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Lipid-Lowering Agents Frontiers in Clinical Drug Research-Diabetes & Obesity, Vol. 7 129
cardiovascular benefits [55]. Furthermore, SGLT2i, by acting on specific
electrolyte transporters within the cardiac muscle, may improve myocardial
energy metabolism and slow cardiac remodeling [55].
Pivotal Clinical Trials Involving SLGT2i
The EMPA-REG trial [7] represented a breakthrough in the treatment of diabetes
in that it was the first trial to demonstrate a significant reduction in clinical
outcomes with the use of SGLT2i. The trial randomized 7,028 patients with DM
and established CVD between 2010 and 2013, with a median follow-up time of
3.1 years. The primary outcome was CVM, MI, or stroke, with the secondary
outcome incorporating the three previous endpoints plus unstable angina (UA)
hospitalization. The composite primary outcome, ACM and HF hospitalizations,
were significantly lower in the empagliflozin group (RRR of 14, 32, and 35%,
respectively), with similar efficacy being shown at both 10 and 25 mg dosages.
The trial also played a pivotal role in the FDA’s 2016 approval of empagliflozin
for the treatment of diabetes, and, in many ways, it set the stage for an oncoming
wave of clinical trials that would change the landscape of diabetes treatment for
years to come.
The CANVAS study consisted of 2 sister trials that aimed to assess canagliflozin's
cardiovascular benefits in high-risk T2DM [8]. There were 10,142 patients in the
CANVAS program, 4,330 patients in the CANVAS trial, and 5,812 in the
CANVAS-R trial, with a combined analysis being conducted to maximize
statistical power. The mean follow-up duration was 188.2 weeks, with a mean
DM history duration of 13.5 years. The primary outcome was CVM, MI, or
stroke, and the secondary outcomes were ACM, CVM, and HF hospitalization.
Canagliflozin significantly improved the primary composite endpoint (RRD of
14%). Though the endpoints of ACM and CVM did not reach statistical
significance, fewer patients assigned to canagliflozin were hospitalized for heart
failure. The rationale behind designing the sister trial (CANVAS-R) was assessing
the renal-protection bestowed by canagliflozin (if any); and indeed, albuminuria
progression was significantly less likely in the canagliflozin arm.
However, these improvements did not come free of cost, with the canagliflozin
arm having a higher rate of amputations, a finding that prompted caution when
prescribing what was –at the time—a relatively new class of medications.
Interestingly, though not the first trial to be published in full, it led to the first-inclass FDA approval in 2013, as the trial was initiated earlier than EMPA-REG
and was approved based on interim results.
The next trial to test canagliflozin’s efficacy was CREDENCE, which assessed
the effects of the SGLT2 inhibitor on renal outcomes in 4401 patients with T2DM
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and albuminuric chronic kidney disease [9]. The primary outcome was a
composite of renal mortality, CVM, end-stage kidney disease, or creatinine
doubling, whereas the secondary outcomes were specified in the following order:
first, a composite of cardiovascular mortality or heart failure hospitalization;
second, a composite of cardiovascular death, myocardial infarction, or stroke;
third, heart failure hospitalizations. Canagliflozin significantly improved the
primary endpoint (HR of 0.7; NNT of 24), the secondary endpoint of CVM, MI,
or stroke (HR of 0.8; NNT of 43), and HF hospitalization (HR of 0.61; NNT of
43).
The significance of CREDENCE was that it was the first beneficial trial dedicated
to patients with T2DM and concomitant kidney disease, which is an invaluable
finding as renal affection in diabetes portends a grimmer prognosis and
accelerates the already deteriorating cardiovascular system, putting these patients
at a particularly high risk of CV events.
Unfortunately, the next major trial, DECLARE-TIMI-58 [10], did not yield results
that were as impressive as its predecessors. It evaluated the impact of 10 mg of
dapagliflozin on renal and cardiac outcomes in a high-risk T2DM population.
Randomization of 17,160 patients was done, 40.6% of whom had established
atherosclerotic disease and a median follow-up of 4.2 years. The primary safety
outcome was CVM, MI, or stroke, along with hospitalization for HF (which was
added half-way through the trial due to the findings of the EMPA-REG trial
mentioned above). Dapagliflozin reduced the composite of CVM and HF
hospitalization (HR of 0.83; NNT of 111); furthermore, renal events (decline in
eGFR, new ESKD, or death due to renal or cardiovascular causes) were also less
likely in the dapagliflozin group (RRR of 24%; NNT of 77).
