Type 2 diabetes and cardiovascular disease: risk reduction and early intervention

Figures & data

Video Abstract

© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group

Figure 1. Administration and dose-escalation information for GLP-1RAs with proven CVD benefit [7–9]. CVD, cardiovascular disease; GI, gastrointestinal; GLP-1RA, glucagon-like peptide-1 receptor agonist.

Table 1. Summary of CV risk factor outcomes in GLP-1RA CVOTs.

	Dulaglutide Gerstein et al. [11]			Liraglutide Marso et al. [13]		Semaglutide Marso et al. [12]
Outcome (change from baseline)	Dulaglutide 1.5 mg	Placebo	Liraglutide 1.8 mg		Placebo		Semaglutide 0.5 mg	Placebo0.5 mg	Semaglutide 1.0 mg	Placebo 1.0 mg
BMI, kg/m^2	–1.08 (0.03)	–0.55 (0.03)	NR		NR		NR	NR	NR	NR
Difference, P value	–0.53 (–0.61, – 0.46), P < 0.0001		NR				NR		NR
Systolic BP, mm Hg	–3.15 (0.13)	–1.44 (0.13)	-		-		–3.44	–2.17	–5.37	–2.78
Difference, P value	–1.70 (–2.07, – 1.33), P < 0.0001		–1.2 (–1.9, – 0.5)				–1.27 (–2.77, 0.23), P = NS		–2.59 (–4.09, – 1.08), P < 0.001
Diastolic BP, mm Hg	–1.93 (0.08)	–2.05 (0.08)	-		-		–1.37	–1.42	–1.57	–1.71
Difference, P value	0.12 (–0.10, 0.34), P = 0.28		0.6 (0.2, 1.0)				0.04 (–0.83, 0.92), P = NS		0.14 (–0.74, 1.03), P = NS
Total cholesterol, mM	–0.20 (0.01)	–0.13 (0.01)	NR		NR		0.97	1.00	0.97	0.99
Difference, P value	–0.07 (–0.10, –0.03), P = 0.0002		NR				0.97 (0.95, 1.00), P < 0.05^a		0.99 (0.97, 1.01), P = NS^a
LDL cholesterol, mM	–0.15 (0.01)	–0.09 (0.01)	NR		NR		0.97	1.01	0.98	0.99
Difference, P value	–0.05 (–0.08, – 0.02), P = 0.001		NR				0.96 (0.93, 0.99), P < 0.05^a		0.99 (0.96, 1.03), P = NS^a
HDL cholesterol	-	-	NR		NR		0.99	0.99	1.01	0.97
Difference, P value	-		NR				1.00 (0.99, 1.02), P = NS^a		1.04 (1.02, 1.06), P < 0.0001^a
Waist:hip (women)	–0.005 (0.001)	0.0 (0.001)	NR		NR		NR	NR	NR	NR
Difference, P value	–0.005 (–0.008, – 0.0012), P = 0.009		NR				NR		NR
Waist:hip (men)	–0.007 (0.001)	–0.004 (0.001)	NR		NR		NR	NR	NR	NR
Difference, P value	–0.003 (–0.006, – 0.0001), P = 0.04		NR				NR		NR

Data are not comparable due to differences between the trials in patient populations and analysis methods.

^aLipid parameters are ratio to baseline (mg/dL) and were analyzed on log-scale with means at baseline presented as geometric means.

BMI, body mass index; BP, blood pressure; CV, cardiovascular; CVOTs, CV outcomes trials; GLP-1RA, glucagon-like peptide-1 receptor agonist; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NR, not reported; NS, non-significant.

Table 2. Key data reported in meta-analyses of GLP-1RA CVOTs.

	Meta-analyses of GLP-1RAs vs placebo
Outcome, HR [95% CI]; P value	Kristensen et al. [17]	Giugliano et al. [18]
MACE	0.88 [0.82, 0.94]; P < 0.001	0.87 [0.80, 0.96]; P < 0.011
All-cause mortality	0.88 [0.83, 0.95]; P = 0.001	0.89 [0.79, 0.99]; P < 0.034
Hospitalization for heart failure	0.91 [0.83, 0.99]; P = 0.028	0.91 [0.86, 0.97]; P = 0.013
Renal^a	0.83 [0.78, 0.89]; P < 0.001	0.83 [0.69, 1.00]; P < 0.047

GLP-1RAs included in the meta-analyses were lixisenatide, liraglutide, s.c. semaglutide, exenatide, albiglutide, dulaglutide, and oral semaglutide (N = 56,004).

