Type 2 diabetes mellitus development programs in the new regulatory environment with cardiovascular safety requirements

Figures & data

Table 1 Options and considerations for patient population selection in an outcome study

	CV event rate	Key consideration	Note
General T2DM population	Low (<1%)	How long/large would it be?	Typical short-term Phase IIIa population, but a larger, longer term study is needed
High-risk/multiple-risk-factor population	Moderate (1%–3%)	Generalizability issues?	Population for most CV outcome studies
ACS population	High (3+%)	Too late to show benefit/detect differences? Generalizability issues?	Selected outcome studies

Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; T2DM, type 2 diabetes mellitus.

Figure 1 Issues in research program design.

Abbreviations: CV, cardiovascular; RR, relative risk; T2DM, type 2 diabetes mellitus.

Table 2 Selected type 2 diabetes mellitus CV outcome studies

Agent, study	Background medications	Population	Comparator	N	Initiated before FDA approval
Alogliptin, EXAMINEa;^Citation17,Citation18	OADs/insulin (no GLP-1RA/DPP-4-I)	≥18 years old with ACS within 15–90 days before randomization; HbA1c 6.5%–11%	PBO	5,400	Yes
Saxagliptin, SAVOR-TIMI 53a;^Citation19,Citation20	OADs/insulin (no GLP-1RA/DPP-4-I)	≥40 years old with CVD or ≥55–60 years with multiple CV risk factors; HbA1c 6.5%–12%	PBO	16,500	No
Dulaglutide, REWIND^Citation21	Drug naïve or two or fewer OADs ± GLP-1RA or basal insulin or basal insulin alone	≥50 years old with CVD, ≥55 years old with subclinical CVD, ≥60 years old with two or more CV risk factors; HbA1c ≤9.5%	PBO	9,622	Yes
Exenatide QW, EXSCEL^Citation22	Three or fewer OADs	≥18 years old with CVD (60%) and CV risk factors (40%); HbA1c 7%–10%	PBO	9,500	No
Linagliptin, CAROLINA^Citation23	Drug naïve/OADs (no GLP-1RA/DPP-4-I/TZD/insulin)	40–85 years old with CVD or two or more specified CV risk factors; HbA1c 6.5%–8.5%	Glimepiride	6,000	Yes
Linagliptin, CARMELINA^Citation24	Drug naïve/any background except GLP-1RA/DPP-4-I/SGLT-2 inhibitor)	≥18 years old with high risk of CV events; HbA1c 6.5%–10.0%	PBO	8,300	Yes
Liraglutide, LEADER^Citation25	OADs/insulin (no GLP-1RA/DPP-4-I)	≥50 years old with CVD or ≥60 years old with CV risk factors; HbA1c.>7%	PBO	8,800	No
Lixisenatide, ELIXA^Citation26	Any antidiabetic treatment (except for GLP-1RA/DPP-4-I)	≥30 years old with ACS event (ie, STEMI, NSTEMI, UA) leading to hospitalization up to 6 months before screening; HbA1c 5.5%–11%	PBO	6,000	Yes
Sitagliptin, TECOS^Citation27	Met/SU/PIO/insulin	≥50 years old with CVD; HbA1c 6.5%–8%	PBO	14,000	No

Note:

a Completed studies.

Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; CVD, cardiovascular disease; DPP-4-I, dipeptidyl peptidase-4 inhibitor; FDA, US Food and Drug Administration; GLP-1RA, glucagon-like peptide 1 receptor agonists; Met, metformin; NSTEMI, non-ST elevation myocardial infarction; OAD, oral antidiabetic drug; PBO, placebo; PIO, pioglitazone; QW, weekly; SGLT-2, sodium glucose cotransporter 2; STEMI, ST elevation myocardial infarction; SU, sulfonylurea; TZD, thiazolidinedione; UA, unstable angina.

Figure 2 Graphic illustration of different trial plans and data analysis strategies.

Abbreviation: RR, relative risk.

Table 3 Study design and testing strategy for selected CV outcome studies

Study	Study design	E1	E2	Glycemic endpoint included?	Testing strategy
EXAMINE^Citation17,Citation18	Noninferiority with RR margin of 1.3	MACE	MACE+	No	E1 for noninferiority → E2 for superiority → E1 for superiority
SAVOR-TIMI 53^Citation19,Citation20	Superiority with 17% RR reduction	MACE	MACE+	Yes: in the “other efficacy endpoints” category, eg: • Rescue (need for increase in dose or addition of new antidiabetic medication); • Insulin (initiation of insulin therapy in patients not receiving insulin therapy at baseline)	E1 for noninferiority → E1 for superiority → E2 for superiority Glycemic endpoint not subject to multiple comparison
CAROLINA^Citation23	Noninferiority with RR margin of 1.3	MACE plus hospitalization due to unstable angina	NA	Yes: in the “secondary outcome” category, eg: • Treatment sustainability; • HbA1c	Only to primary endpoint E1 for noninferiority → E1 for superiority All other analyses are exploratory, with no correction for multiple hypotheses

Abbreviations: CV, cardiovascular; E1, primary CV endpoint; E2, secondary CV endpoint; MACE, major adverse cardiac events; MACE+, additional CV-related events; NA, not applicable; RR, relative risk.

Table S1 Patient population/risk factor comparison for outcome studies

	PROactive^Citation1	ADVANCE^Citation2,Citation3	ADOPT^Citation4	VADT^Citation5,Citation6	ACCORD^Citation7	RECORD^Citation8	BARI 2D^Citation9,Citation10	EXAMINE^Citation11,Citation12	SAVOR-TIMI 53^Citation13,Citation14
Male	66.1%	58%	57.7%	97%	62%	52%	70.4%	69.7%	67%
Age group	35–75 years	>55 years	30–75 years	>40 years	40–79 years	40–75 years	>25 years	29–91 years	>40 years
Mean age	61.8 years	66 years	57 years	60.5 years	62.2 years	58.5 years	62.4 years	60.9 years	65 years
Duration DM	9.5 years	8 years	<3 years	11.5 years	10 years	7 years	10.4 years	7.3 years	10.3 years
Prior CVD	100%	32%	0%	40%	35%	21%	100%	100%	78%
Statin use	40.8%	28%	NA	NA	59.3%	NA	74.9%	20.9%	NA

Abbreviations: CVD, cardiovascular disease; DM, diabetes mellitus; NA, not applicable.

Table S2 Endpoint selection for CV safety evaluation

Traditional CV safety/efficacy endpoint: MACE	Potential safety endpoint (2008 FDA guidelines^Citation15): MACE+
MI	MI
CV death	CV death
Stroke	Stroke
“Plus others*”	Hospitalization due to unstable angina eg, hospitalizations for HF, TIA, revascularizations

Note:

* Additional CV events to be considered.

Abbreviations: CV, cardiovascular; FDA, US Food and Drug Administration; HF, heart failure; MACE, major adverse cardiac events; MACE+, additional CV-related events; MI, myocardial infarction; TIA, transient ischemic attack.

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