However, there was no statistically significant reduction in the rate of the primary
outcome of CVM, MI, or stroke (it was merely non-inferior to placebo), and thus
did not represent as much of a breakthrough as previous trials did. However, these
relatively disappointing results were merely a minor bump on the road for
dapagliflozin, as the next major trial, DAPA-HF, broadened the usage of SGLT2i
to an entirely new patient population.
DAPA-HF [11] was a trial to evaluate the efficacy and safety of 10 mg of
dapagliflozin in patients with heart failure and a reduced ejection fraction,
regardless of the presence of diabetes. 4,744 patients with NYHA class II-IV and
an ejection fraction <40% were randomized in this trial with a follow-up of 18.2
months. The primary endpoint was a dual-composite of worsening heart failure or
death from cardiovascular causes, whereas the secondary endpoint was a
composite of heart failure hospitalization or cardiovascular mortality.
Lipid-Lowering Agents Frontiers in Clinical Drug Research-Diabetes & Obesity, Vol. 7 131
Dapagliflozin significantly reduced the primary outcome (RRR of 26%; NNT of
21) as well as the secondary outcome (RRR of 25%; NNT of 125). More
impressively, the incidence of CVM (RRR of 0.82; NNT of 53) and ACM (RRR
of 0.83; NNT of 44) was also significantly reduced in the dapagliflozin arm.
The benefits of dapagliflozin extended to both patients with and without diabetes,
thus dissipating worries that it may only be useful in select patient populations.
The importance of DAPA-HF cannot be understated: not only did it demonstrate
benefit in a new patient population, but it did so by showing a reduction in the
hardest of all outcomes: mortality (even when taken as a single endpoint in and of
itself). These findings played a significant role in the FDA’s decision to approve
dapagliflozin’s use in heart failure in 2020, further diversifying the
armamentarium of physicians in treating what both a relatively common and
highly fatal condition is.
The next SGLT2i to be trialed was ertugliflozin, with the VERTIS trial aiming to
compare two doses of ertugliflozin (5 and 15 mg) versus placebo in a population
composed of high-risk patients with T2DM, accruing 8,246 patients over six
years, with a large portion of patients having HF and/or a reduced ejection
fraction. Overall, the trial’s results were somewhat of a disappointment, as the
drug resulted in an overall decrease in HF hospitalization (RRR of 30%; NNT of
91), but there was no statistically significant difference in CVM.
Not to be dampened by ertugliflozin’s disappointing results, the EMPERORReduced trial, which was only the second trial after DAPA-HF to target HF,
recruited slightly over 3,700 patients and assigned them 10 mg of empagliflozin
versus placebo. Like DAPA-HF, the trial only included patients with a reduced
ejection fraction, and a significant improvement in a composite of CVM and
hospitalization was seen (RRR of 25%; NNT of 19), though it is worth noting that
most of the composite benefit was derived from a reduction in hospitalizations
rather than mortality. This stands in sharp contrast to DAPA-HF, where a
statistically significant reduction in mortality was observed. Nevertheless, being
only the second large-scale randomized trial to demonstrate a benefit for an
SGLT2i in this patient population, this trial's results will play a key role in
cementing the importance of SGLT2i in HF for many years to come.
Dual SGLT1/2 Inhibitors: The Next Step in the Evolution of SGLT2i?
The next generation of SGLT2i to be trialed were dual SGLT1/2 inhibitors, which
have a theoretical edge over traditional SGLT2i in that traditional SGLT2i
essentially allow the kidney to compensate for SGLT2 inhibition by increasing the
activity of SGLT1; therefore, less glucose is excreted than would typically be
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expected due to the upregulation of SGLT1. By blocking both transporters
simultaneously, one might be able to achieve a greater degree of glucose excretion
and, by extension, improved clinical outcomes [57]. Two recently published 2020
trials, both by Bhatt et al., sought to investigate their efficacy in two different
patient populations, though the trials were hampered by premature termination
[14, 15].
The SOLOIST trial [14], which included T2DM patients recently hospitalized for
HF and requiring diuretic therapy, had a relatively small sample size of just 1,222
patients. Patients were subsequently randomized into the sotagliflozin arm (with a
dose ranging from 200 to 400 mg) or the placebo arm. Nevertheless, despite the
somewhat small sample, the trial results showed a significant reduction in the
composite outcome of CVM, hospitalization, and urgent HF visits (RRR of 33%;
NNT of 4); disappointingly, the trial did not seem to show significant renalprotective effects as there was no significant difference between the two groups in
terms of the decline in estimated GFR.
