Glucose Therapy and Hypoglycemic Drug Clinical Trial Summary (Until August 2022)

Author: Professor Guo Yifang, Hebei Provincial People's Hospital

This paper summarizes randomized controlled (RCT) studies of clinical endpoints in the areas of hypoglycemic therapy and hypoglycemic drugs published as of September 2022, with new DELIVER findings

From the UGDP study published in 1970 to the newly announced trials of a number of new hypoglycemic drugs, foreign scholars have completed a number of RCTs

➤ Hypoglycemic test: In general, the hypoglycemic test first sets different hypoglycemic target values for two groups of subjects, and takes various feasible measures to make the subjects' blood glucose reach the preset goal

➤ Hypoglycemic drug trial: First, set the same blood glucose control goals for both groups of subjects (based on the requirements of current guidelines), and take various feasible measures to achieve blood glucose compliance

First, the hypoglycemic test 1.

2.

3.

4.

5.
VADT Study: Published in 2009
.
The target of ≤ 6.
0% of HbA1c does not reduce the incidence
of macrovascular events compared to the standard hypoglycemic group.

6.
HEART2D study: Published in 2009 in patients with
type 2 diabetes mellitus after acute myocardial infarction.
Insulin therapy controlled fasting blood glucose (target < 6.
7 mmol/l) or postprandial blood glucose (target 7.
5 mmol/l), respectively, showed no significant difference
in the incidence of major compound endpoint events between the two groups.

Second, hypoglycemic drug test 1.
DIGAMI 2 Study: Published in 2005 in patients with type 2 diabetes who
had acute myocardial infarction.
The results showed that intensive insulin therapy did not reduce all-cause mortality
compared with conventional treatment.

2.
PROactive Study: Published in 2005, it was conducted in patients with type 2 diabetes mellitus
with macrovascular complications.
Conventional therapy is supplemented with pioglitazone or placebo
.
The results show no difference in
the incidence rate of the two sets of composite endpoint events.

3.
BARI 2D study: Published in 2009 in diabetic patients with coronary heart disease, comparing whether insulin sensitizers or insulin therapy can delay or prevent the development of
coronary atherosclerotic lesions.
The incidence of the main endpoints was 11.
8% and 12.
1% (P=0.
89) in the insulin sensitizer-treated group and the insulin-treated group, respectively, and the incidence of major adverse cardiac events was 22.
3% and 24.
6% (P=0.
13),
respectively.

4.
RECORD study: Published in 2009, the study subjects were those who
could not meet blood glucose after adequate treatment with metformin or sulfonylureas.
The results showed that the addition of rosiglitazone to metformin or sulfonylurea, or a combination of metformin and sulfonylureas, had no effect on
the incidence of complex cardiovascular endpoint events.

5.
ORIGIN Study: Published in 2012, it was conducted in patients with
impaired fasting blood glucose, impaired glucose tolerance, or new diabetes.
The results showed that the use of insulin glargine for blood glucose control had no effect
on the incidence of major cardiovascular events compared with conventional treatment.

6.
SAVOR-TIMI53 study: Published in 2013, in patients with diabetes mellitus
with a history of cardiovascular events or cardiovascular risk factors.
The results showed that the addition of saxagliptin to conventional treatment had no effect
on the incidence of major composite cardiovascular endpoint events compared with the placebo group.

7.
EXAMINE Study: Published in 2013, it was conducted in patients with type 2 diabetes who
had recently developed acute coronary syndrome.
The results showed that the addition of alogliptin to conventional treatment had no effect
on the incidence of major composite cardiovascular endpoint events compared with the placebo group.

8.
TECOS Study: Published in 2015, the study was conducted in patients with type 2 diabetes who
have a cardiovascular history.
The results showed that the addition of sitigliptin to conventional treatment had no effect
on the primary cardiovascular endpoint event compared with the placebo group.

