Diabetic Kidney Disease

Ryan Bonner, MD, Oltjon Albajrami, MD, James Hudspeth, MD,

Ashish Upadhyay, MD*

KEYWORDS
 Diabetic kidney disease  Diabetic nephropathy  Chronic kidney disease
 Albuminuria

KEY POINTS
 Diabetic kidney disease (DKD) is the most common cause of chronic kidney disease in the
United States and affects 30% to 40% of patients with diabetes mellitus.
 The progression of DKD is characterized by a decline in kidney function and worsening
albuminuria and is associated with increased cardiovascular and all-cause mortality.
 Mainstays of management of DKD continue to be effective glycemic and blood pressure
control and blockade of the renin-angiotensin-aldosterone system.
 Emerging therapies, such as sodium-glucose cotransporter 2 inhibitors and glucagon-like
peptide-1 analogues, in the right setting, can play an important role in slowing DKD
progression.

EPIDEMIOLOGY

Chronic kidney disease (CKD) affects a 15% of Americans, and diabetic kidney dis-
ease (DKD) is the most common cause of kidney failure.1,2 Although the incidence
of diabetes-related kidney failure has slowed over the past 2 decades, approximately
30% of patients with type 1 diabetes mellitus (T1DM) and 40% of patients with type 2
diabetes mellitus (T2DM) develop some form of CKD.1 Because mortality and
morbidity risks rise with CKD progression, it is imperative to prioritize prevention,
recognition, and management of DKD in the primary care setting.3

PATHOGENESIS/PATHOPHYSIOLOGY

DKD is driven primarily by 3 intersecting processes: hyperfiltration injury to the glomer-

ular filtration barrier (GFB), expansion of the glomerular mesangium, and oxidative
stress. Development of these processes is multifactorial and thought to be related
to hemodynamic, metabolic, and immune pathology, which are discussed individually
and summarized in Fig. 1.

Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University
School of Medicine, 800 Harrison Avenue, G009, Boston, MA 02118, USA
* Corresponding author.
E-mail address: [email protected]

Prim Care Clin Office Pract 47 (2020) 645–659

https://doi.org/10.1016/j.pop.2020.08.004 primarycare.theclinics.com
0095-4543/20/ª 2020 Elsevier Inc. All rights reserved.
646 Bonner et al

Fig. 1. Pathophysiology of diabetic kidney disease.

Hemodynamic Alterations
Aberrant activation of the renin-angiotensin-aldosterone system (RAAS) is known to
cause vasoconstriction of the efferent arteriole, leading to an increase in intraglomer-
ular pressure. High intraglomerular pressure and the resultant hyperfiltration injury of
the GFB, over time, manifest as albuminuria and lower glomerular filtration rate
(GFR). Additionally, excess endothelin-1 activity causes vasoconstriction of the
efferent arteriole and also may directly cause mesangial proliferation and raise GFB
permeability.4

Metabolic Derangements
Various metabolic derangements may result in DKD. Hyperglycemia, especially in the
context of oxidative stress and dyslipidemia, can directly modify proteins and
contribute to GFB permeability, mesangial expansion, and glomerular inflammation.
Additionally, increased glycolysis in itself has deleterious consequences, including
raising susceptibility to oxidative stress, promoting cytokine-mediated mesangial
expansion, and worsening hyperfiltration injury.4,5

Immune Dysregulation
Hyperglycemia is associated with an up-regulation of proinflammatory and profibrotic
pathways that result in GFB damage, mesangial expansion, and tubulointerstitial
fibrosis. Importantly, podocyte turnover (a crucial process in maintaining the GFB)
also is impaired by hyperglycemia.4–6

Effect on the Glomerular Filtration Barrier

The mechanisms, described previously, progressively lead to GFB damage, lower
GFR, and albuminuria. Albuminuria rises with GFB damage and may contribute inde-
pendently to downstream tubulointerstitial fibrosis. Thus, albuminuria is both a hall-
mark of and a risk factor for DKD progression.6
 Diabetic Kidney Disease 647

