Overview of Anti-Obesity Strategies in Women with CVD
Treatment of obesity has the potential to improve cardiovascular risk factors and reduce the risk of cardiovascular events. Regular evaluation of BMI, cardiovascular risk factors, CVD, and readiness for weight loss is recommended. For individuals with BMI ≥ 30 or > 27 with CVD or risk factors, comprehensive lifestyle therapies are the first step in treatment [
110,
111]. For individuals with BMI ≥ 40 or > 35 with CVD, evaluation for bariatric surgery is considered. For all patients with inadequate response to lifestyle therapy or with concomitant CVD, pharmacologic therapies can be considered. The backbone of all initial obesity therapies includes lifestyle and behavioral approaches including nutritional counseling and appropriate exercise augmentation. Similarly, weight loss is recommended for prevention of CVD using counseling and lifestyle approaches.
Studies suggest that to achieve cardiovascular benefits from weight loss in obesity, losing > 10% of body weight is needed [
112]. Lifestyle changes with diet and physical activity may result in inadequate weight loss and may be complicated by weight regain [
113]. Long-term studies have shown that bariatric surgical procedures typically lead to a sustainable weight loss of 25% and improvements in cardiovascular outcomes [
65]. However, surgical approaches are an invasive method that is mainly reserved for cases of severe obesity [
111].
There have been recent advances in the development of anti-obesity medications that are altering the treatment landscape. Studies with novel pharmacotherapy approaches for the treatment of obesity are now showing the degree of weight loss that may be relevant to altering CVD course. The focus of the following sections is on recent developments in medication treatment for obesity that is relevant to women with CVD. Earlier medications including orlistat, phentermine, lorcaserin, and naltrexone/buproprion have been reviewed previously, thus they are not the focus of the current review [
114,
115].
Glucagon-Like Peptide-1 Receptor Agonists and CVD in Women
Glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications were developed and approved as glucose lowering agents in patients with T2DM [
116]. Clinical trials in patients with T2DM demonstrated modest weight loss with all GLP-1 RA as shown in Table
1. The degree of weight loss seems largely related to dosing but may also reflect the extent of brain uptake and action. Both liraglutide and semaglutide have been approved for weight loss based on a series of trials in patients with obesity (Table
1). In the STEP trials, semaglutide resulted in an average weight loss of 12% by week 28 [
117••]. The combination of liraglutide with an exercise intervention had enhanced efficacy for maintaining weight loss [
118]. A newer T2DM treatment agent, tirzepatide, that combines GLP-1 RA with glucose-dependent insulinotropic polypeptide (GIP) activity, led to a greater degree of weight loss [
119••]. In patients with BMI ≥ 30 or ≥ 27 with a risk factor, tirzepatide led to up to 20.9% weight loss with the highest dose.
Table 1
Selected clinical trials of GLP-1 RA and SGLT2 inhibitors relevant to obesity and CVD
GLP-1 RA | | | | | |
T2DM + CVD outcome | | | | | |
ELIXA (lixisenatide) [ 120] | T2DM + recent ACS | 30 | MACE | HR 1.02 (0.89–1.17), − 0.6 kg weight loss | Not reported |
LEADER (liraglutide) [ 121] | T2DM + CVD or RF | 36 | MACE | HR 0.87 (0.78–0.97), reduction in kidney dz progression, − 2.3 kg weight loss | HR 0.88 (0.72–1.08) P for interaction 0.84 |
SUSTAIN-6 (semaglutide) [ 122] | T2DM (83% with CVD) | 39 | MACE | HR 0.74 (0.58–0.95), − 4.3 kg weight loss 1.0 mg | HR 0.84 (0.54–1.31) P for interaction 0.45 |
HARMONY (albiglutide) [ 123] | T2DM + CVD | 30 | MACE | HR 0.78 (0·68–0·90), atrial fibrillation 0.82 (0.64–1.06) | HR 0.67 (0.50–0.89) P for interaction 0.23 |
REWIND (dulaglutide) [ 124] | T2DM + CVD or CVD RF | 46 | MACE | 0.88 (0.79–0.99), − 1.46 kg weight loss | 0.85 (0.71–1.02) P for interaction 0.60 |
