Renal Outcomes Associated with the Use of Non-Insulin Antidiabetic Pharmacotherapy: A Review of Current Evidence and Recommendations

Figures & data

Table 1 Study Inclusion Criteria

No.	Category	Inclusion Criteria
1	Language of Publication	English
2	Year of Publication	2012–2020
3	Publication Type	Full-text original research article discussing the effects of AD medication on the renal system.
4	Outcomes Measures	Measuring patients’ renal outcomes, either primary or secondary outcome measures.
5	Methodology	Clinical studies reported the renal outcomes of using non-insulin antidiabetic pharmacotherapy, either observational or experimental.
6	Patients	Adult patients with T2DM.

Figure 1 Flow chart on the selection of literature.

Table 2 Summary of the Main Characteristics, Key Findings, and Conclusion of the Included Studies (n=32)

No.	Authors	Study Design, Participants, and Length of Follow-Up	Objectives	Findings	Conclusion
Metformin (n=4)
1	Bell et al, 2017^Citation9 United Kingdom	Observational study with 25,148 patients from prescribing data (2003–2014). A survival rate at 28 days was assessed.	To examine the potential association between the use of Metformin and increased risk of acute kidney injury (AKI) in terms of lactic acidosis.	There were 32.4 cases vs 44.9 cases of first AKI/1000 person-years in Metformin exposed and unexposed periods. Current metformin usage showed no association with AKI incidence, HR 0.94 (p = 0.15). After AKI, metformin users had a higher survival rate compared to no users (HR 0.81, p=0.006)	Metformin was not associated with increased AKI risk. Instead, it showed a higher survival rate after the incidence of AKI.
2	Christiansen et al, 2015^Citation10 Denmark & United Kingdom	Cohort study with 124,720 patients from different registries (2000–2011). Follow up period linked to GFR decline was 90 days.	To describe the prevalence of decline in eGFR among metformin initiators in two countries.	About 9.0% and 25.2% of metformin initiators had declined eGFR values <60 mL/min/1.73m whereas 0.3% and 0.4% had declined eGFR values <30 mL/min/1.73 in Denmark and the UK, respectively. About 44% and 62% in Denmark and the UK, respectively, have continued Metformin after having their eGFR below 30 mL/min/1.73 m2.	Severe decline of eGFR values is uncommon among the metformin initiators compared to mild and moderate forms. Even with the severe decline, patients were likely to continue their Metformin.
3	Ekstrom et al, 2012^Citation11 Sweden	Observational study with 51,675 patients (2004–2010). Follow up was set at a mean of 3.9 years.	To evaluate the effectiveness and safety of metformin initiation in diabetic patients with varying degrees of renal function.	The usage of Metformin was linked to a significant decrease in the risk of all-cause mortality (HR 0.87) in patients with eGFR 45–60 mL/min/1.73 m^2 compared to other OHA. There was no increment in the risks of serious infection, acidosis, and all-cause mortality among the metformin group with eGFR 30–45 mL/min/1.73 m^2.	Metformin has demonstrated higher benefits compared to risks in diabetic patients with renal impairment.
4	Mariano et al, 2017^Citation12 Italy	Retrospective analysis (2010–2015) involved 141,174 ICU diabetic patients on renal replacement therapy (RRT) and Metformin.	To determine the incidence and outcome of acute kidney injury (AKI)-Metformin Associated Lactic Acidosis (MALA) in patients treated with RRT.	A total of 117 cases reported the incidence of AKI – MALA – RRT, and the survival rate was 78.3%. Most of the admitted patients were dehydrated, affected by shock, and oliguria.	Early, continuous and efficient dialysis led to high survival rates among MALA-RRT cases.
Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitor (n=13)
5	Heerspink et al, 2020^Citation13 Multinational	Multinational observational cohort study involved 65,231 patients. Follow up was set at a mean of 14.9 months.	To determine the effect of sodium-glucose co-transporter-2 inhibitors (SGLT2i) in slowing the progression of chronic kidney disease in diabetic patients.	SGLT2i initiators have experienced slower eGFR decline compared to other antidiabetic agents (p < 0.0001). The incidence of composite kidney outcomes was also lower in the SGLT2i group than other antidiabetic agents (HR 0.49; p < 0.0001).	SGLT2i has a positive effect on slowing down chronic kidney disease progression and was associated with a lower risk of renal related adverse events.