NATURAL HISTORY

The risks of development and progression of DKD primarily depend on the duration of
diabetes, glycemic control, and hypertension control.7,8 For T2DM, approximately
30% of patients develop microalbuminuria within 10 years of diabetes diagnosis,
and approximately 5% progress to overt nephropathy every year.7 Nearly all patients
with low GFR from DKD have preceding albuminuria, and the degree of albuminuria
predicts the rate of GFR decline.8–11 Effective hyperglycemia and hypertension man-
agement can delay the onset of microalbuminuria and slow DKD progression. For
T1DM, the typical progression of DKD is summarized in Table 1.
All-cause mortality increases as DKD progresses, primarily from cardiovascular dis-
eases (CVD).7 According to the data on T2DM from the United Kingdom Prospective
Diabetes Study (UKPDS), the annual rate of CVD-mortality is 0.7% for those without
DKD, 2% for those with microalbuminuria, 3.5% for those with macroalbuminuria,
and 12.1% for those with low GFR or kidney failure.7 The degree of albuminuria is a
predictor of poor CVD outcomes, and reduction in albuminuria has cardioprotective
effects.12

SCREENING, MONITORING, AND DIAGNOSING DIABETIC KIDNEY DISEASE

Given the high morbidity and mortality associated with DKD, effective screening is crit-
ical. The 2019 American Diabetes Association guidelines recommend yearly assess-
ment of GFR and albuminuria via a spot urine albumin–to–creatinine ratio (UACR) in
all patients with T2DM and those with T1DM for greater than or equal to 5 years.13
Despite this, less than or equal to 50% of patients with diabetes are tested for albu-
minuria.2,13,14 Albuminuria should be screened, and, if elevated, confirmed on a sepa-
rate measurement within 6 months, with microalbuminuria defined as UACR of 30 mg/
g to 300 mg/g and macroalbuminuria defined as UACR greater than or equal to
300 mg/g. The presence of UACR greater than or equal to 30 mg/g or estimated
GFR (eGFR) less than 60 mL/min/1.73 m2 for at least 3 months is required for the diag-
nosis of DKD.15

NEPHROLOGY CONSULT/REFERRAL

Approximately 20% of patients with kidney failure from diabetes progress to needing
dialysis without receiving care by a nephrologist.16 Current guidelines recommend
referral to nephrology when eGFR decreases below 30 mL/min/1.73 m2, when the eti-
ology of CKD is in question, or when there are management challenges (resistant hy-
pertension, worsening albuminuria, rapidly declining GFR, and forth).17 Consultation
with a nephrologist should be sought prior to requesting a kidney biopsy. A longer
duration of predialysis nephrology care is associated with better patient readiness
for dialysis and greater 1-year survival after dialysis initiation.18

EVIDENCE-BASED MANAGEMENT

Optimal management of hyperglycemia, blood pressure (BP), and albuminuria is the

cornerstone of evidence-based DKD management. More recently, sodium-glucose
cotransporter 2 inhibitors (SGLT2Is) and glucagon-like peptide-1 (GLP-1) analogues,
agents developed for blood glucose control, have emerged as important agents for
DKD management, because they have been shown to slow DKD progression indepen-
dent of their effect on glucose lowering.13 The results of major clinical trials in DKD are
summarized in Table 2. The evidence-based management approach for DKD is sum-
marized in Table 3 and reviewed.2,14,19,20
 648
Bonner et al
Table 1
Typical progression of diabetic kidney disease due to type 1 diabetes mellitus

Diagnosis of Diabetes Incipient Diabetic Kidney Disease Overt Diabetic Kidney Disease End-stage Kidney Disease
Time since 0–5 y 5–15 y 15–25-y 25–30 y
the onset
of diabetes
Kidney Function [ in GFR Normal GFR Progressive Y in GFR GFR <15 mL/min
Albuminuria Normal albuminuria, Intermittent microalbuminuria to Macroalbuminuria to nephrotic Variable—Y albuminuria with the
or intermittent persistent microalbuminuria range albuminuria Y in the number of functional
microalbuminuria nephrons
Main kidney Normal kidney Mesangial expansion, glomerular Marked glomerular basement membrane thickening, nodular
pathology architecture, or basement membrane glomerulosclerosis (Kimmelstiel-Wilson lesions), tubulointerstitial
findings glomerular thickening, focal mesangial fibrosis
hypertrophy sclerosis
Table 2
Landmark trials in diabetic kidney disease management

