Study population
A total of 837 patients had a first prescription for a GLP-1 RA during the index period. 550 patients met the criteria for inclusion (65.7%). Of those not included, 245 patients (29.3%) did not have the minimum follow-up period of 2 years, 11 (1.3%) had a concomitant active malignancy, 5 (0.6%) were classified as LADA, 15 (1.8%) had bariatric surgery during follow-up, and 11 (1.3%) had secondary diabetes (Figure 1).
Subjects were split into two groups, namely a primary prevention group of persons without a history of CV events (N=395 subjects), and a secondary prevention group of patients with a history of CV events (N=155 subjects), defined as previous stroke, MI, unstable angina, myocardial ischemia on imaging or stress test, or coronary, carotid, or peripheral revascularization.
Baseline clinical and laboratory characteristics of study participants are shown in Table 1. All patients were residents in the Milan metropolitan area.
Table 1. Baseline characteristics.
|
Primary prevention
|
Secondary prevention
|
P
|
N
|
395
|
155
|
|
Gender (males)
|
193 (48.86%)
|
119 (76.77%)
|
<0.001
|
Age, years
|
61.6±10.1
|
66.3±7.8
|
<0.001
|
BMI, kg/m2
|
34.2±5.8
|
32.2±5.9
|
<0.001
|
BMI <30
|
92 (23.35%)
|
62 (40.00%)
|
|
BMI 30-35
|
148 (37.56%)
|
56 (36.13%)
|
|
BMI >35
|
154 (39.09%)
|
37 (23.87%)
|
|
Obese (BMI >30 kg/m2)
|
302 (76.5%)
|
93 (60.0%)
|
<0.001
|
Diabetes duration, years
|
8 (0-48)
|
11 (0-50)
|
<0.001
|
Diabets duration >10 years
|
136 (34.43%)
|
78 (50.32%)
|
|
sBP
|
137.9±15.6
|
132.9±14.7
|
0.001
|
dBP
|
79.9±8.8
|
76.6±8.3
|
<0.001
|
Fasting blood glucose, mg/dL
|
174.1±53.8
|
161.9±50.2
|
0.018
|
HbA1c, %
|
8.22±1.36
|
7.87±1.33
|
0.002
|
HbA1c <7%
|
50 (12.66%)
|
35 (22.58%)
|
0.012
|
Total cholesterol, mg/dL
|
181.6±38.6
|
149.3±32.8
|
-
|
HDL, mg/dL
|
45.8±11.3
|
41.8±10.3
|
-
|
Tryglicerides, mg/dL
|
178.4±122.4
|
159.4±79.6
|
-
|
LDLc*, mg/dL
|
102.7±34.1
|
76.3±26.6
|
<0.001
|
Creatinine, mg/dL
|
0.86±0.26
|
1.01±0.32
|
-
|
eGFR, ml/min/1.73 m2
|
85.3±19.3
|
76.7±20.6
|
<0.001
|
Proteinuria
|
11 (2.89%)
|
9 (6.04%)
|
-
|
Diabetic kidney disease
|
91 (23.27%)
|
52 (33.77%)
|
0.012
|
Diabetic retinopathy
|
51 (12.9%)
|
37 (23.9%)
|
0.001
|
Smoking status
|
|
|
0.001
|
Never
|
236 (59.75%)
|
75 (48.39%)
|
|
Current smokers
|
71 (17.97%)
|
22 (14.19%)
|
|
Former smokers
|
88 (22.28%)
|
58 (37.42%)
|
|
Ischemic heart disease
|
0
|
137 (88.39%)
|
-
|
Stroke
|
0
|
8 (5.16%)
|
-
|
Peripheral artery revascularization
|
0
|
28 (18.06%)
|
-
|
Arterial hypertension
|
296 (74.94%)
|
150 (96.77%)
|
<0.001
|
Dyslipidemia
|
247 (62.53%)
|
149 (96.13%)
|
<0.001
|
> 50% carotid, coronary, or peripheral artery stenosis
|
22 (5.6%)
|
31 (20.6%)
|
<0.001
|
Heart failure
|
7 (1.8%)
|
13 (8.4%)
|
0.002
|
LDLc was calculated using the Friedewald formula. eGFR, estimated glomerular filtration rate calculated with the CKD-EPI formula. sBP, dBP, systolic and diastolic blood pressure, respectively. * Missing values in 68 subjects in primary prevention and in 27 subjects in secondary prevention.