The other trial, SCORED [58], which studied the same intervention, enrolled
high-risk T2DM patients with chronic kidney disease (CKD), defined as an eGFR
of between 25 to 60 ml/min/1.73m2. As a result of the premature halting of the
trial and the lower-than-expected event-rate, the two original primary endpoints
were amended. Both original endpoints, the first being a composite of CVM, MI,
or stroke and the second being a composite of CVM or HF hospitalization,
showed an impressive benefit in the sotagliflozin arm (RRR of 16% and 23%,
respectively). The amended endpoint, a composite of CVM, HF hospitalization, or
urgent visits, was similarly significantly reduced in the sotagliflozin group (RRR
of 26%).
Also, unlike the SOLOIST trial, which found no evidence of improved renal
benefits, the SCORED trial reduced the decline of the eGFR by
1.25ml/min/1.73m2. Unfortunately, the more challenging clinical endpoints of
renal transplantation, long-term dialysis, ≥50% eGFR reduction, or a sustained
eGFR <15ml/min/1.73mm showed no statistically significant differences.
Overall, the addition of SGLT2i to the physician’s arsenal has revolutionized the
landscape of diabetes treatment, with improvements in cardiovascular outcomes
being perhaps the single most significant advantage of this class of drugs. SGLT2i
have gained prominence in recent years and are recommended for diabetic
patients at high-risk for CVD regardless of glycemic control, which is reflective
of a broader move towards more clinically relevant, patient-oriented outcomes as
opposed to merely aiming at keeping glucose levels in check. This has culminated
in this class of drugs featuring heavily in the 2018 ACC guidelines on CV risk
Lipid-Lowering Agents Frontiers in Clinical Drug Research-Diabetes & Obesity, Vol. 7 133
reduction in patients with diabetes and/or atherosclerotic disease [59]. In addition,
the results of these trials, namely DAPA-HF and EMPEROR-Reduced, have also
introduced this new class of medications to the realm of cardiology and heart
failure, as they do feature in the 2021 updated ACC HF treatment optimization
report [60], though, as is often the case with novel classes of drugs,
socioeconomic barriers and financial considerations may form impediments to
broader uptake by patients.
The utilization of dual SGLT1/2 inhibitors may yield an added benefit due to the
blockade of an additional variant of the sodium-glucose transporter; however,
head-to-head trials comparing the two agents, perhaps with a third arm being
assigned to GLP-1RA, may be needed in order to have enough data to structure
the hierarchy of evidence regarding which agent would be ideal to start with (or
indeed if combination therapy with both agents may yield added benefits
compared to monotherapy).
INCRETINS
History of Incretins and their Mechanisms of Action
The insight into the role of incretins is derived from the observation that patients
responded much better in terms of insulin secretion to orally ingested glucose than
to intravenously administered glucose, which prompted the search for the
endogenously produced compounds responsible for this phenomenon [61].
GLP1 is an insulinotropic compound produced and secreted from the intestine. It
has a vital role in glucose metabolism as it moderates the glucose spike occurring
after food intake by coordinating the insulin response and, thus, reducing
uncontrolled spikes in glucose levels. This mechanism has been targeted by two
essential classes of drugs: Dipeptidyl peptidase–4 inhibitors (DPP-4i) and GLP1receptor agonists (GLP1-RA). GLP1-RA are analogs of the endogenously
produced GLP1 molecules and are much more useful clinically due to their longer
half-life, whereas DDP-4i aim at improving the half-life of the already-produced
endogenous GLP-1 by preventing its break down. The first GLP-1RA, exenatide,
was approved by the FDA in 2005, with the first DDP-4i, sitagliptin, following
suit shortly thereafter in 2006 [61].