Average
Study (y) Follow-up (mo) Baseline Characteristics Intervention Comparator Main Findings
Type 1 diabetes mellitus
Collaborative 36 sCr: 1.3 mg/dL Captopril Placebo Captopril Y time to doubling of sCr
Study Group (1993) HbA1c: 11.8% by 43%
N 5 409 Albuminuria: 2.5 g/d
Type 2 diabetes mellitus
IDNT (2001) 31 sCr: 1.7 mg/dL Irbesartan Amlodipine, Placebo Irbesartan Y risk of doubling of
N 5 1715 HbA1c: 8.1% sCr, death, or progression to
Albuminuria: 2.9 g/d kidney failure by 20% compared
with placebo and 23%
compared with amlodipine
RENAAL (2001) 41 sCr: 1.9 mg/dL Losartan Placebo Losartan Y risk of doubling of sCr,
N 5 1513 HbA1c: 8.4% death, or progression to kidney
Albuminuria: 1.2 g/d failure.
EMPAREG (2015) 37 eGFR: 82 mL/min/1.73 m2 Empagliflozin Placebo Empagliflozin Y risk of incident or
N 5 7020 HbA1c: 8.1% worsening nephropathy,
40% with micro/ progression to
macroalbuminuria macroalbuminuria, doubling of
sCr, or time to kidney failure
CANVAS (2017) 43 eGFR: 76 mL/min/1.73 m2 Canagliflozin Placebo Canagliflozin Y progression of

Diabetic Kidney Disease

N 5 10,142 HbA1c: 8.2% albuminuria and risk of eGFR
UACR: 12.3 mg/g reduction, kidney failure, or
death from renal cause
CREDENCE (2019) 31 eGFR: 56 mL/min/1.73 m2 Canagliflozin Placebo Canagliflozin Y risk of doubling of
N 5 4401 HbA1c: 8.3% sCr, kidney failure, or death
UACR: 923 mg/g from kidney or cardiovascular
causes

(continued on next page)

649
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Bonner et al
Table 2
(continued )
Average
Study (y) Follow-up (mo) Baseline Characteristics Intervention Comparator Main Findings
LEADER (2016) 46 eGFR: 80 mL/min/1.73 m2 Liraglutide Placebo Liraglutide Y risk of new onset
N 5 9340 HbA1c: 8.7% persistent macroalbuminuria,
37% with micro/ doubling of sCr, kidney failure,
macroalbuminuria death from kidney causes
REWIND (2019) 65 eGFR: 77 mL/min/1.73 m2 Dulaglutide Placebo Dulaglutide Y risk of new
N 5 9901 HbA1c: 7.3% macroalbuminuria, decrease in
35% with micro/ eGFR by 30%, and kidney failure
macroalbuminuria

Abbreviation: N, number; sCr, serum creatinine.

 Diabetic Kidney Disease 651

Table 3
Clinical management of diabetic kidney disease

Patient Group Suggested Interventions

Everyone with DKD  Hyperglycemia management targeting HbA1c 7.0%, if not
limited by hypoglycemia episodes
 Dyslipidemia management per standard guidelines for
patients with diabetes
 Dietary counseling for those who are overweight or obese,
including referral to intensive behavioral counseling
interventions or weight management programs
 Reducing salt intake to <2 g of sodium (corresponding to 5 g
of sodium chloride) per day
 Smoking cessation counseling and treatment, if applicable
 Avoiding potentially nephrotoxic insults whenever possible
 Nephrology referral if GFR is <30 mL/1.73 m2 or if an
alternate cause of kidney disease is suspected
DKD with hypertension  Targeting BP of <130/80 mm Hg, adding these medications
in a stepwise fashion:
 ACEI or ARB as first-line agents
 Diuretics and/or calcium channel blockers as second/third
line if BP goal is not achieved with ACEI or ARB
 Spironolactone if still not at goal and GFR >30 mL/min/
1.73 m2, unless limited by hyperkalemia
 Nephrology referral if BP control is not achieved with 4
agents
DKD with UACR 30 mg/g  Consideration of ACEI or ARB, if not limited by side effects, if
without hypertension 1 of the following is present:
 Increasing levels of albuminuria over time
 Declining GFR
 Presence of retinopathy, hyperlipidemia, or hyperuricemia
 Family history of hypertension, macrovascular disease, or
DKD
 Consideration for SGLT2I if UACR >300 mg/g and GFR
30 mL/min/1.73 m2
DKD with UACR 30 mg/g  Management of hypertension, as noted previously
and hypertension  Up-titration of ACEI/ARB dosage (maximum dosage: 80 mg
of lisinopril equivalent or 200 mg of losartan equivalent) to
achieve maximum albuminuria reduction as tolerated by BP
and side effects
 SGLT2I in addition to ACEI or ARB if UACR >300 mg/g and
GFR 30 mL/min/1.73 m2
 Spironolactone in addition to the maximum tolerated dose
of ACEI or ARB if UACR remains 300 mg/g and if
GFR >30 mL/min/1.73 m2, unless limited by hyperkalemia