In the primary prevention group, mean age was 61.6 years, 48.9% were males, mean diabetes duration was 8 years, mean glycated hemoglobin at baseline was 8.2%, and 12.7% had a glycated hemoglobin below 7%. The mean duration of follow-up was 5 years. In the secondary prevention group, mean age was 66.3 years, 76.8% were males, mean diabetes duration was 11 years, mean glycated hemoglobin at baseline was 7.8%, and 22.6% had a glycated hemoglobin below 7%.
At baseline, mean BMI was 34.2 kg/m2 and 32.2 kg/m2 in the primary prevention and in the secondary prevention groups respectively. In those without a history of CV events, 62.5% had dyslipidemia, 74.9% had arterial hypertension, 76.5% were obese (BMI>30 kg/ m2), 18.0% were active smokers, 22.3% were former smokers, and 1.8% had a diagnosis of heart failure. In the secondary prevention group, 88.4% had a history of ischemic heart disease, 5.2% had had a stroke, and 18.1% had received an arterial revascularization procedure, 60% were obese (BMI>30 kg/ m2), 14.2% were active smokers, 37.4% were former smokers, and 8.4% had a diagnosis of heart failure.
Treatment patterns
Before the index visit, most patients were taking metformin (86.8% in primary prevention, 83.2% in secondary prevention), whereas 36.7% in primary prevention and 32.3% in secondary prevention were treated with either sulfonylureas or meglitinides, 21% were on insulin in the primary prevention group and 27.7% in the secondary prevention group, 23.3% and 21.3% respectively were on DPP-4 inhibitors, while very few were taking SGLT2 inhibitors (Table 2).
Table 2. Treatment patterns at baseline.
|
Primary prevention
|
Secondary prevention
|
P
|
Ongoing anti-diabetic treatments before index visit
|
|
|
|
Metformin
|
343 (86.8%)
|
129 (83.2%)
|
0.275
|
Pioglitazone
|
68 (17.2%)
|
23 (14.8%)
|
0.500
|
Acarbose
|
5 (1.3%)
|
2 (1.3%)
|
0.982
|
Sulfonylureas or meglitinides
|
145 (36.7%)
|
50 (32.3%)
|
0.326
|
Insulin
|
83 (21%)
|
43 (27.7%)
|
0.091
|
SGLT2 inhibitors
|
12 (3.0%)
|
5 (3.2%)
|
0.909
|
DPP4 inhibitors
|
92 (23.3%)
|
33 (21.3%)
|
0.614
|
Cardioactive therapies at baseline
|
|
|
|
Statins
|
177 (44.8%)
|
140 (90.3%)
|
<0.001
|
Ezetimibe
|
17 (4.3%)
|
19 (12.3%)
|
0.001
|
PCSK-9 inhibitors
|
0
|
1 (0.6%)
|
0.282
|
Antiplatelet agents
|
113 (28.6%)
|
147 (94.8%)
|
<0.001
|
Anti-hypertensives
|
282 (71.4%)
|
151 (97.4%)
|
<0.001
|
ACEi o ARBs o MRAs
|
244 (61.8%)
|
132 (85.2%)
|
<0.001
|
GLP-1 RA prescribed at index visit
|
|
|
0.399
|
Lixisenatide
|
1 (0.3%)
|
0
|
|
Exenatide BID
|
6 (1.5%)
|
1 (0.6%)
|
|
Exenatide LAR
|
4 (1.0%)
|
0
|
|
Liraglutide
|
247 (62.5%)
|
92 (59.4%)
|
|
Dulaglutide
|
134 (33.9%)
|
62 (40%)
|
|
Semaglutide (weekly)
|
3 (0.8%)
|
0
|
|
SGLT2, sodium-glucose cotransporter-2; DPP4 Dipeptidyl peptidase-4; PCSK-9, Proprotein convertase subtilisin/kexin type 9; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MRA, mineralocorticoid receptor antagonist.
As shown in Table 2, in the primary prevention group, 71.4% of the subjects were treated with anti-hypertensive drugs, 28.6% were on anti-platelet drugs, while statins and ezetimibe were used by 44.8% and 4.3% of the subjects respectively. At baseline, 14 of the subjects with hypertension and 61 of those with dyslipidemia were newly diagnosed, and therefore they were not yet receiving pharmacological treatments. In those with previous CV events, nearly all patients were receiving cardioactive therapies in secondary prevention.
The mean duration of follow-up was 3.6 years. After initiating the GLP-1 RA, median duration of treatment was 3.2 years in primary prevention and 2.5 years in secondary prevention (Table 3).