9.
ELIXA study: Ended in 2015 in patients with type 2 diabetes mellitus who
had recently developed acute coronary syndrome.
The results showed that the addition of the GLP-1 agonist risiera to the usual treatment had no effect
on the main cardiovascular endpoint event compared with the placebo group.

10.
EMPA-REG OUTCOME study: Ended in 2015 with patients with type 2 diabetes diagnosed with
cardiovascular disease.
The results showed that the addition of the SGLT-2 inhibitor empagliflozin to conventional treatment compared with the placebo group reduced all-cause mortality by 32% and cardiovascular mortality by 38%, both of which achieved statistically significant differences
.
The study is the first hypoglycemic drug trial
to be shown to reduce the risk of cardiovascular events.

11.
IRIS Study: Published in February
2016.
The study found that treatment with the insulin sensitizer pioglitazone in insulin-resistant patients significantly reduced the risk
of stroke and myocardial infarction compared to the placebo group.
Since the subjects were insulin-resistant rather than diabetic, and although there were slight differences in fasting blood glucose between the two groups, it was unlikely to constitute the primary beneficiary mechanism, the main reason for the reduction of macrovascular events may have been improved insulin sensitivity
.
Since the subjects of this study were insulin resistant, they are not strictly speaking, they are not part of the hypoglycemic therapy trial
.

12.
LEADER Study: Results
will be announced during the ADA Annual Meeting in June 2016.
The aim of this study was to explore the effect of
GLP-1 agonist liraglutide therapy on cardiovascular endpoint events in patients with cardiovascular comorbidities or high-risk factors in type 2 diabetes.
The results showed that the addition of the GLP-1 receptor analogue liraglutide to conventional treatment significantly reduced the incidence
of major compound endpoint events in patients with type 2 diabetes mellitus compared with the placebo group.
This study makes liraglutide the second hypoglycemic drug
to be randomized in clinical trials to confirm cardiovascular benefits after the SGLT-2 inhibitor empagliflozin.

13.
SUSTAIN-6 study: Results
published in September 2016.
The study aimed to assess the effect
of semeglutide therapy on cardiovascular events and other long-term outcomes in patients with type 2 diabetes.
The primary endpoint was the first major adverse cardiovascular event (including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke
).
After 2.
1 years of follow-up, the incidence of primary endpoint events was reduced by 26% (8.
9% vs.
6.
6%, non-inferiority test p<0.
001, and efficacy test p=0.
02)
compared with placebo group.
Among them, the cardiovascular mortality rate was 2.
8% and 2.
7% (p=0.
92), the non-fatal myocardial infarction was 3.
9% and 2.
9% (p=0.
12), and the nonfatal stroke was 2.
7% and 1.
6% (p=0.
04),
respectively.
This research makes semeglutide the second GLP-1 receptor agonist to be shown to have cardiovascular benefit after liraglutide, and the third hypoglycemic drug
to be shown to have cardiovascular benefit after empagliflozin and liraglutide.

14.
CANVAS Study: Results
announced in June 2017.
The study randomized patients with type 2 diabetes who had confirmed cardiovascular disease or had a high risk factor for cardiovascular events, randomly divided into 3 groups in a 1:1:1 ratio, and received caragliflozin (100 mg, QD), capagliflozin (300 mg, QD), or placebo on the basis of conventional treatment, respectively, with the primary endpoint being the composite endpoint
consisting of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke 。 The results showed that the incidence of cardiovascular compound endpoints was reduced by 14% (HR=0.
86; 95% CI, 0.
75-0.
97) in the carpagliflozin-treated group compared with the placebo group, but the difference between components of the compound endpoint and all-cause death between the two groups did not reach a statistical difference
.
The carpagliflozin-treated group had a 33% reduction in the risk of hospitalization for heart failure and a 40%
reduction in the risk of renal compound outcomes compared with the placebo group.