Glycemic Control
Achieving and maintaining euglycemia are crucial elements in avoiding the onset and
progression of DKD related to both T1DM and T2DM. Several studies have demon-
strated the benefit of adequate glycemic control as it pertains to the development
of microvascular complications. In the landmark Diabetes Control and Complications
Trial (DCCT), 1993, improved glycemic control (hemoglobin A1C [HbA1C]) <6% versus
around 9%) in patients with T1DM without DKD was associated with 39% reduction in
the rate of microalbuminuria and 54% reduction in the rate of macroalbuminuria over
6.5 years of follow-up.21 Although the original trial did not show any benefit for hard
652 Bonner et al

CKD-related or CVD-related outcomes, the long-term follow-up of DCCT participants

showed 42% lower rate of CVD over 10 years and 50% lower rate of CKD over 22-year
in the intensive glucose control group.22,23 Similarly, for T2DM, aggressive glycemic
control was associated with a significantly lower rate of microvascular complications
in the UKPDS trial.24 The Action to Control Cardiovascular Risk in Diabetes trial
(ACCORD), 2008; the Action in Diabetes and Vascular Disease: Preterax and Diami-
cron Modified Release Controlled Evaluation (ADVANCE) trial, 2008; and the Veterans
Affairs Diabetes Trial (VADT), 2009, are 3 large trials in T2DM investigating glycemic
control and CVD outcomes that also have secondarily examined kidney outcomes.
Of these, only ADVANCE demonstrated an association between lower HbA1c target
(6.3% vs 7.0%) and improved kidney outcomes.25–27
Although this is primarily a discussion of glycemic control in the context of DKD, it is
relevant to discuss the relationship between tight glycemic control and cardiovascular
outcomes, given the co-occurrence of DKD and CVD. ACCORD, ADVANCE, and
VADT all included patients at high cardiovascular risks and compared cardiovascular
outcomes in individuals with strict versus conventional glycemic control. In ACCORD,
strict control (target HbA1c <6% vs HbA1c 7%–7.9%) was associated with a higher risk
of mortality, and subgroup analysis demonstrated elevated risk in participants with a
prior history of CVD.25 The ADVANCE and VADT trials did not demonstrate an elevated
cardiovascular risk with strict HbA1c targets (6.3% and 6.9%, respectively); however,
there was a significantly higher risk of hypoglycemia without any appreciable cardio-
vascular benefit.25–27 Overall, the results of these trials raise a concern that a very strict
glycemic control may result in harm without improving macrovascular complications in
T2DM.
Comorbidities, drug metabolism, and side-effect profile are some of the factors that
need to be taken into consideration when selecting a glucose-lowering medication for
patients with DKD. Certain sulfonylureas that are cleared by kidneys, in particular gly-
buride, glibenclamide, and glimepiride, should be used with caution in individuals with
CKD due to the risk for severe hypoglycemia. Glipizide and gliclazide are cleared pri-
marily by the liver and are relatively safer. Although thiazolidinediones are metabolized
by the cytochrome P450 system and do not exhibit excess hypoglycemia in DKD pa-
tients, they should be used with caution in DKD due to their association with fluid
retention, anemia, and osteoporosis. Kidneys are involved in one-third of exogenous
insulin degradation and it is important to reduce insulin dosage and have a higher vig-
ilance for hypoglycemia in patients with advanced DKD. Metformin, SGLT2I, and GLP-
1 analogues (GLP-1As) are discussed in detail later, given their specific implications
for DKD.
Although kidney disease and diabetes guidelines recommend a target HbA1C of
7.0% in patients with DKD, patient comorbidities need to be taken into consideration,
and the known benefit of aggressive diabetes control for kidney outcomes needs to be
balanced with the risks of hypoglycemia and CVD events.2,13,14 Thus, it is recommen-
ded that the goal HbA1C be individualized for each patient.