Liraglutide and dulaglutide were the most frequently prescribed GLP-1 RAs (liraglutide: 65.1% and 60.6%, dulaglutide: 46.1% and 51.6% in primary and in secondary prevention respectively). 33.7% of the subjects in primary prevention and 20.6% of those in secondary prevention were prescribed two or more different medications during follow-up, mostly because of switching from daily to weekly formulations.
The majority of the subjects in both groups were on metformin in association to the GLP-1 RA, more than one third was on sulfonylureas or meglitinides, about 27% were on insulin, while pioglitazone was used by 21.8% of those in primary prevention and by 9.7% of those with a history of CV events (Table 3).
The percentage of patients still taking the GLP-1 RA gradually declined during follow-up, from 84% in primary prevention and 78% in secondary prevention at one year, to 65% and 56% at four years, and 60% and 50% at eight years, respectively (Table 3). The most common causes of drug discontinuation were either gastrointestinal side effects (31% of those who discontinued the GLP-1 in primary prevention and 39% in secondary prevention) or inefficacy to achieve glycemic targets or weight loss (46% in primary prevention and 40.3% in secondary prevention).
After GLP-1 discontinuation, half of the patients started a sodium-glucose cotransporter-2 (SGLT-2) inhibitor (48% in primary prevention and 58% in secondary prevention), whereas the proportion of insulin and sulfonylurea users increased (insulin: 62% and 69%, sulfonylureas/meglitinides: 52% and 42% in primary and in secondary prevention respectively). 25% of those in primary prevention and 36% of those in secondary prevention were switched to a DPP-4 inhibitor (Table 3).
Table 3. Treatment patterns during follow-up.
|
Primary prevention
|
Secondary prevention
|
P
|
Duration of follow-up
|
5.0 (0.25-10.8)
|
3.6 (0-10.3)
|
0.001
|
GLP-1 RA during follow-up *
|
|
|
|
Lixisenatide
|
2 (0.5%)
|
0
|
-
|
Exenatide BID
|
6 (1.5%)
|
1 (0.6%)
|
0.679
|
Exenatide LAR
|
12 (3.0%)
|
3 (1.9%)
|
0.574
|
Liraglutide
|
257 (65.1%)
|
94 (60.6%)
|
0.332
|
Dulaglutide
|
182 (46.1%)
|
80 (51.6%)
|
0.242
|
Semaglutide (weekly)
|
63 (15.9%)
|
7 (4.5%)
|
<0.001
|
Insulin degludec+liraglutide
|
21 (5.3%)
|
5 (3.2%)
|
0.299
|
Duration of GLP-1 treatment, years
|
3.2 (0-10.8)
|
2.5 (0-10.3)
|
<0.001
|
Duration of GLP-1 treatment >3 years
|
213 (53.9%)
|
57 (36.8%)
|
<0.001
|
GLP-1 RA discontinuation
|
159 (40.25%)
|
63 (40.65%)
|
0.870
|
Reasons for GLP-1 RA discontinuation
|
|
|
0.962
|
GI symptoms
|
50 (31.4% ¥)
|
24 (38.1% ¶)
|
|
Inefficacy
|
74 (46.5% ¥)
|
25 (40.0% ¶)
|
|
Noncompliance
|
11 (6.9% ¥)
|
3 (4.8% ¶)
|
|
Other (e.g.: drug discontinued during hospitalizations, prescription expired, switch to SGLT2i...)