15.
ACE Study: Results
published in September 2017.
The aim of this study was to explore whether treatment with acarbose reduces the incidence
of adverse cardiovascular events in patients with coronary heart disease or acute coronary syndrome with impaired glucose tolerance.
After 5 years of follow-up, acarbose therapy was shown to reduce the risk of new diabetes mellitus in patients with impaired sugar regulation (13% vs.
16%, p=0.
005), but did not reduce the incidence of major cardiovascular endpoint events (14% vs.
15%, p=0.
73).

16.
TOSCA IT Study: Results
published in September 2017.
A total of 3028 patients with type 2 diabetes mellitus aged 50-75 years, with a duration of at least 2 years, treated with metformin monotherapy for at least 2 months, and HbA1c 7.
0% to 9.
0% were enrolled in this study, and pioglitazone or sulfonylurea hypoglycemic drugs
were randomly added on the basis of metformin treatment.
The primary endpoint was a composite endpoint consisting of all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, and non-elective revascularization
.
The median follow-up was 57 months
.
The results showed that there was no significant difference
in the incidence of primary endpoint events between the sulfonylurea-treated group and the pioglitazone-treated group.
The results suggest that there was no significant difference
in the incidence of cardiovascular endpoint events with the addition of sulfonylureas (gliclazide or glimepiride) or pioglitazone in patients with type 2 diabetes mellitus who did not respond well to metformin monotherapy.

17.
EXSCEL Study: Results
published in September 2017.
The aim of this study was to explore the effect
of the addition of exenatide (once a week) to conventional treatment compared with placebo on cardiovascular outcomes in patients with type 2 diabetes.
The primary efficacy endpoint and the primary safety endpoint were composite endpoints
consisting of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.
The results showed that during the 3.
2-year follow-up period, there was no significant difference
in the incidence of the primary compound endpoint between the exenatide treatment group and the placebo-treated group.
There were also no significant differences
between the two groups for the secondary endpoints (incidence of death due to cardiovascular death, nonfatal myocardial infarction, fatal or nonfatal stroke death, and hospitalization due to heart failure and acute coronary syndrome).

DECLARE-TIMI 58 Study: Results
published in October 2018.
A total of 17,160 patients with type 2 diabetes mellitus with confirmed ASCVD or those with high risk factors for ASCVD were randomized into two groups and treated with dapagliflozin or placebo on a conventional basis
, respectively.
The primary compound endpoint was cardiovascular death, myocardial infarction, or ischemic stroke
.
After 4.
2 years (median time), the results showed no statistically significant decrease in the incidence of major compound endpoint events in the dapagliflozin-treated group compared with the placebo group (8.
8% vs.
9.
4%, p=0.
17), but the incidence of cardiovascular death or hospitalization due to heart failure was significantly reduced in patients in the dapagliflozin group (4.
9% vs.
5.
8%, p=0.
005), and this benefit was mainly driven
by reduced hospitalization for heart failure.
Renal endpoint events were significantly reduced by 24% in the dapagliflozin-treated
group.

19.
Harmony Outcomes Study: Results
published in October 2018.
A total of 9574 patients with type 2 diabetes who had confirmed atherosclerotic cardiovascular disease (coronary heart disease, cerebrovascular disease, or peripheral arterial disease) (9463 patients included in final data analysis) were enrolled in the study and were randomly grouped on a standard basis for the standard of care and then treated with the GLP-1 agonist abiratide (albiglutide) or placebo
, respectively.
The primary compound endpoint was the first cardiovascular death, myocardial infarction, or stroke
.
At the end of follow-up, the incidence of the main compound endpoint was reduced by 22% in patients treated with abiraglutide compared with the placebo group (non-inferiority p<0.
0001; efficacy p=0.
0006).
<b14>

20.
CARMELINA Study: Results
published in October 2018.
The objective of this study was to assess the effect
of the use of rillogliptin (5 mg, QD) or placebo on cardiovascular outcomes in patients with type 2 diabetes mellitus at high cardiovascular risk, based on standard treatment.
A total of 6979 adult patients with type 2 diabetes mellitus were included, and the median time observed in the study was 2.
2 years
.
The results showed that the incidence of primary endpoint events in the riogliptin group and placebo group was 12.
4% and 12.
1% (HR=1.
02; 95% CI 0.
89-1.
17),
respectively.
It was concluded that the addition of ripagliptin or placebo had similar cardiovascular safety
on the basis of conventional treatment.