Blood Pressure Control

BP control slows DKD progression and decreases cardiovascular mortality.28–31
Despite the evidence that lower BP slows DKD progression, the BP goal for patients
with diabetes is somewhat controversial. The Systolic Blood Pressure Intervention
Trial, 2015, demonstrated that in patients with high cardiovascular risk, lower target
BP (systolic BP <120 vs <140) is associated with improved cardiovascular and all-
cause mortality.32 These results, however, are not directly applicable to patients
with diabetes because they were excluded from the trial. The ACCORD-Blood
 Diabetic Kidney Disease 653

Pressure study investigated the effect of strict BP control on cardiovascular outcomes

specifically in patients with diabetes and high CVD risk. Results demonstrated that a
lower BP target (systolic BP <120 vs <140) was associated with a lower risk for albu-
minuria progression and stroke without any benefit for composite fatal and nonfatal
CVD events over 5 years of follow-up.29 Serious adverse events attributable to antihy-
pertensive treatment were more common in the low BP arm (3.3% vs 1.3%). In midst
of these uncertainties, current guidelines recommend a BP goal of less than 130/80 for
patients with diabetes.33

Renin-Angiotensin-Aldosterone System Blockade

Blockade of RAAS is a mainstay strategy in the management of DKD. The benefit of
RAAS blockade in DKD is independent of BP lowering and likely is primarily from
lowering of intraglomerular pressure and the resultant hyperfiltration injury and albu-
minuria. Because albuminuria reduction is linked with slowing DKD progression and
improving CVD outcomes, controlling albuminuria is an important goal in DKD man-
agement.30,34 Angiotensin-converting enzymes inhibitors (ACEIs), angiotensin-II re-
ceptor blockers (ARBs), mineralocorticoid antagonists, and direct renin inhibitors
(DRIs) are major RAAS blockers studied in DKD.
Large trials (see Table 2) demonstrating the efficacy of RAAS blockade in the treat-
ment of DKD were published as early as 1993, when captopril, independent of BP
reduction, was shown to lower the risk of doubling of serum creatinine by 48% over
3 years in individuals with T1DM and high-grade albuminuria.21 This was assessed
further in subjects with T2DM and high-grade proteinuria in the Reduction of End-
points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) and Irbesartan
Diabetic Nephropathy (IDNT) trials, which showed that, independent of BP reduction,
ARB use was associated with the reduction of a composite endpoint of doubling of
serum creatinine, death, and kidney failure by 16% and 20%, respecitvley, over
approximately 3 years respectively.35,36 Further analysis of RENAAL data demon-
strated that those with a higher baseline albuminuria (UACR 3 g/g) were at a much
higher risk of progressing to kidney failure.37 Similarly, the same analysis showed
that the reduction in albuminuria was proportionally related to kidney protection,
with every 50% reduction in albuminuria in the first 6 months of the trial being associ-
ated with a 45% reduction in the risk for kidney failure during approximately 3-year of
subsequent follow-up. These results have been replicated in post hoc analysis of other
large trials.38
Up to a 30% rise in serum creatinine is expected shortly after ACEI/ARB initiation
becaus the decrease in intraglomerular pressure also leads to decrease in creatinine
clearance. ACEI/ARB, however, should not be stopped with this initial rise in serum
creatinine because the long-term rate of GFR decline slows with ACEI/ARB
use.21,35,36 Even then, it is reasonable to check serum creatinine and potassium values
within 2 weeks of ACEI/ARB initiation because patients with coexisting renovascular
disease may exhibit higher than expected increase in serum creatinine or hyperkale-
mia. If greater than 30% rise in serum creatinine or hyperkalemia is noted, then it is
reasonable to refer the patient to a nephrologist and stop ACEI/ARB. Likewise, the
risk for hyperkalemia increases in individuals with eGFR of less than 30 mL/min/
1.73 m2. Although ACEI/ARB has been shown to delay the onset of kidney failure
even in people with eGFR of 15 mL/min/1.73m2 to 30 mL/min/1.73 m2, it is prudent
to refer patients with advanced CKD to a nephrologist to closely manage potential
hyperkalemia and to initiate preparation for renal replacement therapy.39
There is some evidence that patients with diabetes may benefit from ACEI/ARB
prior to the development of albuminuria. Ruggenenti and colleagues40 investigated
654 Bonner et al