|
11 (6.9% ¥)
|
3 (4.8% ¶)
|
|
Worsening of kidney function
|
5 (3.1% ¥)
|
1 (1.6% ¶)
|
|
Malaise, fatigue, dizziness or myalgias
|
4 (2.5% ¥)
|
2 (3.2% ¶)
|
|
Allergic or cutaneous reactions
|
3 (1.9% ¥)
|
2 (3.2% ¶)
|
|
Incident pancreatitis or biliary disorders
|
2 (1.3% ¥)
|
1 (1.6% ¶)
|
|
Tachycardia
|
1 (0.6% ¥)
|
1 (1.6% ¶)
|
|
Treatment persistence
|
|
|
|
GLP-1 RA ongoing at year 1
|
333 (84.3%)
|
121 (78.1%)
|
0.053
|
GLP-1 RA ongoing at year 2
|
297 (75.2%)
|
104 (67.1%)
|
0.047
|
GLP-1 RA ongoing at year 4
|
163 (64.9% #)
|
42 (56% #)
|
0.160
|
GLP-1 RA ongoing at year 6
|
100 (57.1% #)
|
24 (55.8% #)
|
0.875
|
GLP-1 RA ongoing at year 8
|
65 (60.2% #)
|
14 (50.0% #)
|
0.330
|
GLP-1 RA ongoing at year 10
|
15 (53.6% #)
|
3 (75% #)
|
0.613
|
Switched to a different GLP-1 RA
|
133 (33.7%)
|
32 (20.6%)
|
0.014
|
Treated with a single molecule
|
262 (66.3%)
|
123 (79.4%)
|
|
Switched to lixisenatide
|
0
|
0
|
|
Switched to exenatide BID
|
0
|
0
|
|
Switched to exenatide LAR
|
6 (1.5%)
|
3 (1.9%)
|
|
Switched to liraglutide
|
9 (2.3%)
|
2 (1.3%)
|
|
Switched to dulaglutide
|
46 (11.6%)
|
17 (11.0%)
|
|
Switched to semaglutide
|
56 (14.2%)
|
6 (3.9%)
|
|
Switched to insulin degludec + liraglutide
|
15 (3.8%)
|
4 (2.6%)
|
|
Anti-diabetic medications taken with GLP-1 RAs
|
|
|
|
Metformin
|
359 (90.89%)
|
134 (86.45%)
|
0.017
|
Pioglitazone
|
86 (21.77%)
|
15 (9.68%)
|
0.004
|
Acarbose
|
9 (2.28%)
|
1 (0.65%)
|
0.296
|
Sulfonylureas/meglitinides
|
158 (40.00%)
|
53 (34.19%)
|
0.128
|
Insulin
|
109 (27.59%)
|
42 (27.10%)
|
0.556
|
SGLT-2 inhibitors
|
13 (3.29%)
|
4 (2.58%)
|
0.790
|
Anti-diabetic medications after GLP-1 RA withdrawal
|
|
|
|
Metformin
|
139 (86.3% §)
|
51 (82.3% †)
|
0.612
|
Pioglitazone
|
32 (19.9% §)
|
5 (8.1% †)
|
0.039
|
Acarbose
|
8 (5.0% §)
|
2 (3.2% †)
|
0.733
|
Sulfonylureas/meglitinides
|
84 (52.2% §)
|
26 (41.9% †)
|
0.236
|
Insulin
|
100 (62.1% §)
|
43 (69.4% †)
|
0.560
|
SGLT-2 inhibitors
|
77 (47.8% §)
|
36 (58% †)
|
0.330
|
DPP-4 inhibitors
|
40 (24.8% §)
|
22 (35.5% †)
|
0.175
|
Severe hypoglycemic events
|
5 (1.0%; 3 patients with 1 episode, 1 patient with 2 episodes)
|
0
|
|
* During follow-up, patients could switch to different GLP-1 RAs from the ones prescribed at baseline; ¥ Percentage of those who discontinued the drug, n=159 in primary prevention; ¶ Percentage of those who discontinued the drug, n=63 in secondary prevention # The percentages refer to the numbers of patients still on follow-up: year 4, primary prevention 251, secondary prevention 75; year 6 primary 175, secondary 43; year 8 primary 108, secondary 28; year 10 primary 28, secondary 4. § percentage of 159 patients who discontinued the GLP-1 RA. † percentage of 63 patients who discontinued the GLP-1 RA.
CV outcomes
During a median follow-up of 5.0 years in primary prevention and 3.6 years in secondary prevention, the primary composite outcome (MACE) occurred in 34 patients (8.6%) in the first group and 32 patients (20.7%) in latter. The total number of events in primary prevention was: 9 (2.3%) myocardial infarctions or unstable anginas, 6 (1.5%) strokes, and 20 (5.1%) deaths. In those with a history of previous CV events, there were 12 (7.7%) myocardial infarctions or unstable anginas, 7 (4.5%) strokes, and 18 (11.6%) deaths. Five patients had more than one component of the composite endpoint. In the survival analyses, the first event was included as MACE. Data are summarized in Table 4.
Table 4. CV events during follow-up.
|
Primary prevention
|
Secondary prevention
|
MACE
|
34 (8.61%)
|
32 (20.65%)
|
Stroke
|
6 (1.52%)
|
7 (4.52%)
|
Myocardial infarction or unstable angina
|
9 (2.28%)
|
12 (7.74%)
|
All-cause death
|
20 (5.06%)
|
18 (11.61%)
|
Hospitalizations for HF
|
16 (4.05%)
|
14 (9.03%)
|
MACE + HF hospitalizations
|
43 (10.89%)
|
40 (25.81%)
|
The main composite CV outcome (MACE) included non-fatal myocardial infarction or unstable angina, non-fatal stroke, all-cause death. HF, heart failure.
