Combination therapy with SGLT-2 inhibitors and GLP-1 receptor agonists as complementary agents that address multi-organ defects in type 2 diabetes

Figures & data

Figure 1. The multiple defects in type 2 diabetes and the classes of drugs that affect each defect. Reprinted by permission from Macmillan Publishers Limited, Nat Rev Dis Primers, DeFronzo RA, Ferrannini E, Groop L, Henry RR, et al, Type 2 diabetes mellitus, 15,019, Copyright (2015) [22].

AMPK: AMP-activated protein kinase; DPP-4: dipeptidyl peptidase-4; GLP1-RA: glucagon-like peptide 1 receptor agonists; IκB: inhibitor of NF-κB; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor-κB; RA: receptor agonist; ROS: reactive oxygen species; SGLT-2: sodium–glucose cotransporter-2; TLR4: Toll-like receptor 4; TNF: tumor necrosis factor; TZDs: thiazolidinediones.

Figure 2. Summary of guideline recommendations (ADA, AACE/ACE, ADA/EASD) for add-on glucose-lowering therapy in patients with type 2 diabetes [3–5].

A1c: glycated hemoglobin; AACE: American Association of Clinical Endocrinologists; ACE: American College of Endocrinology; ADA, American Diabetes Association; CVD: cardiovascular disease; CKD: chronic kidney disease; DPP-4i: dipeptidyl peptidase-4 inhibitor; EASD: European Association for the Study of Diabetes; GLP-1RA: glucagon-like peptide-1 receptor agonist; HF: heart failure; INS: insulin; MET: metformin; SGLT-2i: sodium–glucose cotransporter-2 inhibitor; SU: sulfonylurea; TZD: thiazolidinedione.

Figure 3. Effect of stepwise treatment approach compared with early and aggressive treatment of type 2 diabetes on A1c target attainment. Reprinted from Mayo Clin Proc, Vol. 85(12 Suppl), Schwartz SS, Kohl BA, Glycemic control and weight reduction without causing hypoglycemia: the case for continued safe aggressive care of patients with type 2 diabetes mellitus and avoidance of therapeutic inertia, S15-S26, Copyright (2010) with permission from Mayo Foundation for Medical Education and Research [6].

A1c: glycated hemoglobin; OAD: oral antidiabetes drug.

Table 1. Summary of clinical studies of combination therapy with a SGLT-2i and a GLP-1RA in patients with type 2 diabetes.

Study (duration)	Design	No. of pts	Background therapy	Add-on therapy	Clinical outcomes^a
DURATION-8 (52 weeks) [61]	R, DB	695	MET	ExQW + DAPA	↓ A1c, FPG, BW, and SBP
				ExQW + PBO	No major hypoglycemia reported
				DAPA + PBO
AWARD-10 (24 weeks) [64]	R, DB	424	SGLT-2i ± MET	DULA 0.75 mg	↓ A1c (both DULA doses)
				DULA 1.5 mg	↓ FPG, BW, and SBP (DULA 1.5 mg)
				PBO	1 episode of severe hypoglycemia
Curtis et al. (48 weeks) [65]	Ret, Obs	14	GLP-1RA ± MET ± SU	SGLT-2i	↓ A1c and BW
					Most common AEs were UTI and polydipsia
Deol et al. (3–6 months) [67]	Ret, Obs	79	GLP-1RA ± MET ± INS	SGLT-2i	↓ A1c, BW, BMI, and INS dose
Harashima et al. (52 weeks) [63]	Non-R, PMS	71	LIRA	CANA	↓ A1c, FPG, BW, and SBP; ↑ HDL-C
					Mild hypoglycemia only
Saroka et al. (mean 10.7 months) [66]	Obs	75	GLP-1RA ± other GLTs	CANA	↓ A1c, BW, SBP, and DBP; ↑ HDL-C
					Drug-related AEs were yeast infections, UTI, dry mouth, diarrhea, and hypotension
Seino et al. (52 weeks) [62]	Non-R	76	LIRA	LUSEO	↓ A1c, FPG, BW, fat mass, and waist circumference
					Mild hypoglycemia only
					Most common AE was nasopharyngitis

^aWith combination therapy versus comparator (in randomized studies) or baseline (in non-randomized or observational studies); downward arrow indicates significant reduction; upward arrow indicates significant increase.

A1c: glycated hemoglobin; AE: adverse event; BMI: body mass index; BW: body weight; CANA: canagliflozin; DAPA: dapagliflozin; DB: double blind; DBP: diastolic blood pressure; DULA: dulaglutide; ExQW: exenatide once weekly; FPG: fasting plasma glucose; GLP-1RA: glucagon-like peptide-1 receptor agonist; GLT: glucose-lowering therapy; HDL-C: high-density lipoprotein cholesterol; INS: insulin; LIRA; liraglutide; LUSEO: luseogliflozin; MET: metformin; Non-R: non-randomized; Obs: observational; PBO: placebo; PMS: postmarketing study; R: randomized; Ret: retrospective; SBP: systolic blood pressure; SGLT-2i: sodium–glucose cotransporter-2 inhibitor; SU: sulfonylurea; UTI: urinary tract infection.

Table 2. Effect of SGLT-2is, GLP-1RAs, and their combination on cardiovascular risk factors or pathophysiologic mechanisms [43,57].^a

	SGLT2is	GLP-1RAs	SGLT-2is + GLP-1RAs
Glycemia (A1c)	↓↓	↓↓	↓↓↓
Insulin sensitivity	↑	↑	↑↑
β-cell function	↑↑	↑↑↑	↑↑↑
Hemodynamics	↑↑	↑	↑↑
Blood pressure	↓	↓	↓↓
Lipid profile	–	↑	↑
Body weight	↓	↓↓	↓↓↓
Visceral fat	↓	↓	↓↓
Endothelial function	–	↑	↑
Natriuresis	↑↑	↑	↑↓
Inflammation	–	↓	↓

Adapted from DeFronzo RA. Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes Obes Metab. 2017;19(10):1353–1362, Copyright 2017, with permission from John Wiley & Sons Ltd [57].

^aUpward arrows indicate improvement or increase; downward arrows indicate reduction; dashes indicate neutral effect. The number of arrows represent the relative potency of the effect where ↓ = moderate, ↓↓ = strong, and ↓↓↓ = very strong.

A1c: glycated hemoglobin; GLP-1RA: glucagon-like peptide-1 receptor agonist; SGLT-2i: sodium–glucose cotransporter-2 inhibitor.

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