6	Mosenzon et al, 2019^Citation14 Multinational	Detailed analyses of renal outcomes of trial with 17,160 patients. Follow up was set at a median of 4.2 years.	To report renal outcomes of the DECLARE– TIMI 58 trial, including components of the cardiorenal and renal-specific composite outcomes	Dapagliflozin participants had a lower risk for composite renal outcomes than the placebo (1.5% to 2.8%, HR 0.53) Dapagliflozin reduced the risk of ESRD or renal-related death (0.1% vs 0.3%, HR 0.41) as compared to the placebo.	Dapagliflozin prevents and reduces DKD progression in patients with and without cardiovascular disease
7	Fioretto et al, 2016^Citation15 Italy	Post hoc analysis included 166 diabetic patients with CKD stage 3. Follow up was set at 104 weeks.	To inspect changes in the urinary/creatinine ratio (UACR) of diabetic patients due to the long-term effects of dapagliflozin.	Dapagliflozin 10 mg and 5 mg groups have shown a lower value of UACR (−57.2% vs −43.8%) compared to the placebo. There were no significant differences in severe renal adverse effects among the dapagliflozin 5 mg, 10 mg, and placebo (1.9%, 1.8%, and 1.8%, respectively).	The use of dapagliflozin by CKD stage 3 diabetic patients has decreased their UACR levels without a rise in the significant adverse renal effects.
8	Fioretto et al, 2018^Citation16 Italy	Randomized controlled trial with 321 patients. Follow up was set at 24 weeks.	To evaluate dapagliflozin’s efficacy and safety for diabetic patients with moderate renal impairment (CKD 3A).	Dapagliflozin group experienced a substantial decrease in HbA1c and a more significant reduction in eGFR (returned baseline 3-week post-treatment) relative to placebo. There was no rise in frequent and serious adverse reactions (41.9% and 5.6%, respectively) relative to placebo groups (47.8% and 8.7%, respectively).	The use of dapagliflozin in diabetic patients with CKD 3A has shown more benefit relative to risk throughout treatment.
9	Kadowaki et al, 2019^Citation17 Japan	Post hoc analysis included 1517 Asian patients. Follow up was set at 164 weeks.	To determine the effects of empagliflozin on kidney among Asian patients with established CVD as part of the EMPA-REG OUTCOME^® trial.	Compared to placebo, empagliflozin was significantly associated with reduced risk of nephropathy (HR 0.64), microalbuminuria (HR 0.64), and renal death (HR 0.48). Empagliflozin users have also experienced a lower eGFR decline rate and better UACR reduction (at week 12 and beyond) compared to the placebo group.	Asian patients on empagliflozin have experienced kidney protective effects compared to the placebo group.
10	Kashiwagi et al, 2015^Citation18 Japan	Randomized controlled trial (LANTERN study) with 165 patients. Follow up was set at a total of 52 weeks.	To investigate the safety and efficacy in the use of ipragliflozin by diabetic patients that have renal impairment.	Statistically significant decreases in the level of HbA1c and FPG were observed in patients with mild-RI but not in patients with moderate-RI. Ipragliflozin has not been associated with any significant safety issues.	In patients with mild but not moderate renal impairment, ipragliflozin could improve glycemic control.
11	Wanner et al, 2016^Citation19 Multinational	Analysis of the secondary outcomes of the EMPA-REG OUTCOME trial that involved with 6185 patients. Follow up for reported key findings was adjusted at 48 months.	To investigate the long-term renal effects of empagliflozin on the secondary renal outcomes among patients with type 2 diabetes at high risk for cardiovascular events.	Empagliflozin was associated with a lower incidence of worsening nephropathy (12.7% vs 18.8%) than a placebo. (HR 0.61; 95%; P<0.001). Empagliflozin group experienced a lower occurrence of doubling the serum creatinine level compared to placebo (1.5% vs 2.6%) with a significant relative risk reduction of 44%.	Empagliflozin was linked to lower clinically significant renal events correlated with slower development of kidney disease than placebo.