Within the two groups, we compared subjects who took a GLP-1 RA for longer than the median duration of treatment (3.0 years in the overall population; denoted by GLP1>3) to those who took it for less than three years (denoted by GLP1<3).
The proportion of subjects who continued the GLP-1 for over three years was 53.9% in primary prevention and 36.8% in secondary prevention (Table 3).
In the primary prevention group, the primary composite outcome occurred in 11.0% of the GLP1<3 patients, and 6.6% of those GLP1>3 (hazard ratio [HR] 0.35, 95% C.I. 0.18-0.70, P=0.003). In secondary prevention, 22.5% in the shorter treatment duration group and 17.5% in the longer treatment duration group experienced a MACE (HR 0.35, C.I. 0.16-0.79, P=0.011).
Kaplan-Meier curves for MACE in patients stratified by GLP-1 duration therapy are shown in Figure 2 and in Figure 3.
In the univariate Cox regression analysis for those in primary prevention (Table 5) older age (HR 1.10, 95% CI 1.04-1.15, P<0.001), longer diabetes duration (HR 1.07, 95% CI 1.03-1.10, P<0.001), the presence of kidney disease (HR 2.17, 95% CI 1.10-4.31, P=0.026), and GLP-1 RA withdrawal (HR 2.67, 95% CI 1.27-5.62, P=0.009) were associated to an increased HR for MACE, while duration of GLP-1 RA treatment (HR 0.85, 95% CI 0.76-0.95, P=0.003), duration of treatment with GLP-1 RA ≥3 years (HR 0.35, 95% CI 0.18-0.70, P=0.003), diastolic blood pressure at baseline (HR 0.96, 95% CI 0.93-1.00, P=0.046), and better kidney function at baseline (HR 0.97, 95% CI 0.96-0.99, P<0.001) were associated to a lower HR for MACE. Also, the use of pioglitazone during the follow up turned out to be protective (HR 0.35, 95% CI 0.12-1.01, P=0.052).
In the multivariate model (Table 6), after adjustment for interactions and year of index visit, duration of GLP-1 RA treatment of over 3 years (HR 0.19, 95% CI 0.04-0.96, p=0.044) and use of pioglitazone (HR 1.01x10-6, 95% CI 2.74x10-12-0.37, p=0.035) were independently associated to a reduction in the risk of developing a MACE, while older age (HR 1.06, 95% CI 1.01-1.11, p=0.022) and GLP-1 RA withdrawal (HR 5.58, 95% CI 1.84-16.87, P=0.034) conferred a significantly increased risk.
In secondary prevention, age (HR 1.05, 95% CI 1.00-1.11, P=0.038), GLP-1 RA treatment duration (HR 0.83, 95% CI 0.72-0.95, P=0.007), GLP1>3 (HR 0.35, 95% CI 0.16-0.79, P=0.011), GLP-1 RA withdrawal (HR 2.11, 95% CI 1.01-4.41, P=0.047), the presence of an arterial stenosis >50% (HR 4.00, 95% CI 1.97-8.14, P<0.001), total cholesterol (HR 1.01, 95% CI 1.00-1.02, P=0.035), and kidney function (HR 0.98, 95% CI 0.96-1.00, P=0.022) were associated to MACE risk (Table 5). In the multivariate analysis, GLP1>3 (HR 0.07, 95% CI 0.01-0.30, P<0.001) and GLP-1 RA withdrawal (HR 4.93, 95% CI 1.37-17.69, P=0.014) remained significant with respect to the composite outcome. Data are shown in Table 6.
Table 5. Results of the univariate Cox regression analysis.
