1.8.4.0 Se­lec­tion of Glu­cose-‍Low­er­ing Med­i­ca­tions for Pa­tients With Chron­ic Kid­ney Dis­ease

For pa­tients with type 2 di­a­betes and es­tab­lished CKD, spe­cial con­sid­erations for the se­lec­tion of glu­cose-low­er­ing med­i­ca­tions in­clude lim­i­ta­tions to avail­able med­i­ca­tions when eGFR is di­min­ished and a de­sire to mit­i­gate high risks of CKD pro­gres­sion, CVD, and hy­po­glycemia (48,49). Drug dos­ing may re­quire modifi­cation with eGFR <60 mL/‍min/‍1.73 m² (1).

The U.S. Food and Drug Ad­min­is­tra­tion (FDA) re­vised its guid­ance for the use met­formin in CKD in 2016 (50), rec­om­mend­ing use of eGFR in­stead of serum Cr to guide treat­ment and ex­pan­ding the pool of pa­tients with kid­ney dis­ease for whom met­formin treat­ment should be con­sid­ered. The re­vised FDA guid­ance states that met­formin is contrain­di­cat­ed in pa­tients with an eGFR <30 mL/‍min/‍1.73 m², eGFR should be mon­i­tored while tak­ing met­formin, the benefits and risks of con­tin­u­ing treat­ment should be reas­sessed when eGFR falls <45 mL/‍min/‍1.73 m², met­formin should not be ini­ti­at­ed for pa­tients with an eGFR <45 mL/ min/1.73 m², and met­formin should be tem­porar­i­ly dis­con­tin­ued at the time of or be­fore io­d­i­nat­ed con­trast imag­ing pro­ce­dures in pa­tients with eGFR 30–60 mL/‍min/‍1.73 m². With­in these con­straints, met­formin should be con­sid­ered the first-‍line treat­ment for all pa­tients with type 2 di­a­betes, in­clud­ing those with CKD. SGLT2 in­hibitors and GLP-1 RA should be con­sid­ered for pa­tients with type 2 di­a­betes and CKD who re­quire an­oth­er drug added to met­formin to at­tain tar­get A1C or can­not use or tol­er­ate met­formin. SGLT2 in­hibitors and GLP-1 RA are sug­gested be­cause they ap­pear to re­duce risks of CKD pro­gres­sion, CVD events, and hy­po­glycemia.

A num­ber of large car­dio­vas­cu­lar out­comes tri­als in pa­tients with type 2 di­a­betes at high risk for CVD or with ex­ist­ing CVD ex­am­ined kid­ney ef­fects as sec­ondary out­comes. These tri­als in­clude EMPA-REG OUT­COME [BI 10773 (Em­pagliflozin) Car­dio­vas­cu­lar Out­come Event Trial in Type 2 Di­a­betes Mel­li­tus Pa­tients], CAN­VAS (Canagliflozin Car­dio­vas­cu­lar As­sess­ment Study), LEAD­ER (Li­raglu­tide Ef­fect and Ac­tion in Di­a­betes: Eval­u­a­tion of Car­dio­vas­cu­lar Out­come Re­sults), and SUSTAIN-‍6 (Trial to Eval­u­ate Car­dio­vas­cu­lar and Other Long-‍term Out­comes With Semaglu­tide in Sub­jects With Type 2 Di­a­betes) (42,44,47,51).

Specifically, com­pared with place­bo, em­pagliflozin re­duced the risk of in­ci­dent or wors­en­ing nephropa­thy (a com­pos­ite of pro­gres­sion to UACR >300 mg/g Cr, dou­bling of serum Cr, ESRD, or death from ESRD) by 39% and the risk of dou­bling of serum Cr ac­com­pa­nied by eGFR ≤45 mL/‍min/‍1.73 m² by 44%; canagliflozin re­duced the risk of pro­gres­sion of al­bu­minuria by 27% and the risk of re­duc­tion in eGFR, ESRD, or death from ESRD by 40%; li­raglu­tide re­duced the risk of new or wors­en­ing nephropa­thy (a com­pos­ite of per­sis­tent macro-al­bu­minuria, dou­bling of serum Cr, ESRD, or death from ESRD) by 22%; and semaglu­tide re­duced the risk of new or wors­en­ing nephropa­thy (a com­pos­ite of per­sis­tent UACR >300 mg/g Cr, dou­bling of serum Cr, or ESRD) by 36% (each P <0.01).