GLP1-RA mediate their glucoregulatory effects by stimulating the GLP-1
receptor, thus increasing insulin release after glucose intake. DPP-4i, on the other
hand, prevents the breakdown and inactivation of both GLP-1 and glucosedependent insulinotropic polypeptide, which increases the levels of these
substances and likewise improves the insulin response to glucose loads. In
addition to their glucoregulatory effect, GLP-1 has also been linked with
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endothelial function, myocardial metabolism, and ventricular contractility, which,
coupled with glycemic control, may explain some of the beneficial cardiovascular
effects they have in terms of cardiovascular outcomes [55]. Another essential
advantage this class of drugs provides is a reduction in appetite and food intake,
resulting in a loss of body weight (particularly in the case of GLP-1RA [62]),
which is especially important in diabetes due to the role that obesity has to play in
the disease process. Several trials were conducted to delineate the benefits of
GLP-1RA and DPP-4i concerning glycemic control and cardiovascular outcomes,
the most recent of which are discussed below.
Safety and Efficacy of DDP-4i
The SAVOR-TIMI-53 [63] trial, the largest of all trials evaluating DDP-4i drugs,
was launched in 2010 and was designed to examine the cardiovascular effect of
saxagliptin in patients with DM who were at high risk of cardiovascular events. A
total of 16,492 patients were involved in the SAVOR trial, with a median followup of 2.1 years. The primary endpoints of the SAVOR-TIMI-53 trial were CVM,
MI, or stroke, where it showed no evidence of benefit. Concerning glycemic
control, HbA1c levels in the saxagliptin group were marginally lower across the
trial (a reduction of 0.2%). Perhaps due to better glycemic control in the
saxagliptin group, a reduction in albuminuria development/progression was
achieved. However, patients in the saxagliptin group had significantly more
hypoglycemic events and a sizeable increase in HF hospitalizations.
Another selective DPP-4i, alogliptin, was investigated in the EXAMINE [17]
trial, which was conducted from 2009 to 2013. It sought to demonstrate the noninferiority of alogliptin to placebo regarding cardiovascular events in patients with
T2DM and a recent ACS. A total of 5,380 patients were recruited for this purpose,
with a primary endpoint of CVM, MI, or stroke. The secondary safety endpoint
included the components of the primary composite endpoint with the addition of
urgent revascularization due to UA within 24 hours after hospital admission.
Reassuringly, the trial showed the non-inferiority of alogliptin to placebo for
major cardiovascular events despite the high-risk patients recruited, though
superiority was not demonstratable. In addition, alogliptin improved glycemic
control as the HbA1c levels were reduced by 0.36%. The trial had a relatively
modest duration of 1.5 years, which may have limited the observation of longterm benefits or risk of alogliptin and lessened its ability to reveal any
cardiovascular benefits the drug may have, as this is the shortest time-duration of
any of the DDP-4i clinical trials.
The TECOS [18] trial, which recruited over 14,500 patients with T2DM and
established CVD, showed similar findings with 50 or 100 mg of sitagliptin, with
Lipid-Lowering Agents Frontiers in Clinical Drug Research-Diabetes & Obesity, Vol. 7 135
non-inferiority being demonstrated in terms of a composite endpoint of CVM, MI,
stroke or UA hospitalization. Furthermore, improved glycemic control was
demonstrated in the intervention arm, as seen by an HbA1c reduction of 0.29%.
Another trial on DPP-4i drugs was that of Sheu et al., which investigated the
efficacy and optimal dosing regimen of MK-3102 [19] (omargliptin), a potent,
selective, once-weekly DPP-4i. The trial included 685 patients who were
randomly allocated to either placebo or omargliptin. The omargliptin group was
subdivided into 5 dosing regimens (0.25 mg, 1 mg, 3 mg, 10 mg, 25 mg). The
primary hypothesis to be tested was if treatment by omargliptin would provide a
more significant reduction in HbA1c levels in comparison to placebo. The
secondary endpoints studied were whether omargliptin provides a more
significant reduction in 2-hour post-meal glucose and fasting plasma glucose in a
dose-related manner after 12 weeks of treatment.
After 12 weeks, significant reductions in HbA1c levels were achieved and
maintained across all dosing sub-groups of omargliptin, with the maximal
decrease in HbA1c occurring between 18-46 weeks and a decline in efficacy in
the following period. In addition, the secondary outcomes, post-meal glucose and
fasting plasma glucose, showed a dose-related improvement in the omargliptin
groups at 12-weeks.
The MARLINA study by Groop et al. was a relatively small study of 360 patients,
which assessed the efficacy of 5 mg of linagliptin on renal outcomes in patients
with T2DM and renal dysfunction (defined as an elevated urine albumin-t-
-creatinine ratio (UACR) or as albuminuria). Despite the usual improvement in
HbA1c, the linagliptin arm showed no significant changes in their UACR or GFR
in relation to the placebo arm.