|
Primary prevention
|
Secondary prevention
|
Univariate analysis
|
HR (95% CI)
|
P
|
HR (95% CI)
|
P
|
Gender (male)
|
0.91 (0.46-1.81)
|
0.780
|
1.17 (0.52-2.65)
|
0.698
|
Age, years
|
1.10 (1.04-1.15)
|
<0.001
|
1.05 (1.00-1.11)
|
0.038
|
Smoking
|
|
|
|
|
Never
|
1
|
|
1
|
|
Current
|
0.63 (0.21-1.82)
|
0.391
|
1.09 (0.40-3.01)
|
0.864
|
Former
|
0.90 (0.39-2.10)
|
0.806
|
0.99 (0.44-2.20)
|
0.976
|
BMI, kg/m2
|
1.01 (0.95-1.07)
|
0.758
|
1.03 (0.97-1.09)
|
0.378
|
<30
|
1
|
|
1
|
|
30-35
|
0.46 (0.18-1.19)
|
0.108
|
1.69 (0.70-4.08)
|
0.243
|
>35
|
0.66 (0.29-1.51)
|
0.325
|
1.34 (0.52-3.43)
|
0.548
|
sBP at baseline
|
1.00 (0.98-1.02)
|
0.998
|
1.00 (0.98-1.02)
|
0.817
|
dBP at baseline
|
0.96 (0.93-1.00)
|
0.046
|
0.98 (0.94-1.02)
|
0.264
|
FBG, mg/dl
|
1.00 (1.00-1.01)
|
0.344
|
1.00 (0.99-1.01)
|
0.915
|
HbA1c, %
|
1.08 (0.87-1.35)
|
0.471
|
1.04 (0.81-1.35)
|
0.739
|
HbA1c<7%
|
0.32 (0.08-1.35)
|
0.121
|
0.66 (0.20-2.22)
|
0.507
|
Total cholesterol, mg/dl
|
1.01 (1.00-1.01)
|
0.168
|
1.01 (1.00-1.02)
|
0.035
|
HDL, mg/dl
|
1.00 (0.97-1.04)
|
0.813
|
1.00 (0.97-10.04)
|
0.831
|
Triglycerides, mg/dl
|
1.001 (0.998-1.004)
|
0.539
|
1.003 (0.999-1.008)
|
0.174
|
LDLc, mg/dl
|
1.01 (1.00-1.02)
|
0.172
|
1.01 (1.00-1.02)*
|
0.056
|
eGFR, ml/min/1.73 m2
|
0.97 (0.96-0.99)
|
<0.001
|
0.98 (0.96-1.00)
|
0.022
|
Diabetes duration, years
|
1.07 (1.03-1.10)
|
<0.001
|
1.02 (0.99-1.06)
|
0.197
|
Diabetes duration >10 years
|
2.13 (1.08-4.19)
|
0.029
|
1.51 (0.72-3.18)
|
0.278
|
Duration of GLP-1 RA treatment, years
|
0.85 (0.76-0.95)
|
0.003
|
0.83 (0.72-0.95)
|
0.007
|
Duration of GLP-1 RA treatment ≥3 years
|
0.35 (0.18-0.70)
|
0.003
|
0.35 (0.16-0.79)
|
0.011
|
GLP-1 RA withdrawal
|
2.67 (1.27-5.62)
|
0.009
|
2.11 (1.01-4.41)
|
0.047
|
>50% coronary, carotid, or lower extremity artery stenosis
|
1.96 (0.68-5.63)
|
0.213
|
4.00 (1.97-8.14)
|
<0.001
|
Diabetic kidney disease
|
2.17 (1.10-4.31)
|
0.026
|
1.91 (0.94-3.92)
|
0.076
|
Anti-diabetic medications taken with GLP-1 RAs
|
|
|
|
|
Metformin + GLP-1
|
0.49 (0.17-1.41)
|
0.188
|
0.53 (0.20-1.39)
|
0.196
|
Sulphonylureas + GLP-1
|
2.01 (0.97-4.17)
|
0.062
|
1.49 (0.72-3.08)
|
0.282
|
Pioglitazone + GLP-1
|
0.35 (0.12-1.01)
|
0.052
|
0.94 (0.32-2.74)
|
0.909
|
Acarbose +GLP-1
|
3.72 (0.87-15.83)
|
0.076
|
NC
|
|
Insulin + GLP-1
|
1.05 (0.50-2.19)
|
0.906
|
1.40 (0.68-2.90)
|
0.363
|
Cardioactive therapies at baseline
|
|
|
|
|
Statins
|
0.70 (0.35-1.39)
|
0.306
|
|
|
Ezetemibe
|
2.48 (0.75-8.17)
|
0.134
|
|
|
Antiplatelet agents
|
0.90 (0.42-1.93)
|
0.783
|
|
|
Anti-hypertensives
|
1.89 (0.73-4.90)
|
0.190
|
|
|
ACEi o ARBs o MRAs
|
1.09 (0.53-2.24)
|
0.811
|
|
|
Other CV risk factors
|
|
|
|
|
Arterial hypertension
|
2.10 (0.74-5.97)
|
0.164
|
|
|
Dyslipidemia
|
0.91 (0.45-1.82)
|
0.780
|
|
|
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MRA, mineralocorticoid receptor antagonist; CV, cardiovascular; LDL was calculated using the Friedewald formula; eGFR, estimated glomerular filtration rate calculated with the CKD-EPI formula. *missing values in 27 subjects.
