Oral semaglutide in patients with type 2 diabetes and cardiovascular disease, renal impairment, or other comorbidities, and in older patients

Figures & data

Figure 1. A summary of factors to consider for use of glucose-lowering medications in patients with cardiovascular disease, renal impairment, and in older patients. Adapted from [5,15,16]

*In older patients who are at increased risk of hypoglycemia, treatments with a lower risk of hypoglycemia are preferred [5]. ASCVD, atherosclerotic cardiovascular disease; (C)HF, (congestive) heart failure; DKA, diabetic ketoacidosis; CKD, chronic kidney disease; CVD, cardiovascular disease; DPP-4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1RAs, glucagon-like peptide-1 receptor agonists; SGLT2i, sodium-glucose co-transporter-2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione.

Table 1. Overview of PIONEER 5 and PIONEER 6 trial designs [25,26]

Trial design characteristic	PIONEER 5	PIONEER 6
Patient population	324 adults (age ≥18 years) T2D for ≥90 days eGFR 30–59 mL/min/1.73 m^2 Stable doses of 1–2 oral glucose-lowering agents (metformin or SU) or basal insulin ± metformin for ≥90 days HbA1c 7.0–9.5% (53–80 mmol/mol)	3183 adults with T2D age: – ≥50 years with established CVD or CKD or – ≥60 years with CV risk factors only Standard-of-care glucose-lowering background regimen, excluding a DPP-4i, a GLP-1RA, or pramlintide
Treatment arms and duration of therapy		PIONEER 6 was an event-driven CVOT that reached completion with the accrual of ≥122 MACE
Background therapy	Glucose-lowering agents: – Metformin (75%) – SU (40%) Basal insulin (35%)	Standard-of-care background regimen: – Glucose-lowering agents: ▪ Metformin (77%) ▪ Insulin (61%) ▪ SU (32%) ▪ SGLT2i (10%) – Other medications: ▪ Antihypertensive (94%) ▪ Lipid-lowering (85%) ▪ Antiplatelet or antithrombotic (79%)
Primary endpoint	Change from baseline to week 26 in HbA1c	Time to first MACE (CV death, nonfatal stroke, or nonfatal MI)
Key secondary endpoints	Change from baseline to week 26 in body weight Change in other parameters of efficacy, safety, and tolerability	Time to all-cause death Time to expanded MACE endpoint*

*Expanded MACE endpoint consisted of the primary outcome plus unstable angina requiring hospitalization, or HF requiring hospitalization.

CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA_1c, glycated hemoglobin; HF, heart failure; MACE, major adverse cardiovascular event; MI, myocardial infarction; SGLT2i, sodium-glucose co-transporter-2 inhibitor; SU, sulfonylurea; T2D, type 2 diabetes.

Figure 2. Composite primary outcome in PIONEER 6 [25]

Cumulative incidence plots for the primary outcome (first major adverse cardiovascular events, representing a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). A stratified Cox proportional-hazards model was used for the primary outcome analysis, with trial group as a fixed factor. CI, confidence interval. From New England Journal of Medicine, Husain M. et al, Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes, volume 381, pages 841–51, copyright© (2019) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Figure 3. Incidence of adverse events during PIONEER 5 and 6 (on-treatment data) [25,26]

*Severe as per American Diabetes Association classification [47]; ^†confirmed by plasma glucose <3.1 mmol/L (<56 mg/dL); ^‡in-trial data. AE, adverse event; BG, blood glucose; GI, gastrointestinal; NR, not reported.

Table 2. Change from baseline in HbA_1c by age subgroup in select PIONEER studies comparing oral semaglutide 14 mg with placebo or an active comparator [27]

	Age subgroups
	<45 years	≥45–<65 years	≥65 years
PIONEER 1*
N	130	430	143
Mean baseline HbA1c, %	8.0	8.0	7.8
Change from baseline in HbA1c to week 26, %
Oral semaglutide 14 mg	–1.6	–1.5	–1.5
Placebo	0.1	–0.2	0.0
PIONEER 2
N	94	512	215
Mean baseline HbA1c, %	8.4	8.2	7.9
Change from baseline in HbA1c to week 26, %
Oral semaglutide 14 mg	–1.5	–1.4	–1.4
Empagliflozin 25 mg	–1.0	–0.8	–0.9
PIONEER 3*
N	183	1179	501
Mean baseline HbA1c, %	8.4	8.4	8.1
Change from baseline in HbA1c to week 26, %
Oral semaglutide 14 mg	–1.2	–1.4	–1.5
Sitagliptin 100 mg	–0.5	–0.7	–1.0
PIONEER 4
N	86	475	150
Mean baseline HbA1c, %	8.1	8.0	7.8
Change from baseline in HbA1c to week 26, %
Oral semaglutide 14 mg	–1.4	–1.3	–1.4
Placebo	0.3	–0.1	–0.4
Liraglutide 1.8 mg	–0.8	–1.1	–1.2
PIONEER 5
N	0	65	259
Mean baseline HbA1c, %	–	8.0	8.0
Change from baseline in HbA1c to week 26, %
Oral semaglutide 14 mg	–	–1.0	–1.2
Placebo	–	0.3	–0.2
PIONEER 8*
N	43	410	278
Mean baseline HbA1c, %	8.3	8.2	8.1
Change from baseline in HbA1c to week 26, %
Oral semaglutide 14 mg add-on to insulin	–1.6	–1.4	–1.4
Placebo add-on to insulin	0.5	–0.1	0.0

*Oral semaglutide 3 and 7 mg dose not shown.

HbA_1c, glycated hemoglobin; N, number of patients.

Figure 4. Summary of key clinical implications for use of oral semaglutide in patients with comorbidities. CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; GI, gastrointestinal

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