PIONEER-6 (oral semaglutide) [ 125] | T2DM + CVD or CKD | 32 | MACE | 0.79 (0.57–1.1) | Not reported |
AMPLITUDE-O (efpeglenatide) [ 126] | T2DM + CVD or CKD | 33 | MACE | 0.73 (0.58–0.92), − 2.6 kg weight loss | 0.56 (0.36–0.86) P for interaction = NS |
| Obesity + CVD | | MACE | News report 20% reduction | |
Obesity | | | | | |
STEP-1 (semaglutide) [ 128] | Obesity/overweight with RF | 73 | Weight loss | − 14.9% vs − 2.4% active vs. placebo, P < 0.001 | Not reported |
SCALE (liraglutide) [ 129] | Obesity/overweight with RF | 78 | Weight loss | − 5.6 kg, P < 0.001 | Not reported |
GLP-1 RA + GIP | | | | | |
Obesity | | | | | |
SURMOUNT-1 (tirzepatide) [ 119••] | Obesity/overweight with RF | 67 | Weight loss | − 15% (5 mg), − 19.5% (10 mg), − 20.9% (15 mg) vs. − 3.1% (placebo), all P < 0.001 | Not reported |
SGLT2 inhibitor | | | | | |
T2DM: CVD outcome | | | | | |
EMPA-REG (empagliflozin) [ 130] | T2DM + CVD | 28 | MACE | 0.86 (0.74–0.99), − 2 kg weight loss | P = 0.81 for interaction |
CANVAS (canagliflozin) [ 131] | T2DM + CVD or RF | 36 | MACE | 0.86 (0.75–0.97), − 1.6 kg weight loss | 0.84 (0.66–1.06), P for interaction 0.26 |
DECLARE-TIMI 58 (dapagliflozin) [ 132] | T2DM + CVD or RF | 37 | MACE | 0.93 (0.84–1.03), − 1.8 kg weight loss | 0.80 (0.68–0.94) P = 0.77 |
VERTIS CV (ertugliflozin) [ 133] | T2DM + CVD | 30 | MACE | 0.99 (0.88–1.12), − 2 kg weight loss | 0.90 (0.68–1.18) |
SCORED (sotagliflozin) [ 134] | T2DM + CVD, CKD or RF | 44 | MACE | 0.77 (0.65 − 0.91) | 0.77 (0.60–0.99) |
Heart failure | | | | | |
DAPA-HF (dapagliflozin) [ 135] | CHF EF ≤ 40% | 23 | CV death or HF hosp | 0.74 (0.65–0.85) | 0.79 (0.59–1.06) |
EMPEROR-reduced (empagliflozin) [ 136] | CHF EF ≤ 40% | 23 | CV death or HF hosp | 0.75 (0.68–0.86) | 0.59 (0.44–0.80) |
EMPEROR-preserved (empagliflozin) [ 137] | CHF, EF > 40% | 44 | CV death or HF hosp | 0.79 (0.69–0.90) | 0.75 (0.61–0.87) |
SOLOIST-WHF (sotagliflozin) [ 138] | T2DM + CHF hosp | 33 | CV death or HF hosp | 0.67 (0.52–0.85) | Not reported |
DELIVER (dapagliflozin) [ 139] | CHF, EF > 40% | 44 | CV death or HF hosp | 0.82 (0.73–0.92) | 0.82 (0.71–0.96) |
Given the FDA requirement to evaluate cardiovascular safety of T2DM treatments, there have been dedicated cardiovascular studies for all GLP-1 RA medications [
140]. All the cardiovascular outcome studies evaluated composite outcomes of MACE (cardiovascular death, myocardial infarction, and stroke) and enrolled patients with T2DM with a varying prevalence of pre-existing CVD. As shown in Table
1, selected GLP-1 RA’s demonstrated superiority compared to placebo for reduction of MACE. Meta-analyses confirm the benefits of GLP-1 RA’s in reducing individual endpoints including myocardial infarction, stroke, cardiovascular mortality, and all-cause mortality with only moderate heterogeneity across the agents [
141,
142]. Among patients with T2DM, the benefit appeared similar for MACE events in individuals with established CVD compared to high burden of risk factors [
142]. There was also a suggestion of reduction in hospitalization for heart failure though numbers of events were low and in heart failure with reduced ejection fraction, liraglutide did not show benefits [
141]. It seems possible that a greater extent of cardiovascular benefit from GLP-1 RA medications is from the impact on atherosclerotic events. A recent trial (AMPLITUDE-O) looked at the effect of GLP-1 RA, efpeglenatide, for reducing the risk of cardiovascular events in patients with T2DM and CVD and was shown beneficial in reducing MACE compared to placebo [
143]. The ongoing SELECT trial is evaluating semaglutide in patients with established CVD without T2DM and preliminary favorable results were reported in a press release [
127]. Additional ongoing studies include in patients with atrial fibrillation as well as cardiovascular outcomes with tirzepatide. Multiple potential mechanisms have been proposed for the GLP-1 RA medications including direct vascular effects, alteration of risk factor profile, reduction of inflammation, and plaque stabilization [
144‐
146].