21.
CREDENCE Study: Results
published in April 2019.
To explore the effect
of carpagliflozin on renal endpoint events in patients with type 2 diabetes mellitus with stage 2 or stage 3 CKD and massive proteinuria.
A total of 4401 patients with CKD with a albumin-creatinine ratio of 300-5000 after ARB treatment were randomized to receive carpagliflozin or placebo therapy on the basis of conventional treatment, and the main endpoint was the composite endpoint
consisting of end-stage renal disease, serum creatinine multiplication, renal or cardiovascular death.
Due to the significant benefit of the capagliflozin group, the study ended
early at follow-up of 2.
62 years (median time).
The results showed a 30% reduction in the incidence of primary endpoint events and a 34% reduction in renal compound endpoints (end-stage renal disease, serum creatinine multiplication, and renal death) compared with the placebo group
.
At the same time, the incidence of compound cardiovascular endpoint events (cardiovascular death, myocardial infarction, or stroke) in the carpagliflozin-treated group was reduced by 20%, and hospitalization for heart failure was reduced by 39%.

There was no significant difference
in the risk of amputation or fracture between the two groups.
The study concluded that carpagliflozin significantly reduced the incidence of renal compound endpoints and cardiovascular events in patients with type 2 diabetes mellitus with CKD, but did not increase the risk of
amputation and fracture.

22.
CAROLINA study: Results
published in June 2019.
The aim of this study was to compare the effects of the use of ripagliptin or glimepiride on diabetes morbidity and mortality in
patients with type 2 diabetes mellitus with cardiovascular risk factors.
A total of 6033 patients with type 2 diabetes mellitus, aged 40-85 years, were included to exclude patients
treated with thiazolidinedione, GLP-1RA, DPP-4 inhibitors, or any type of insulin.
Patients were randomly divided into two groups to receive ripagliptin (5 mg, QD) or glimepiride (1-4 mg, QD
).
The primary compound endpoints were fatal myocardial infarction, nonfatal myocardial infarction, fatal stroke, nonfatal stroke, or hospitalization
for unstable angina.
The median follow-up was 6.
2 years
.
The results showed that patients in the rixagliptin group were "not inferior" to glimepiride (11.
8% vs 12.
0%)
in reducing the three compound endpoints of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

23.
REWIND Study: Preliminary results
announced in June 2019.
The aim of this study was to explore the effect
of the addition of dula glycopeptide on major adverse cardiovascular events in patients with type 2 diabetes mellitus.
The study was designed in a randomized double-blind parallel group and enrolled 9901 patients with type 2 diabetes mellitus ≥ 50 years of age, including participants with confirmed clinical vascular disease (≥ 50 years), subclinical vascular disease (≥ 55 years), or at least two cardiovascular risk factors (≥ 60 years
).
They were randomly divided into two groups and given dullacarbine 1.
5 mg subcutaneously, once a week, or placebo on top of usual hypoglycemic therapy
.
The median follow-up was 5.
4 years
.
The primary endpoint was a composite endpoint
consisting of the first cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
The results showed that the incidence of major cardiovascular compound endpoint events was reduced by 12% (13.
4% vs 12.
0%) in patients in the dula glycopeptide-treated group compared with the placebo-treated group; HR 0.
88，95%CI 0.
79-0.
99，P=0.
026）
。

24.
PIONEER 6 Study: Results
published in June 2019.
3183 patients with type 2 diabetes mellitus with cardiovascular risk factors were included and treated with smeglutide (14 mg orally (14 mg, QD) or placebo at
the same dose, respectively.
The median follow-up was 16 months
.
The results showed that the incidence of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) in the oral smeglutide group was reduced by 21%, but no statistically significant difference
was reached.
In a single endpoint, cardiovascular death was reduced by 51% (p=0.
03) and all-cause deaths by 49% (p=0.
008).