the effect of RAAS blockade on patients with T2DM and hypertension without micro-
albuminuria and found that ACEI treatment delayed the onset of microalbuminuria. In
addition, preemptive use of ACEI in patients with T2DM without hypertension or micro-
albuminuria also has been shown to attenuate the decline in kidney function and
reduce the absolute level of albuminuria.41 Given the lack of hard outcome data, how-
ever, preemptive ACEI/ARB is not currently recommended in clinical practice
guidelines.
Use of more than 1 class of RAAS blockers in combination has been studied in DKD.
ACEI plus ARB therapy compared with monotherapy consistently has been shown to
lower BP and proteinuria but raises the risk for significant adverse events.19,42–49 DRIs
in combination with ACEI/ARB also have been shown to modestly improve BP and
proteinuria without affecting clinical CVD and kidney endpoints, resulting in higher
rates of severe adverse events like hyperkalemia and hypotension.50,51 In 1 study,
combining spironolactone with ACEI was found to slow albuminuria progression
compared with ACEI plus ARB combination without significantly increasing adverse
effects.19 The safety and efficacy of this combination, however, have not been
assessed further in well-powered trials. In view of these data, ACEI plus ARB and
DRI plus ACEI/ARB combinations should not be used in DKD; spironolactone plus
ACEI/ARB can be considered in refractory cases of high-grade proteinuria as long
as GFR is not less than 30 mL/min/1.73 m2 given the risk for hyperkalemia, and DRI
or spironolactone alone should be considered only if patients have significant intoler-
ance to ACEI/ARBs.
Although post hoc analyses of trials suggest that reduction in albuminuria propor-
tionally confers kidney protection, the specific albuminuria target is an area of uncer-
tainty. Until a specific albuminuria target is better defined in clinical trials, it is
reasonable to use ACEI/ARB to lower BP to at least less than 130/80 mm Hg and
achieve maximum albuminuria reduction as tolerated by BP and side effects. In addi-
tion, there is evidence that high salt intake may reduce the antiproteinuric effect of
RAAS blockade, so the importance of a low-salt diet should be emphasized to all pa-
tients with DKD.52

Metformin
Metformin remains the foundation of antiglycemic therapy in clinical practice guide-
lines, with demonstrated benefits to patients with and without CKD.53 Historically,
concern for metformin provoking lactic acidosis lead to its avoidance in patients
with CKD, but, since 2010, several studies have shown that there is no increase in lac-
tic acidosis in patients with mild to moderate kidney impairment, and metformin
potentially may confer a mortality benefit.54,55 These recent studies ultimately led
the Food Drug Administration to update metformin labeling in 2016. The current label-
ing supports metformin initiation in patients with an eGFR of greater than 45 mL/min/
1.73 m2 and continuation (but not initiation) in patients whose eGFR fall between
30 mL/min/1.73 m2 and 45 mL/min/1.73 m2 if the risk outweighs the benefits (possibly
with a dose reduction) and considers an eGFR of less than 30 mL/min/1.73 m2 a
contraindication to metformin use.56 Metformin does not have a well-demonstrated
impact on the progression of DKD beyond its reduction in hyperglycemia, but, given
a possible mortality benefit, it should be used when feasible in patients with T2DM.