Table 6. Results of the multivariate Cox regression analysis.
Multivariate analysis
|
|
|
Primary prevention
|
HR (95% CI)
|
P
|
Age, years
|
1.06 (1.01-1.11)
|
0.022
|
Duration of GLP-1 RA treatment ≥3 years
|
0.19 (0.04-0.96)
|
0.044
|
GLP-1 RA withdrawal
|
5.58 (1.84-16.87)
|
0.034
|
Pioglitazone + GLP-1
|
1.01x10-6
(2.74x10-12–0.37)
|
0.035
|
Secondary prevention
|
|
|
Duration of GLP-1 RA treatment ≥3 years
|
0.07 (0.01-0.30)
|
<0.001
|
GLP-1 RA withdrawal
|
4.93 (1.37-17.69)
|
0.014
|
Results of the multivariate Cox regression analysis, after adjustment for year of GLP-1 RA first prescription and for interactions. Significant interactions in the primary prevention group: pioglitazone x age, HR 1.22 (95% CI 1.01-1.46), P=0.034; GLP-1 RA withdrawal x GLP-1>3 years, HR 0.16 (95% CI 0.03-0.93), P=0.041. Significant interactions in the secondary prevention group: GLP-1 RA>3 years x GLP-1 RA withdrawal, HR 0.05 (95% CI 0.01-0.30), P=0.001.
When extending the analysis to include hospitalizations for heart failure in the composite outcome, the duration of GLP-1 RA therapy remained significant with respect to reduction of HR in the multivariate model in both groups. Data are shown in Table 7.
Table 7. Results of multivariate Cox regression analysis for the composite outcome MACE and hospitalizations for HF.
Primary prevention*
|
HR (95% CI)
|
P
|
Age, years
|
1.07 (1.02-1.12)
|
0.004
|
GLP-1>3
|
0.06 (0.01-0.27)
|
<0.001
|
GLP-1 RA withdrawal
|
6.66 (2.44-18.21)
|
<0.001
|
Pioglitazione+GLP-1 RA
|
8.51x10-6 (1.85x10-10-0.39)
|
0.033
|
Diabetic kidney disease
|
2.46 (1.32-4.59)
|
0.005
|
|
|
|
Secondary prevention**
|
|
|
GLP-1>3
|
0.28 (0.12-0.64)
|
0.003
|
Arterial stenosis >50%
|
3.90 (1.83-8.26)
|
<0.001
|
* Adjusted for year and interactions. Significant interactions: pioglitazone x age, HR 1.21 (1.03-1.42), p=0.021. GPL-1>3 x GLP-1 withdrawal, HR 0.10 (0.02-0.51), p=0.005. ** adjusted for year. HF heart failure.
Glycemic control and weight changes
Weight changes, fasting blood glucose, and HbA1c during follow-up in primary and secondary prevention are shown in Table 8, comparing subjects who continued the GLP-1 RA for more or less than 3 years. Of note, there were significant differences in metabolic parameters between GLP1>3 and GLP1<3 (weight loss, fasting blood glucose at years 1 and 2, HbA1c) mainly in the primary prevention group.
Table 8. Weight changes, fasting blood glucose, and HbA1c during follow-up.