12	Lambers Heerspink et al, 2013^Citation20 Canada, USA, and Netherlands	Randomized, placebo-controlled, double-blind trial with 75 subjects. Follow up was set at 12 weeks.	To compared dapagliflozin and hydrochlorothiazide (HCTZ) effects on glomerular filtration rate (GFR).	The administration of dapagliflozin to the patients causes a higher reduction in GFR (−10.8% vs –3.4%) than HCTZ. Both dapagliflozin and HCTZ were associated with decreased body weight.	Initiation of dapagliflozin can cause GFR and bodyweight reduction, thus having a diuretic-like effect.
13	Nadkarni et al, 2017^Citation21 USA	Propensity matched analysis involved 1584 SGLT2i users from two cohorts. Follow up was set at 14 months.	To investigate the risk of acute kidney injury in new SGLT2i users among patients with T2DM.	In both cohorts, SGLT2i users tend to have lower unadjusted hazards (HR 0.4; P = 0.01 and HR 0.5; P < 0.01, respectively) of acute kidney injury compared to the non-users.	The use of SGLT2i was not linked to increment in the risk of acute kidney injury among T2DM patients.
14	Mahaffey et al, 2019^Citation22 Multinational	Analysis of the results of the CREDENCE trial that involved 4401 participants. Follow-up was set at a median of 2.62 years.	To assess the outcomes of using canagliflozin in people with T2D, CKD with (secondary prevention), or without (primary prevention) preexisting CVD.	The risk of the primary composite renal outcome was consistently reduced with canagliflozin in both the primary and secondary prevention groups.	Canagliflozin showed protective renal outcomes in T2DM patients with no underlying CVD.
15	Perkovic et al, 2018^Citation23 CANVAS Program (30 countries)	Two randomized controlled trials involved a total of 10,142 participants. Follow up was set at least 78 weeks (average 3–4 years).	To investigate the long-term effects of canagliflozin on various renal outcomes.	Canagliflozin group has a lesser possible association with ESRD’s composite outcomes, renal-related deaths compared to the placebo group (HR 0.53, 95% CI 0·33–0·84). Canagliflozin receivers experienced a slower annual eGFR decline and 18% lower mean UACR than the placebo group.	Canagliflozin has been shown to have a possible renoprotective effect on long term use among T2DM patients.
16	Yamout et al, 2014^Citation24 USA	Analysis of 4 randomised controlled trial results focused on a cohort of 1085 T2DM subjects with stage 3 CKD. Follow up for the reported renal outcome was set at 26 weeks.	To evaluate the safety of using canagliflozin in T2DM patients with stage 3 chronic kidney disease.	During the early treatment with canagliflozin, there have been initial declines in eGFR, but the value then improved back towards the baseline over time. Canagliflozin groups have a higher incidence of renal-related adverse effects (8.9 vs 3.7) than the placebo group.	Canagliflozin was generally well tolerated by the patients with T2DM and stage 3 CKD.
17	Cherney et al 2020^Citation25 Canada	Post hoc analyses of 2 randomized control trials (VERTIS SU & VERTIS MET) involved 1936 T2DM patients. Follow up was set at 104 weeks.	To assess the impact of ertugliflozin on eGRF and UACR compared to glimepiride or placebo/glimepiride.	Ertugliflozin group showed lower values for eGRF decline at 104 weeks, although it was higher at 6 weeks. Among patients with albuminuria, the ertugliflozin group was associated with consistently higher UACR reductions across the follow-up period of 104 weeks.	Despite the initial eGRF decline, ertugliflozin showed renoprotective effects of preserving eGRF and reducing UACR values at 104 weeks.
Dipeptidyl Peptidase IV Inhibitors (DPP4i) (n=7)
18	Rosenstock et al, 2019^Citation26 27 countries	Randomized, placebo-controlled, multicenter noninferiority trial in 6979 patients. Follow up was set at a median of 2.2 years.	To assess the effect of linagliptin on renal outcomes in T2DM patients at high CV and kidney risk.	There was no significant difference in the risk of developing the renal composite outcome in participants using linagliptin compared to those using a placebo (9.4 vs 8.8%, HR 1.04). Linagliptin users had a significantly lower odds of albuminuria progression than the placebo group (35.3 vs 38.5%, HR 0.86).	Linagliptin was non-inferior to placebo on its impact on the renal outcomes among T2DM patients at high risk of CV and kidney events.
