assistance
Sam Mason and Germanicus Hansa-Wilkinson of Watermeadow Medical provided
medical writing and editorial support. This was sponsored by Novo Nordisk.
Authorship
All named authors meet the International Committee of Medical Journal Editors
(ICMJE) criteria for authorship for this article, take responsibility for the integrity of the
work as a whole, and have given their approval for this version to be published.
Prior Presentation
Data from this analysis have been presented at ADA 2018 and EASD 2018.
Disclosures
Aslam Amod has received personal fees related to advisory boards and lectures
from Novo Nordisk, Sanofi (South Africa), AstraZeneca, Merck Sharp and Dohme Corp., Lilly South
Africa, Boehringer Ingelheim, Merck Biopharma, and Novartis South Africa. John B. Buse’s
contracted consulting fees are paid to the University of North Carolina by Adocia, AstraZeneca,
Dance Biopharm, Eli Lilly, MannKind, NovaTarg, Novo Nordisk, Senseonics, vTv Therapeutics, and
Zafgen; he has received grant support from Novo Nordisk, Sanofi, and vTv Therapeutics. He is a
consultant to Cirius Therapeutics Inc., CSL Behring, Neurimmune AG, and Pendulum Therapeutics.
He holds stock options in Mellitus Health, Pendulum Therapeutics, PhaseBio, and Stability
Health. He is supported by a grant from the National Institutes of Health (UL1TR002489). Darren
K. McGuire has received personal fees from Boehringer Ingelheim, Janssen Research and
Development LLC, Sanofi US, Merck Sharp and Dohme Corp., Eli Lilly USA, Novo Nordisk,
GlaxoSmithKline, AstraZeneca, Lexicon Pharmaceuticals, Eisai, Pfizer, Metavant, Applied
Therapeutics, and Esperion. Thomas R. Pieber has received research support from Novo Nordisk
and AstraZeneca (paid directly to the Medical University of Graz) and personal fees as a
consultant from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Novo Nordisk, and Roche Diabetes
Care. TRP is also the Chief Scientific Officer of CBmed (Center for Biomarker Research in
Medicine), a public-funded biomarker research company. Rodica Pop-Busui has received research
support (to the University of Michigan) from AstraZeneca, and is supported by grants from the
National Institutes of Health (NIDDK-1-R01-DK-107956-01, UC4 DK101108). Payment for Richard E.
Pratley’s services were directed to AdventHealth (formerly Florida Hospital), a non-profit
organization; he also received consultancy and speaker fees from AstraZeneca, Takeda, and Novo
Nordisk; consultancy fees from Boehringer Ingelheim, GlaxoSmithKline, Hanmi Pharmaceutical Co.
Ltd., Janssen Scientific Affairs LLC, Ligand Pharmaceuticals, Inc., Eli Lilly, Merck, Pfizer,
and Eisai, Inc.; and research grants from Gilead Sciences, Lexicon Pharmaceuticals, Ligand
Pharmaceuticals, Inc., Eli Lilly, Merck, Sanofi US LLC, and Takeda. Bernard Zinman has received
grant support from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk and consulting fees from
AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi. Ting
Jia is a full-time employee of and holds stock in Novo Nordisk A/S. Marco Bo Hansen is a
full-time employee of and holds stock in Novo Nordisk A/S. Thomas Mark is a full-time employee
of and holds stock in Novo Nordisk A/S. Neil R. Poulter has received personal fees from
Servier, Takeda, Novo Nordisk, and AstraZeneca in relation to speakers’ fees and advisory board
activities (concerning diabetes mellitus); and research grants for his research group (relating
to type 2 diabetes mellitus) from Diabetes UK, National Institute for Health Research Efficacy
and Mechanism Evaluation (NIHR EME), Julius Clinical, and the British Heart Foundation.
Compliance with Ethics Guidelines
DEVOTE is registered with ClinicalTrials.gov (NCT01959529) and was conducted in
accordance with the Declaration of Helsinki and the Good Clinical Practice Guideline of the
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human
Use [27, 28]. The protocol was approved by an independent ethics committee or
institutional review board for each center; written informed consent was obtained from each
patient before any trial-related activities.
Data Availability
The datasets obtained and/or analyzed during the current study are available
from the corresponding author on reasonable request.
Open Access
This article is distributed under the terms of the Creative Commons
Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any
medium, provided you give appropriate credit to the original author(s) and the source, provide
a link to the Creative Commons license, and indicate if changes were made.
Glomerular Filtration Rate and Associated Risks of Cardiovascular Events, Mortality, and Severe Hypoglycemia in Patients with Type 2 Diabetes: Secondary Analysis (DEVOTE 11)
verfasst von
Aslam Amod John B. Buse Darren K. McGuire Thomas R. Pieber Rodica Pop-Busui Richard E. Pratley Bernard Zinman Marco Bo Hansen Ting Jia Thomas Mark Neil R. Poulter the DEVOTE Study Group