The CARMELINA [21] trial aimed to assess the cardiovascular and renal safety
of 5 mg of linagliptin in T2DM. There were 6,979 patients enrolled in this study
with 2.2 years of follow-up, with the primary endpoint being CVM, MI, or stroke.
Linagliptin was not inferior to placebo regarding the endpoint mentioned above;
however, superiority could not be demonstrated. As in the previous trials, the
linagliptin arm had a relatively greater significant reduction in glycated
hemoglobin.
Another study involving linagliptin was CAROLINA [22], which examined the
effect of 5 mg linagliptin versus glimepride (rather than placebo) on
cardiovascular and glycemic outcomes. A total of 6,042 patients were randomly
allocated into one of the two arms and subsequently followed up for 6.3 years. As
in previous trials, the primary endpoint was time to first occurrence of CVM, MI,
or stroke. The results were not significantly different from previous trials, with
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linagliptin showing non-inferiority to glimepride and a lack of superiority on
further statistical probing. As the control group involved an active hypoglycemic
agent, HbA1c reductions were roughly equal between the two groups; however,
hypoglycemic events were significantly less likely in the linagliptin group (RRR
of 77%; NNT of 4).
In the RENALIS study, Muskiet et al. tested the efficacy of 5 mg linagliptin
versus 1 mg glimepride to reduce the degree of renal dysfunction in 46 patients
with T2DM and a GFR of >60 ml/min/1.73m2, with 23 being randomized to each
arm of the trial. There were no significant HbA1c reductions between the two
hypoglycemic agents. Moreover, no significant differences were noted in UACR
or GFR. Although there may have been a signal for increased fractional sodium
and potassium excretion indicating higher natriuresis, it did not reach statistical
significance.
Trials Evaluating the Safety and Efficacy of GLP-1ras
The ELIXA [24] trial examined the safety and efficacy of lixisenatide (10 to 20
mg) on cardiovascular outcomes in patients with diabetes and recent ACS and
was the first study conducted on this class of drugs powered to detect differences
in hard cardiovascular outcomes, such as mortality, stroke or hospitalization. In
this study, there were 6,068 patients with a median follow-up duration of 25
months, from 2013 to 2015. The primary endpoint was CVM, MI, stroke, or UA
hospitalization, for which the non-inferiority criteria were met; however,
superiority testing failed to show a statistically significant difference. Though the
follow-up period mentioned above may not seem long enough to detect significant
differences, the authors noted that the event-rate was sufficiently high enough. It
is reasonable to conclude that no nonglycemic cardiovascular benefits could be
had using lixisenatide. Lixisenatide also significantly improved glycemic control
as measured by glycated hemoglobin.
Another vital trial in this realm, the LEADER [64] initiated in 2010, studied the
effect of adding 1.8 mg of liraglutide on cardiovascular outcomes. There were
9,340 patients included in the trial, all of whom were patients with diabetes with
CVD or risk factors thereof, and they were then divided into 2 groups, one
received liraglutide at a dose of 1.8 mg and the other received placebo with a
follow-up extending over 3.8 years.
The primary composite outcome was the CVM, MI, or stroke. There was a
significant reduction of CVM in the liraglutide group (RRR of 22%; NNT of 77)
as well as a reduction in ACM (RRR of 15%; NNT of 72). In addition, liraglutide
lowered the rate of renal microvascular events. Improvements in weight and
Lipid-Lowering Agents Frontiers in Clinical Drug Research-Diabetes & Obesity, Vol. 7 137
systolic blood pressure were also noted in the liraglutide group. Despite the
impressive reductions in mortality, the composite endpoint of CVM, MI, or stroke
did not show a statistically significant difference between the two groups.
Regarding glycemic control, the reduction in HbA1c was accompanied by a
significantly lower rate of severe hypoglycemia (RRR of 31%).
A similar study that assessed the cardiovascular safety and the long-term
outcomes of semaglutide is SUSTAIN-6 [26], which was also conducted on
relatively high-risk patients with T2DM. The trial’s total patient population was
3,297 patients with a median observational time of 2.1 years. Participants were
randomized to either semaglutide (maintenance dose of 0.5 mg or 1 mg achieved
after a fixed-dose escalation procedure) or placebo.