Sodium-glucose Cotransporter 2 Inhibitors

SGLT2Is in the proximal tubule have been a known therapeutic target for glucose-
lowering since 2013. More recently, SGLT2Is, also known as gliflozins, have been
 Diabetic Kidney Disease 655

shown to have cardioprotective and kidney-protective effects independent of glucose

lowering (see Table 2).
The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
(EMPAREG) was the first large trial to show that empagliflozin not only reduced
CVD outcomes, the trial’s primary endpoint, but also slowed DKD progression.57,58
Follow-up studies, including the Canagliflozin Cardiovascular Assessment Study
(CANVAS) and the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in
Myocardial Infarction 58 (DECLARE-TIMI 58) trial, also supported the idea that this
class of medication could slow DKD progression.59–61 These early trials, however,
were not specifically powered to detect kidney outcomes.
The Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy
(CREDENCE) was the first trial specifically powered to assess kidney outcomes in par-
ticipants with T2DM who already were on a maximal tolerated dose of ACEI/ARB.62 In
this large trial involving greater than 4000 high-risk participants followed over 2.5 years,
the risk for composite outcome of doubling of serum creatinine level, kidney failure, or
death from kidney or cardiovascular causes was 30% lower in the canagliflozin group
compared with placebo, resulting in the number needed to treat of 22 to prevent 1 ma-
jor outcome. Rates of severe adverse events were similar in 2 groups, although the
rates of diabetic ketoacidosis, although low, were higher in the canagliflozin arm
(2.2 vs 0.2, respectively, per 1000 patient-years).
The renoprotective mechanism for SGLT2Is is thought to be multifactorial.63
SGLT2Is increases sodium and glucose delivery to the distal tubule, resulting in tubu-
loglomerular feedback that leads to afferent arteriolar vasoconstriction and reduction
in intraglomerular pressure (similar to RAAS blockers). SGLT2Is also may have anti-
inflammatory mechanisms and improve intrarenal oxygenation.
SGLT2Is consistently have shown remarkable cardiorenal benefits in multiple large
trials, and, since the publication of the CREDENCE study, the use of SGLT2Is is
becoming the standard of care adjunct to RAAS blockers for patients with T2DM
and mild to moderate CKD (estimated GFR >30 mL/min/1.73 m2) and UACR of greater
than 300 mg/g.13 Patients initiated on these agents should be counseled to be vigilant
about urinary infections, in particular mycotic infections, given the inevitable glycos-
uria that occurs with these agents. In addition, patients also should be educated on
symptoms of diabetic ketoacidosis, and it is reasonable to hold the drug if patients
were to develop any systemic illness or conditions that would limit oral intake or result
in significant volume loss. Further studies are under way to assess the effect of
SGLT2Is in patients with T1DM.

Glucagon-like Peptide-1 Receptor Analogues

GLP-1 receptor analogues are relatively new medications that also have shown prom-
ise in slowing DKD progression, independent of their glucose-lowering effect. Trials,
such as the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular
Outcome Results (LEADER), Researching Cardiovascular Events with a Weekly Incre-
tin in Diabetes (REWIND), and Assessment of Weekly Administration of Dulaglutide in
Diabetes 7 trials have shown reduction in CVD outcomes as well as greater than 25%
decreased risk of new-onset persistent macroalbuminuria over 3.8 years in T2DM par-
ticipants with high CVD risk.64–68 The mechanism for renoprotection with these agents
is unclear and may be related to reduction in both oxidative stress and inflammation.69
Although guidelines suggest GLP-1A as an add-on to metformin in patients with
atherosclerotic CVD, GLP-1A also can be considered as a possible adjunct to metfor-
min and SGL2I in patients with DKD from T2DM.53
656 Bonner et al

SUMMARY

The morbidity and mortality associated with diabetes are both intimately linked to the
evolution of DKD. Primary care physicians treat a large number of patients with dia-
betes and must remain vigilant in their efforts to screen for the development of DKD
and make it a priority to manage DKD with an evidence-based approach targeting
effective BP and glycemic control, RAAS blockade, and, when appropriate, sodium-
glucose cotransporter 2 inhibition or GLP-1 receptor agonism.

DISCLOSURE

The authors have nothing to disclose.

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