It was concluded that the effect of oral semeglutide on cardiovascular endpoint events in patients with diabetes mellitus was not inferior to placebo
.

25.
DAPA-HF study: Results
published in September 2019.
A total of 4744 patients with heart failure with reduced ejection fraction (45% of whom were diabetic) were included, who were randomly divided into two groups and administered dapagliflozin (10 mg, QD) or placebo on the basis of usual treatment
.
The primary endpoint was a composite endpoint
consisting of cardiovascular death, hospitalization for heart failure, and clinics for heart failure emergencies.
The median follow-up was 18.
2 months
.
The results showed that the incidence of major compound endpoint events (HR 0.
74, p=0.
00001, NNT=21)
was significantly reduced by the SGLT-2 inhibitor of dapagliflozin in heart failure patients with reduced ejection fraction.
More importantly, the drug reduced the risk of all-cause death in subjects by 17% (HR 0.
83, p=0.
022) and cardiovascular death by 18% (HR 0.
82, p=0.
03).

Subgroup analyses showed that the benefits were comparable for both diabetics and non-diabetics
.
There was no significant difference
in the incidence of adverse events between the two groups.

26.
VERTIS CV Study: Results
published in June 2020.
8246 patients with type 2 diabetes with cardiovascular disease were enrolled and randomized to receive etogliflozin (ertugliflozin) 15 mg, 5 mg or placebo on the basis of conventional treatment
.
Maximum follow-up of 6.
1 years
.
The primary compound endpoints included cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke
.
The results showed that the incidence of the main endpoint events in both the etogliflozin-treated group and the placebo group was 11.
9%.