Inclusion of women in the cardiovascular outcome trials of GLP-1 RA medications in patients with T2DM ranged from 30 to 46% and reporting on sex-specific results has not been consistent. One meta-analyses indicated similar benefits in women with T2DM with a HR of 0.88 (0.79–0.99,
P = 0.03) for MACE compared to placebo [
147••]. Another study using registry medication data sources suggested a higher degree of relative risk reduction with GLP-1 RA in women compared to men [
148]. In the obesity trials with GLP-1 RA’s, the proportion of women has been higher consistent with many studies of weight loss interventions. In the STEP studies, more than 70% were women, but there is limited information about sex-specific effects. In the SURMOUNT-1 trial with tirzepatide, women comprised 67% of the study participants, but no information was provided in the initial report regarding sex-specific weight loss effects.
The most common adverse effects of GLP-1 RA medications include nausea, vomiting, and diarrhea [
149]. In many patients, the intensity is mitigated by gradual dose escalation. The safety during pregnancy is not known and thus not recommended to be used during pregnancy. In general for both T2DM and for obesity management, GLP-1 RA represents a chronic therapeutic agent with evidence of weight regain when the medications are stopped.
Sodium-Glucose Transporter 2 Inhibitors and CVD in Women
Similar to GLP-1 RA medications, sodium-glucose transporter 2 (SGLT2) inhibitors were developed for treatment of T2DM and have expanded into cardiovascular health impact. The role in obesity management is more variable [
150,
151]. In trials of patients with T2DM, SGLT2 inhibitors reduce body weight by 1.5–2 kg in a dose-dependent manner that appears maintained over 4 years [
152•]. Weight loss with SGLT2 inhibitors appears similar for patients without T2DM [
153]. The SGLT2 inhibitor-induced weight loss is much more pronounced when combined with GLP-1 RA suggesting that the combination of glycosuria with appetite suppression may have additive benefits in patients with T2DM [
154,
155].
There is robust evidence supporting the use of SGLT2 inhibitors to reduce cardiovascular risk in patients with T2DM and for the treatment of heart failure. Multiple agents demonstrate favorable cardiovascular outcome trials of SGLT2 inhibition in patients with T2DM as shown in Table
1. In meta-analyses, there is reduction of MACE only in patients with established atherosclerotic disease and heart failure outcomes in those with and without established CVD [
156•]. A subsequent meta-analysis suggested primary MACE prevention in patients with CKD [
157]. Subsequent trials have shown benefit in stable patients with heart failure with reduced and with preserved ejection fraction as well as in patients with chronic kidney disease (Table
1). Studies have shown that SGLT2 inhibitors improve cardiovascular outcomes and HF symptoms in patients with heart failure and preserved ejection fraction (HFpEF) and obesity, and this improvement is accompanied by weight loss [
158]. Ongoing trials are evaluating outcomes with unstable coronary disease along with heart failure.
In patients with T2DM, the CV benefits of SGLT2 inhibitors appear similar in women compared to men. In a patient level meta-analysis of the dapagliflozin trials in heart failure for both reduced and preserved ejection fraction, there were no observed sex-based differences in the treatment benefits with a HR for women of 0.74 (0.66–0.84) [
159]. Current guideline recommendations for both T2DM with CVD and for heart failure include the use of SGLT2 inhibitors [
160]. Potential adverse effects of SGLT2 inhibitors include urinary tract infections and genital mycotic infections in women. The impact during pregnancy is not known and, thus, not recommended. Prior reports suggesting an increase in amputation risk have largely been refuted by more recent evidence suggesting safety in patients with peripheral artery disease [
161]. It is important to note that SGLT2 inhibitors are not approved for weight management but for treatment of T2DM and heart failure though the combination with GLP-1 RA for patients with T2DM may augment weight loss.