19	Groop et al, 2017^Citation27 12 countries	Randomized controlled trial (MARLINA-T2D trial) with 360 patients. Follow up was set at 24 weeks.	To investigate the renal effects of linagliptin among diabetic patients with albuminuria.	Linagliptin recipients had a lower, nonsignificant change in UACR from baseline about 6.0% (P = 0.1954) compared to the placebo group. There were no significant differences in the event of adverse effects and changes in eGFR between the two groups.	Among diabetic patients with kidney disease, linagliptin had no significant lowering of albuminuria.
20	Kim et al, 2016^Citation28 Republic of Korea	Retrospective observational cohort study with 414 T2DM patients. Outcomes were reported at 1 and 4 years intervals.	To evaluate the renoprotective effects of DPP4i in terms of their impact on albuminuria and glomerular filtration rate. (GFR) among diabetic patients.	At 1 year, DPP4i was linked to a significant reduction in the average UACR among all patients. Those with macroalbuminuria showed reduced albumin levels. There was a slower eGFR reduction rate among patients with microalbuminuria at 4 years, while it was reversed in the macro- or normoalbuminuric groups.	DPP4i treatment exerted renoprotective effects by reducing urine albumin excretion and alleviate the decline of eGFR in diabetic patients.
21	Mosenzon et al, 2017^Citation29 Multinational	Randomised controlled trial (SAVOR-TIMI 53 Trial) involved 16,492 patients over two years follow up.	To investigate the presence of a protective effect in diabetic nephropathy by saxagliptin.	Saxagliptin group experienced a significant reduction in the ACR level throughout the trial compared to the placebo. No significant changes can be seen in the GFR and renal safety profile between the two groups.	Saxagliptin has shown benefit to the patients by improving ACR levels that were not linked to changes in the eGFR level.
22	Scott et al, 2018^Citation30 Multinational	Randomised controlled trial (CompoSIT-R Study) with 613 T2DM patients on Metformin ± SU. Follow up was set at 24 weeks.	To compare the safety of sitagliptin in comparison with dapagliflozin among T2DM patients with mild renal insufficiency.	Both sitagliptin and dapagliflozin groups have similar results regarding the percentage of the participants who experience eGFR decline. Sitagliptin has shown lower percentages of drug-related adverse events than dapagliflozin (7.8% vs 13.7%).	Sitagliptin showed a similar impact on the eGFR with an overall better safety profile compared to dapagliflozin.
23	von Eynatten et al, 2013^Citation31 Boehringer Ingelheim Pharmaceuticals (USA & Germany)	Pooled analysis of six phases III clinical trials with 512 T2DM patients with microalbuminuria and hypertension. Outcomes were reported at 18 and 24 weeks intervals.	To assess linagliptin’s renal safety in a T2DM cohort with two vascular risk factors, microalbuminuria, and hypertension.	Linagliptin group showed no significant difference in the eGFR compared to the placebo group. Linagliptin groups experience a minor reduction in UACR from baseline in comparison to the placebo group.	Among this high-risk cohort, linagliptin was generally well tolerated.
24	Cornel et al, 2016^Citation32 38 countries	Post hoc analysis of randomized trial (TECOS) with 14,671 T2D patients and established cardiovascular disease. Outcomes were reported at a median period of 3 years.	To assess CKD outcomes in patients with T2D when treated with sitagliptin based on their baseline (eGFR) level.	Sitagliptin group had slightly lower (eGFR) values compared to the placebo. Sitagliptin group demonstrated a marginally lower (by 0.18 mg/g) mean UACR than participants receiving placebo.	The shown slight differences do not confer clinically significant impact of sitagliptin on CKD outcomes.
Glucagon-Like Peptide-1 Analogues (n= 6)
25	Gerstein et al, 2019^Citation33 24 countries	Analysis of data from randomized controlled study (REWIND) with 9901 T2DM patients. Follow up was set at a median of 5.4 years.	To investigate the long-term effects of dulaglutide on renal outcomes in T2DM patients.	Dulaglutide was associated with a lower incidence of the composite renal outcomes (17.1% vs 19.6%, HR 0.85, p=0.0004) compared to the placebo. Dulaglutide was linked to a decrease in the incidence of the new macroalbuminuria (p<0.0001).	Long term use of dulaglutide was associated with renoprotective effects.
