Effects of anti-diabetes medications on cardiovascular and kidney outcomes in Asian patients with type 2 diabetes: a rapid evidence assessment and narrative synthesis

Figures & data

Table 1. Cardiovascular outcomes trials of glucose-lowering drugs with Asian participants

Trial	Treatment	Comparator	Primary endpoint	Follow-up time	Number of patients	Number of Asian patients	Countries defined as Asian if subgroup by region was reported	Outcomes reported for Asians
DPP-4 inhibitors
SAVOR-TIMI 53 [31–33]	Saxagliptin	Placebo	3P-MACE^a	2.1 years	16,492	Asian (race) ITT NR by arm; combined arms: 1775 Asian (region) ITT NR by arm; combined arms: 1553	Not author-defined^e; Asian countries include: Hong Kong, India, Taiwan, Thailand (excludes Australia/New Zealand)	3P-MACE
EXAMINE [34–37]	Alogliptin	Placebo	3P-MACE^a	1.5 years	5380	Asian (region) ITT Alogliptin: 506 Placebo: 504	Hong Kong; India; Japan; Korea; Malaysia; Philippines; Taiwan; Thailand	3P-MACE; CV death
TECOS [38–41]	Sitagliptin	Placebo	4P-MACE^b	3.0 years	14,671	Asian (race) ITT Sitagliptin: 1654 Placebo: 1611 Asian (region) ITT Sitagliptin: 2313 Placebo: 2252	Not author-defined^e; Asian countries include: China, Hong Kong, India, Korea, Malaysia, Singapore, Taiwan (may include Australia/New Zealand)	4P-MACE; non-fatal MI, hHF
CARMELINA [24–27]	Linagliptin	Placebo	3P-MACE^a	2.2 years	6979	Asian (race from Asian region) treated^d Linagliptin: 272 Placebo: 283 Asian (race) treated^d Linagliptin: 307 Placebo: 333	Japan, China, Korea, Taiwan, Malaysia	3P-MACE; 4P-MACE; MI; stroke; CV death; non-CV death; ACM; hHF; hHF or CV death; hHF or ACM; hUA; all-cause hospitalization; composite kidney outcomes; doubling of SCr; albuminuria progression; composite microvascular endpoint; composite ocular endpoint
CAROLINA [28–30]	Linagliptin	Glimepiride	3P-MACE^a	6.3 years	6033	Asian (race) treated^d Linagliptin: 531 Glimepiride: 530 Asian (region) treated^d Linagliptin: 465 Glimepiride: 468	Hong Kong, India, Japan, Korea, Malaysia, Philippines, Taiwan	3P-MACE; 4P-MACE; ACM; CV death; non-CV death; MI; stroke; TIA; hUA, coronary revascularization; hHF; hHF or CV death; investigator-reported HF; confirmed CV event
SGLT2 inhibitors
EMPA-REG OUTCOME [42–47]	Empagliflozin	Placebo	3P-MACE^a	3.1 years	7020	Asian (race) treated^d Empagliflozin 25 mg: 501 Empagliflozin 10 mg: 505 Placebo: 511	Asian region subpopulation not reported^f	3P-MACE; 4P-MACE; ACM; CV death; MI; stroke; hHF; hHF or CV death; composite kidney outcomes, progression to macroalbuminuria
CANVAS Program [48–50]	Canagliflozin	Placebo	3P-MACE^a	~2.4 years	10,142	Asian (race) ITT Canagliflozin: 777 Placebo: 507	Asian region subpopulation not reported	3P-MACE; composite kidney outcome
DECLARE-TIMI 58 [55–58]	Dapagliflozin	Placebo	3P-MACE^a	4.2 years	17,160	Asian (region) treated^d Dapagliflozin: 1093 Placebo: 1093	Australia, China, Hong Kong, India, Taiwan, Thailand, Japan, Philippine, Korea, Vietnam	3P-MACE; hHF or CV death, composite kidney outcome
CREDENCE [52–54]	Canagliflozin	Placebo	Composite cardiorenal outcome^c	2.62 years	4401	Asian (race) ITT Canagliflozin: 425 Placebo: 452	Asian region subpopulation not reported	3P-MACE; composite cardiorenal outcome
VERTIS CV [59]	Ertugliflozin	Placebo	3P-MACE	3.5 years	8246	Asian (race) ITT Ertugliflozin: 336 Placebo: 162 Asian (region) ITT Ertugliflozin: 350 Placebo: 173	Not author-defined^e: Asian countries include: Hong Kong, Korea, Philippines, Taiwan, Thailand	3P-MACE; hHF
GLP-1 receptor agonists
ELIXA [61,62]	Lixisenatide	Placebo	4P-MACE^b	2.1 years	6068	Asian (race) ITT Lixisenatide: 404 Placebo: 367 Asian (region) ITT Lixisenatide: 374 Placebo: 329	Not author-defined^e; Asian countries include: China, India, Japan, Korea, Philippines, Taiwan (May include Australia)	4P-MACE
LEADER [63,64]	Liraglutide	Placebo	3P-MACE^a	~3.8 years	9340	Asian (race) ITT Liraglutide: 471 Placebo: 465 Asian (region) ITT Liraglutide: 360 Placebo: 351	China, India, Korea, Taiwan	3P-MACE
SUSTAIN-6 [73]	Semaglutide (injection)	Placebo	3P-MACE^a	~2.1 years	3297	Asian (race) ITT Semaglutide: 121 Placebo: 152	Asian region subpopulation not reported	3P-MACE
EXSCEL [65–67]	Exenatide	Placebo	3P-MACE^a	3.2 years	14,752	Asian (race) ITT Exenatide: 725 Placebo: 727 Asian (region) ITT Exenatide: 769 Placebo: 760	Australia; Hong Kong; Malaysia; New Zealand; Philippines; Korea; Taiwan; Thailand; China	3P-MACE; hHF
HARMONY Outcomes [68,69]	Albiglutide	Placebo	3P-MACE^a	1.6 years	9463	Asian (race) ITT Albiglutide: 228 Placebo: 242 Asian (region) ITT Albiglutide: 185 Placebo: 191	Not author-defined^e; Asian countries include: Hong Kong, Korea, Philippines, Taiwan, Thailand (does not include Australia or New Zealand)	3P-MACE
REWIND [70–72]	Dulaglutide	Placebo	3P-MACE^a	5.4 years	9901	Asian (race) ITT Dulaglutide: 216 Placebo: 218 Asian (region) ITT Dulaglutide: 232 Placebo: 238	Australia, New Zealand, Korea, Taiwan^g	3P-MACE; stroke
PIONEER-6 [74,75]	Semaglutide (oral)	Placebo	3P-MACE^a	1.3 years	3183	Asian (race) ITT Semaglutide: 324 Placebo: 306	Asian region subpopulation not reported	3P-MACE
Insulins
DEVOTE [76,77]	Insulin degludec	Insulin glargine	3P-MACE^a	1.99 years	7637	Asian (region) ITT Degludec: 319 Glargine: 330	Not author-defined^e; Asian countries include: India, Japan, Malaysia, Korea, Thailand (does not include Australia/New Zealand)	3P-MACE