The primary composite outcome was CVM, MI, or stroke, for which semaglutide
showed an impressive benefit (RRR of 26%; NNT of 44). As for HbA1c levels,
the semaglutide group achieved significant and sustained reduction compared to
placebo with a similar hypoglycemia rate. Also, more patients assigned to placebo
received anti-hyperglycemic agents and cardiovascular medications, including
antihypertensives, diuretics, and lipid-lowering drugs, which may indicate an
overall improved cardiovascular profile after taking semaglutide.
Focusing on microvascular outcomes, like the LEADER trial, the semaglutide
group had a reduced risk of new/worsening nephropathy. However, semaglutide
also significantly increased the risk of diabetic retinopathy, unlike in LEADER,
where the differences did not reach statistical significance.
The FREEDOM-1 [27] trial investigated the efficacy and tolerability of 2 doses of
ITCA 650 (exenatide at a dose of 40 or 60 mg administered as an automated
pump) versus placebo in 460 patients who had T2DM for an average duration of
8.9 years and whose HbA1c levels were elevated despite consistent therapy for
three or more months. ITCA 650 significantly improved HbA1c and fasting
plasma glucose levels, in addition to a meaningful improvement in weight.
Regarding the differences between the efficacy of the two-dose of ITCA 650,
HbA1c reduction was similar between the two doses. However, the higher dose
showed higher overall efficacy in an aggregate outcome of glycemic control
measures in addition to weight loss, without increased adverse effects. Mild
significant improvements in the lipid parameters were also noted.
The HARMONY [28] trial was aimed to assess albiglutide's cardiovascular safety
and efficacy (a GLP-1RA formed via the genetic fusion of modified human GLP1 to human albumin) in patients with T2DM and CVD. There were 9,503 patients
assigned randomly to either placebo or 30 to 50 mg of albiglutide who were
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followed up for a median of 1.5 years. The primary endpoint was a composite of
CVM, MI, or stroke, which albiglutide managed to reduce significantly (RRR of
22%; NNT of 50). However, only myocardial infarction from the primary
composite showed a statistically significant improvement in the albiglutide group,
and, unlike the LEADER trial, it did not manage to show a statistically significant
benefit when outcome analysis was restricted solely to the occurrence of CVM,
which may have been partially attributable to a shorter follow-up period. Further,
both systolic blood pressure and body weight improved in the albiglutide group.
As in other trials, the authors noted a delay between initiation of treatment and the
appearance of benefits, with the magnitude of improvement being proportional to
the amount of time since initiation.
Requiring add-on glucose-lowering therapies was a more common finding in the
placebo arm, which, coupled with the reduction in HbA1c bestowed by
albiglutide, indicates an improved glycemic profile. Fortunately, unlike the
SUSTAIN-6 trial, there was no evidence of new/worsening retinopathy in the
albiglutide arm.
In the EXCSEL trial, which was aimed to assess the benefit of adding 2 mg of
exenatide in a study recruiting 14,752 patients (16.2% of whom had HF at
baseline) with T2DM and a history of CVD, exenatide showed great promise.
Though the trial did not show an improvement in the primary outcome of CVM,
MI, or stroke, it did show a significant benefit with regards to ACM (RRR of
14%; NNT of 100); however, due to the hierarchical scheme of the statistical
analysis, this result was not deemed statistically significant.
Dulaglutide is a GLP-1RA comprised of two modified human GLP-1 molecules
covalently linked to an IgG4 heavy chain. The REWIND [30] trial assessed
whether the addition of 1.5 mg of dulaglutide to the medication regimen of
middle-aged and older people with high-risk T2DM improves cardiovascular
outcomes compared with placebo. A total of 12,133 patients were screened from
August 2011 to August 2013, with follow-up ending in August 2018 and
providing the most prolonged follow-up duration of all GLP-1RA trials.
The primary endpoint was a composite of CVM, MI, or stroke, dulaglutide
significantly improved (RRR of 12%; NNT of 72), with a greater degree of
benefit being derived from its beneficial effect on stroke over MI.
In 2019, Husain et al. published the results of the landmark (and aptly named)
PIONEER-6 [31] trial. The trial enrolled nearly 3,200 high-risk T2DM patients
over 2 years and allocated them to either semaglutide (target dose of 14 mg) or
placebo. Similar to the EXCSEL trial, in which the primary composite endpoint
was not statistically significant, PIONEER-6 failed to demonstrate a statistically
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