|
Primary prevention
|
Secondary prevention
|
|
n
|
GLP1<3y
|
n
|
GLP1>3y
|
P
|
n
|
GLP1<3y
|
n
|
GLP1>3y
|
P
|
Weight changes vs. baseline, kg
|
Year 1
|
172
|
-1.26±5.94
|
209
|
-3.37±4.97
|
<0.001
|
95
|
-1.7±4.67
|
57
|
-3.2±5.15
|
0.836
|
Year 2
|
172
|
-1.54±7.97
|
209
|
-3.26±6.12
|
<0.001
|
91
|
-1.4±5.34
|
55
|
-3.37±6.69
|
0.142
|
Year 4
|
69
|
-0.69±8.8
|
178
|
-3.57±6.24
|
<0.001
|
33
|
-0.73±7.16
|
42
|
-4.3±5.79
|
0.015
|
Year 6
|
48
|
-0.43±7.68
|
125
|
-5±7.43
|
0.001
|
17
|
-3.16±9.1
|
26
|
-4.49±9.01
|
0.593
|
Year 8
|
35
|
0.18±11.47
|
72
|
-5.94±10.11
|
0.004
|
11
|
-4.36±14.99
|
16
|
-7.99±12.78
|
0.490
|
Year 10
|
9
|
5.22±10.01
|
17
|
-4.72±11.79
|
0.033
|
2
|
-19.1±21.78
|
2
|
-1.1±1.13
|
0.121
|
Final
|
180
|
-1.12±8.67
|
212
|
-2.91±10.54
|
0.001
|
96
|
-2.09±7.46
|
57
|
-4.09±9.83
|
0.257
|
95%CI final
|
180
|
-2.39; 0.16
|
212
|
-4.33; -1.48
|
|
96
|
-3.61; -0.58
|
57
|
-6.70; -1.49
|
|
Fasting blood glucose, mg/dl
|
Baseline
|
178
|
184.2±59.31
|
209
|
165.51±47
|
<0.001
|
94
|
160.6±50.4
|
56
|
164.21±50.27
|
0.595
|
Year 1
|
161
|
156.58±45.9
|
208
|
135.36±34.23
|
<0.001
|
89
|
142.92±37.42
|
57
|
136.21±36.45
|
0.197
|
Year 2
|
168
|
161.51±52.62
|
206
|
139.22±39.67
|
<0.001
|
92
|
143.15±48.34
|
56
|
139.05±30.35
|
0.978
|
Year 4
|
69
|
160.2±57.09
|
178
|
145.47±45.06
|
0.052
|
30
|
153.87±57.28
|
42
|
145.52±40.56
|
0.932
|
Year 6
|
47
|
153.68±61.07
|
121
|
147.12±40.93
|
0.846
|
17
|
136.65±45.72
|
25
|
149.12±43.01
|
0.377
|
Year 8
|
35
|
149.66±45.14
|
67
|
136.91±38.21
|
0.118
|
12
|
132.75±46.79
|
16
|
155.06±61.79
|
0.330
|
Year 10
|
10
|
161.2±104.15
|
15
|
123.8±25.41
|
0.488
|
2
|
173±33.94
|
2
|
123±16.97
|
0.121
|
Final
|
175
|
150.86±47.81
|
206
|
143.68±45.8
|
0.020
|
94
|
141.59±51.79
|
56
|
146.2±40.53
|
0.295
|
Baseline vs. final
|
|
<0.001
|
|
<0.001
|
|
|
<0.001
|
|
0.068
|
|
HbA1c, %
|
Baseline
|
176
|
8.31±1.42
|
212
|
8.14±1.31
|
0.223
|
95
|
7.84±1.5
|
55
|
7.94±1.01
|
0.153
|
Year 1
|
167
|
7.47±1.28
|
208
|
6.94±0.84
|
<0.001
|
91
|
7.28±1.14
|
56
|
7.08±0.79
|
0.495
|
Year 2
|
169
|
7.65±1.53
|
206
|
6.98±1.02
|
<0.001
|
93
|
7.34±1.34
|
56
|
7.07±0.71
|
0.760
|
Year 4
|
68
|
8.1±1.59
|
179
|
7.14±1.13
|
<0.001
|
30
|
8.1±1.34
|
39
|
7.19±0.86
|
0.001
|
Year 6
|
48
|
7.93±1.61
|
123
|
7.24±1.09
|
0.009
|
17
|
7.75±1.28
|
25
|
7.27±1.2
|
0.218
|
Year 8
|
35
|
8.26±2.15
|
71
|
6.96±0.89
|
0.002
|
95
|
7.16±1.29
|
56
|
7.06±0.81
|
0.026
|
Year 10
|
10
|
8.34±1.79
|
17
|
6.77±0.65
|
0.015
|
11
|
7.73±1.18
|
16
|
6.91±1.04
|
0.121
|
Final
|
176
|
7.57±1.44
|
208
|
7.16±1.11
|
0.002
|
2
|
8.5±0.28
|
2
|
6.15±0.35
|
0.583
|
Baseline vs. final
|
|
<0.001
|
|
<0.001
|
|
|
<0.001
|
|
<0.001
|
|
Weight changes, fasting blood glucose, and HbA1c during follow-up, in primary and secondary prevention, comparing subjects who continued the GLP-1 RA for more or less than 3 year. "Final" refers to the last visit available for each patient.
There were five severe hypoglycemic events, defined as hypoglycemia requiring external assistance for reversal, in four patients (0.7%).