These anal­y­ses were lim­it­ed by eval­u­a­tion of study pop­u­la­tions not se­lect­ed pri­mar­i­ly for CKD and ex­am­i­na­tion of renal ef­fects as sec­ondary out­comes. How­ev­er, all of these tri­als in­cluded large num­bers of peo­ple with kid­ney dis­ease (for ex­am­ple, the base­line preva­lence of al­bu­minuria in EMPA-‍REG OUT­COME was 53%), and some of the car­dio­vas­cu­lar out­comes tri­als (CAN­VAS and LEAD­ER) were en­riched with pa­tients with kid­ney dis­ease through el­i­gi­bil­i­ty cri­te­ria based on al­bu­minuria or re­duced eGFR. In ad­di­tion, sub­group anal­y­ses of CAN­VAS and LEAD­ER sug­gested that the renal benefits of canagliflozin and li­raglu­tide were as great or greater for par­tic­i­pants with CKD at base­line (19,46) and in CAN­VAS were sim­i­lar for par­tic­i­pants with or with­out atheroscle­rot­ic car­dio­vas­cu­lar dis­ease (ASCVD) at base­line (52). Small­er, short­er-‍term tri­als also demon­strate fa­vor­able renal ef­fects of med­i­ca­tions in these class­es (53, 53a). To­geth­er, these con­sis­tent re­sults sug­gest like­ly renal benefits of both drug class­es.

Sev­er­al large clin­i­cal tri­als of SGLT2 in­hibitors fo­cused on pa­tients with CKD, and as­sessment of pri­ma­ry renal out-‍comes are com­plet­ed or on­go­ing. Canagliflozin and Renal End­points in Di­a­betes with Es­tab­lished Nephropa­thy Clin­i­cal Eval­u­a­tion (CRE­DENCE), a place­bo-‍con­trolled trial of canagliflozin among 4,401 adults with type 2 di­a­betes, UACR ≥300 mg/g, and eGFR 30–90 mL/‍min/‍1.73 m², has a pri­ma­ry com­pos­ite end point of ESRD, dou­bling of serum Cr, or renal or car­dio­vas­cu­lar death (54). It was stopped early due to pos­i­tive efficacy, with de­tailed re­sults ex­pect­ed in 2019.

In ad­di­tion to renal ef­fects, some SGLT2 in­hibitors and GLP-1 RA have demon­strated car­dio­vas­cu­lar benefits. Name­ly, in EMPA-‍REG OUT­COME, CAN­VAS, and LEAD­ER, em­pagliflozin, canagliflozin, and li­raglu­tide, re­spec­tive­ly, each re­duced car­dio­vas­cu­lar events, eval­u­ated as pri­ma­ry out­comes, com­pared with place­bo (see Sec­tion 10 “Car­dio­vas­cu­lar Dis­ease and Risk Man­age­ment” for fur­ther dis­cus­sion). The glu­cose-low­er­ing ef­fects of SGLT2 in­hibitors are blunt­ed with eGFR (18,51). How­ev­er, the car­dio­vas­cu­lar benefits of em­pagliflozin, canagliflozin, and li­raglu­tide were sim­i­lar among par­tic­i­pants with and with­out kid­ney dis­ease at base­line (42,44,51,55). Most par­tic­i­pants with CKD in these tri­als also had di­ag­nosed ASCVD at base­line, though ap­prox­i­mate­ly 28% of CAN­VAS par­tic­i­pants with CKD did not have di­ag­nosed ASCVD (19).

Im­por­tant caveats limit the strength of ev­i­dence sup­port­ing the rec­om­men­da­tion of SGLT2 in­hibitors and GLP-1 RA in pa­tients with type 2 di­a­betes and CKD. As noted above, pub­lished data ad­dress a lim­it­ed group of CKD pa­tients, most­ly with coex­ist­ing ASCVD. Renal events have been ex­am­ined pri­mar­i­ly as sec­ondary out­comes in pub­lished large tri­als. Also, ad­verse event profiles of these agents must be con­sid­ered. Please refer to Table 9.1 for drug-‍specific fac­tors, in­clud­ing ad­verse event in­for­ma­tion, for these agents. There­fore, ad­di­tional clin­i­cal tri­als are need­ed to more rig­or­ous­ly as­sess the benefits and risks of these class­es of drugs among peo­ple with CKD.

For pa­tients with type 2 di­a­betes and CKD, the se­lec­tion of specific agents may de­pend on co­mor­bidity and CKD stage. SGLT2 in­hibitors may be more use­ful for pa­tients at high risk of CKD pro­gres­sion (i.e., with al­bu­minuria or a his­to­ry of doc­u­ment­ed eGFR loss) (Fig. 9.1) be­cause they ap­pear to have large beneficial ef­fects on CKD in­ci­dence. Em­pagli-‍ flozin and canagliflozin are only ap­proved by the FDA for use with eGFR ≥45 mL/ min/1.73 m² (though piv­otal tri­als for each in­cluded par­tic­i­pants with eGFR ≥30 mL/‍min/‍1.73 m² and demon­strated benefit in sub­groups with low eGFR) (18,19), and da­pagliflozin is only ap­proved for eGFR ≥60 mL/‍min/‍1.73 m². Some GLP-1 RA may be used with lower eGFR and may have greater benefits for re­duc­tion of ASCVD than for CKD pro­gres­sion or heart fail­ure.