^aComposite kidney outcome including macroalbuminuria consisted of development of macroalbuminuria, doubling of serum creatinine or 40% or greater decline in estimated glomerular filtration rate, development of end-stage kidney disease, or death due to kidney disease.

CI, confidence interval; CVOT, cardiovascular outcomes trial; GLP-1RA, glucagon-like peptide-1 receptor agonist; HR, hazard ratio; MACE, major adverse cardiovascular events; s.c., subcutaneous.

Table 3. Management of common GI AEs associated with GLP-1RAs with proven CV benefit.

	Percentage of patients with AE in placebo-controlled clinical trials									Management strategies
	Placebo [8]	Dulaglutide [8]		Placebo [9]	Liraglutide [9]		Placebo [7]	Semaglutide [7]		Implement slower dose escalation if required [7–9] Avoid eating food that is high in fat [37] Smaller meal sizes [46] Avoid eating beyond the feeling of being full [7–9]
		0.75 mg	1.5 mg		1.2 mg	1.8 mg		0.5 mg	1.0 mg
N	568	836	834	661	645	1,024	262	260	261
Any GI AEs, %	21.3	31.6	41.0	-	-	-	15.3	32.7	36.4
Nausea	5.3	12.4	21.1	5.0	18.0	20.0	6.1	15.8	20.3
Vomiting	2.3	6.0	12.7	2.0	6.0	9.0	2.3	5.0	9.2
Diarrhea	6.7	8.9	12.6	4.0	10.0	12.0	1.9	8.5	8.8

Data pooled across placebo-controlled randomized trials for each agent. Direct comparisons between agents may not be possible.

AE, adverse event; CV, cardiovascular; GI, gastrointestinal; GLP-1RA, glucagon-like peptide-1 receptor agonist.

Figure 2. Treatment decision-making infographic [4–6].

^aIf SGLT2i is not tolerated or contraindicated. ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA_1c, glycated hemoglobin; HF, heart failure; OAD, oral antihyperglycemic drug; SGLT2i, sodium-glucose cotransporter-2 inhibitor; T2D, type 2 diabetes.

Table

AACE/ACE	American Association of Clinical Endocrinologists and AmericanCollege of Endocrinology
ACC	American College of Cardiology
ADA	American Diabetes Association
AE	adverse event
ASCVD	atherosclerotic cardiovascular disease
BMI	body mass index
BP	blood pressure
CI	confidence interval
CKD	chronic kidney disease
CV	cardiovascular
CVD	cardiovascular disease
CVOT	cardiovascular outcomes trial
DRC	diabetic retinopathy complications
GI	gastrointestinal
GLP-1RA	glucagon-like peptide-1 receptor agonist
HbA1c	glycated hemoglobin
HDL	high-density lipoprotein
HF	heart failure
HR	hazard ratio
LDL	low-density lipoprotein
MACE	major adverse cardiovascular events
MI	myocardial infarction
MTC	medullary thyroid cancer
NR	not reported
NS	non-significant
OAD	oral antihyperglycemic drug
s.c.	subcutaneous
SGLT2i	sodium-glucose cotransporter-2 inhibitor
SoC	standard of care
TNF	tumor necrosis factor
T2D	type 2 diabetes

Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121–130.

 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;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;375(19):1834–1844.

 PubMed Web of Science ®Google Scholar

Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7(10):776–785.

 PubMed Web of Science ®Google Scholar

Giugliano D, Maiorino MI, Bellastella G, et al. GLP-1 receptor agonists for prevention of cardiorenal outcomes in type 2 diabetes: an updated meta-analysis including the REWIND and PIONEER 6 trials. Diabetes Obes Metab. 2019;21(11):2576–2580.

 PubMed Web of Science ®Google Scholar

US Food and Drug Administration [internet]. Trulicity prescribing information. 2020 [cited 2021 Jan 11]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125469s036lbl.pdf

 Google Scholar

US Food and Drug Administration [internet]. Victoza prescribing information. 2020 [cited 2021 Jan 11]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022341s036lbl.pdf

 Google Scholar

US Food and Drug Administration [internet]. Ozempic prescribing information. 2020 [cited 2021 Jan 11]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209637s003lbl.pdf

 Google Scholar

Reid TS. Practical use of glucagon-like peptide-1 receptor agonist therapy in primary care. Clin Diabetes. 2013;31(4):148–157.

 Google Scholar

Hinnen D. Glucagon-like peptide 1 receptor agonists for type 2 diabetes. Diabetes Spectr. 2017;30(3):202–210.

 PubMedGoogle Scholar

Data availability statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.