3P-MACE: 3-point major adverse cardiovascular events; 4P-MACE: 4-point major adverse cardiovascular events; ACM: all-cause mortality; CV: cardiovascular; DPP-4: dipeptidyl peptidase-4; GLP-1: glucagon-like peptide-1; hHF: hospitalization for heart failure; hUA: hospitalization for unstable angina; ITT: intention to treat; MI: myocardial infarction; NR: not reported; SCr: serum creatinine; SGLT2: sodium-glucose co-transporter-2; TIA: transient ischemic attack. ^aCV death, non-fatal MI, or non-fatal stroke. ^bCV death, non-fatal MI, non-fatal stroke, or hUA. ^cEnd-stage kidney disease, doubling of serum creatinine, or death from kidney or CV causes. ^dTreated population: does not include all randomized patients as per ITT; only includes patients who received ≥1 dose of randomized treatment. ^eAuthors of the cited papers did not define Asian region; the listed countries represent those classified as Asian by the rapid evidence assessment researchers. ^f11 Asian countries (Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Philippines, Singapore, Sri Lanka, Taiwan, Thailand) participated in the EMPA-REG OUTCOME trial; however, all patients of Asian race were included, irrespective of their geographic location. ^gCountries included in Asian region were determined by calculating N from ClinicalTrials.gov record and comparing with subpopulation N.