26	Tuttle et al, 2018^Citation34 9 countries	Randomized controlled trial (AWARD-7) with 577 T2DM patients. Outcomes were reported at 52 weeks.	To assess kidney-related safety of once-weekly dulaglutide compared with daily insulin in T2DM patients with moderate-to-severe CKD.	Dulaglutide 0.75 mg and 1.5 mg showed higher eGFR levels compared to insulin glargine (p=0∙009 and p=0.005, respectively). Dulaglutide 0.75 mg and 1.5 mg showed no significant impact on UACR reduction compared to insulin glargine.	Dulaglutide was associated with attenuation in the (eGFR) decline compared to insulin glargine.
27	Marso et al, 2016^Citation35 20 countries	Randomised controlled trial (SUSTAIN-6) in 3297 T2DM patients at high CVD risk. Follow up was set at a median of 3.8 years.	To investigate the effect of semaglutide on renal outcome compared to placebo.	Semaglutide reduced the risk of new or worsening nephropathy (3.8% vs 6.1%, HR 0.64, P = 0.005) compared to placebo.	Semaglutide group experienced a lower incidence of renal adverse outcomes compared to the placebo.
28	Bethel et al, 2019^Citation36 Multinational	Analysis of data from a randomized controlled trial (EXSCEL) in 13,844 T2DM patients. Follow up was set at a median of 3.2 years.	To investigate the effect of exenatide on renal outcomes in diabetic patients.	Overall composite renal outcomes were significantly reduced among exenatide users as per adjusted analyses. There were no significant differences between exenatide and placebo in the levels of (eGFR) and the incidence of new macroalbuminuria as per intention to treat analyses.	Exenatide seems to have potential, although inconsistent overall impact on the renal outcomes when considered for T2DM patients.
29	Mann et al, 2017^Citation37 32 countries	Analysis of data from a randomized controlled trial (LEADER) involved 9340 T2DM patients. Follow up was set at a median of 3.84 years.	To investigate the impact of long-term use of liraglutide on renal outcomes in T2DM patients.	Liraglutide had significantly lower macroalbuminuria rates than the placebo group (161 vs 215 patients, HR 0.74; P = 0.004). Liraglutide group had similar rates of renal adverse events compared to the placebo group.	Liraglutide initiation has been associated with lower rates of diabetic kidney disease progression compared to the placebo group.
30	Muskiet et al, 2018^Citation38 Netherlands	Analysis of data from a randomized controlled trial (ELIXA) involved 5978 T2DM patients. Outcomes were reported at 108 weeks.	Investigate the effect of lixisenatide on renal outcomes focusing on UACR measures.	Lixisenatide was linked to significantly lower new-onset macroalbuminuria (HR 0·80; p=0·04) compared with placebo. There were no significant differences between groups in the measured levels of eGFR decline or renal adverse events.	Lixisenatide showed an impact on reducing UACR in patients with macroalbuminuria and decreasing the risk of new-onset cases.
Thiazolidinediones (TZD), Acarbose, Sulphonylureas (SU) (n=2)
31	Chen et al, 2016^Citation39 Taiwan	A randomized, open-labeled, controlled study with 60 patients treated with Metformin and sulfonylureas (SU) therapy. Follow up was set at six months.	To evaluate the effect of adding pioglitazone on urinary albumin to creatinine ratio (UACR) and (eGFR) of diabetic patients, compared to acarbose.	The Pioglitazone group had no significant differences in eGFR and UACR values compared to the acarbose group. The Pioglitazone group was more prone to gain weight and had lower fasting blood glucose values than the acarbose group.	The addition of pioglitazone or acarbose to patients treated with SU and Metformin for six months did not show significant changes in eGFR and UACR.
32	Van Dalem et al, 2016^Citation40 Netherlands	Population-based cohort study with 120,803 diabetic patients (2004–2012). Follow up was set at a mean of 3.7 years.	To assess the risk of hypoglycemia and the use of SU and its effect on renal function, compared to Metformin.	Compared to Metformin, SU users experienced a significant increment of the hypoglycemia risk (aHR 2.50). Hypoglycemia incidence was higher among patients with an eGFR rate lower than 30 mL/min/1.73 m^2.	SU for diabetic patients with lower eGFR should consider the possible increase in the risk of hypoglycemia.

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