27.
EMPEROR-Reduced Study: Final results announced in August 2020 (study period from March 2017 to July 2020
).
Thirty-seven 30 patients with heart failure with reduced chronic ejection fraction (with or without diabetes mellitus) were randomized to receive empagliflozin (10 mg, QD) or placebo on a basis of usual treatment
.
The primary compound endpoint was cardiovascular death or hospitalization
for heart failure.
The results showed that the incidence of primary endpoint events in the empagliflozin-treated group (1863 patients) and the placebo-treated group (1867 patients) was 19.
4% and 24.
7% (HR: 0.
75; 95% CI 0.
65-0.
86; P<0.
001),<b19> respectively.
The benefit was the same
for the empagliflozin treatment group, regardless of whether diabetes was co-existent.
28.
DAPA-CKD study: Final results
to be announced in August 2020.
A total of 4304 patients with CKD (32.
5% of whom did not have diabetes) were included, all of whom had received the maximum tolerated dose of ACEI or ARB for at least 4 weeks
.
Participants were randomly divided into two groups and treated with dapagliflozin (10 mg, QD) or placebo on top of usual treatment
.
The primary compound endpoint was deterioration of renal function (defined as a persistent decrease in eGFR ≥ 50% or the development of end-stage renal disease), or renal or cardiovascular death
.
The results showed a 39% reduction in primary compound endpoint events and a 31% reduction in all-cause mortality from one of the secondary endpoints compared with the placebo group, both of which were statistically significant differences
.
The benefit of dapagliflozin treatment is the same regardless of whether the patient has diabetes mellitus or not
.
29.
SOLOIST-WHF Study: Results
published in November 2020.
1222 patients with T2DM who were hospitalized for heart failure and requiring diuretic therapy were randomized to receive sotagliflozin (sotagliflozin) or placebo on the basis of conventional treatment
.
The primary compound endpoints were cardiogenic death, hospitalization for heart failure, and emergency visits
.
The median follow-up was 9.
2 months
.
The results showed that initiating sopagliflozin therapy in patients with T2DM with decompensated heart failure before or shortly after discharge reduced the incidence
of cardiovascular death, hospitalization due to heart failure, or emergency events.
30.
SCORED study: Results
published in November 2020.
10,584 patients with T2DM with CKD were included in the randomization of sopagliflozin or placebo on the basis of conventional treatment
.
The primary compound endpoints were cardiovascular death, hospitalization due to heart failure, and emergency care
due to heart failure.
The median follow-up was 16 months
.
The results showed that sopagliflozin treatment significantly reduced the incidence
of cardiovascular death, hospitalization for heart failure, or emergency department of heart failure in patients with T2DM with CKD.
31.
EMPEROR-Preserved Study: Results
to be announced in July 2021.
To explore the safety and efficacy of empagliflozin in the treatment of patients with chronic ejection fraction-preserving heart failure, whether with or without diabetes mellitus
.
A total of 5988 participants were included, and the main composite endpoint was cardiovascular death or hospitalization
due to heart failure.
Preliminary results show that empagliflozin treatment significantly reduces the incidence
of major compound endpoint events (cardiovascular death versus hospitalization due to heart failure).
Following the EMPEROR-Reduced study that empagliflozin can significantly improve the prognosis of patients with HFrEF, the results of this study confirm that the drug can significantly reduce the occurrence of adverse endpoint events in patients with HFpEF
.
Based on these two findings, empagliflozin is the first drug
to be shown to improve chronic heart failure (regardless of ejection fraction, whether diabetes is combined or not) by an RCT with sufficient statistical efficacy.
Because of this, the EMPEROR-Preserved study is a landmark clinical trial in the field of HFpEF drug therapy, bringing HFpEF treatment into a new era
.
32.
AMPLITUDE-O Study: The results of the study were officially published
in September 2021.
4076 patients with T2DM who had ASCVD or CKD or at least one cardiovascular disease risk factor were randomly divided into 3 groups and treated with efpeglenatide subcutaneous injection (4 mg once a week), efpeglenatide subcutaneous injection (6 mg once a week) or placebo on the basis of conventional treatment
, respectively.
The primary compound endpoints were cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke
.
Average follow-up was 1.
8 years
.
The results showed that compared with the placebo group (n=1359), the incidence of major composite endpoint events in the efpeglenatide group (n=2717) was reduced by 27%, and the incidence of compound renal endpoint events was reduced by 32%, all of which reached a statistically significant difference
.
33.
DELIVER Study: The results of the study will be announced in August 2022
.
This is a randomized controlled trial
using dapagliflozin for patients with mildly reduced ejection fraction heart failure (HFmrEF, LVEF 41-49%) and ejection fraction-preserving heart failure (HFpEF, LVEF≥50%).
A total of 6263 patients with HFmrHF or HFpEF aged
≥ 40 years old, NYHA grade II-IV were included.
They were randomly divided into two groups, with dapagliflozin (10 mg, QD) or placebo respectively on the basis of conventional treatment
.
The primary endpoint was a composite endpoint consisting of cardiovascular death, hospitalization for heart failure, and acute clinic for heart failure
.
The median follow-up was 2.
3 years
.
The results showed that the incidence of major composite endpoint events was 16.
4% and 19.
5% in the dapagliflozin and placebo groups, respectively (HR=0.
82, 95% CI 0.
73–0.
92; p<0.
001).

The incidence of worsening heart failure was 11.
8% and 14.
5% in the dapagliflozin and placebo groups (HR=0.
79; 95% CI 0.
69–0.
91), respectively, and cardiovascular mortality was 7.
4% and 8.
3% (HR 0.
88; 95% CI: 0.
74–1.
05),
respectively.

Source: Guo Yifang Heart Frontier