Figure 1. PRISMA flow diagram of literature search and selection process. PRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses

Figure 2. Cardiovascular outcomes of Asian patients. 3P-MACE: 3-point major adverse CV events (CV death, non-fatal myocardial infarction, or non-fatal stroke); 4P-MACE: 4-point major adverse CV events (CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina); CI: confidence interval; CV: cardiovascular; DPP-4: dipeptidyl peptidase-4; GLP-1: glucagon-like peptide-1; SGLT2: sodium-glucose co-transporter-2. ^a95.47% CI. ^b95.6% CI. ^cNumerical data not provided but forest plot indicates no effect of treatment on outcome (CI crosses 1.00) [61]. Point size is proportional to size of trial cohort (number of patients)

Figure 3. Kidney outcomes of Asian patients. CI: confidence interval; CV: cardiovascular; DPP-4: dipeptidyl peptidase-4; eGFR: estimated glomerular filtration rate; ESKD: end-stage kidney disease; RRT: renal-replacement therapy; SCr: serum creatinine; SGLT2: sodium-glucose co-transporter-2. ^aeGFR was measured in ml/min/1.73 m². ^bMacroalbuminuria was defined as urinary albumin-to-creatinine ratio >300 mg/g. Point size is proportional to size of trial cohort (number of patients)

Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020 Oct 8;383(15):1425–1435.

 PubMed Web of Science ®Google Scholar

Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015 Dec 3;373(23):2247–2257.

 PubMed Web of Science ®Google Scholar

Bentley-Lewis R, Aguilar D, Riddle MC, et al. Rationale, design, and baseline characteristics in Evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo. Am Heart J. 2015 May;169(5):631–638 e7.

 PubMed Web of Science ®Google Scholar

Marso SP, Poulter NR, Nissen SE, et al. Design of the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial. Am Heart J. 2013 Nov;166(5):823–30 e5.

 PubMed Web of Science ®Google Scholar

Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016 Jul 28;375(4):311–322.

 PubMed Web of Science ®Google Scholar

Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016 Nov 10;375(19):1834–1844.

 PubMed Web of Science ®Google Scholar

Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018 Oct 27;392(10157):1519–1529.

 PubMed Web of Science ®Google Scholar

Green JB, Hernandez AF, D’Agostino RB, et al. Harmony outcomes: a randomized, double-blind, placebo-controlled trial of the effect of albiglutide on major cardiovascular events in patients with type 2 diabetes mellitus-Rationale, design, and baseline characteristics. Am Heart J. 2018;203:30–38.

 PubMed Web of Science ®Google Scholar

Bain SC, Mosenzon O, Arechavaleta R, et al. Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: rationale, design and patient baseline characteristics for the PIONEER 6 trial. Diabetes Obes Metab. 2019 Mar;21(3):499–508.

 PubMed Web of Science ®Google Scholar

Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019 Aug 29;381(9):841–851.

 PubMed Web of Science ®Google Scholar

Marso SP, McGuire DK, Zinman B, et al. Design of DEVOTE (trial comparing cardiovascular safety of insulin degludec vs insulin glargine in patients with type 2 diabetes at high risk of cardiovascular events) - DEVOTE 1. Am Heart J. 2016;179:175–183.

 PubMed Web of Science ®Google Scholar

Marso SP, McGuire DK, Zinman B, et al. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017 Aug 24;377(8):723–732.

 PubMed Web of Science ®Google Scholar

Data availability

The data that support the findings of this study are available from the corresponding author, F.Y., upon reasonable request.