Gregory M. Weiss, M.D.

This article was originally published on 

Cardiovascular disease (CVD) remains the leading cause of death in the world. This fact holds true for women as well as men.

 In the last two decades observational studies have noticed that the risk for coronary heart disease increases significantly following the transition into menopause.

While women generally develop coronary heart disease (CHD) later than men, a clear inflection point at midlife warranted an explanation. Studies looking for a reason for this increase in CHD risk discovered distinct patterns of alterations in endogenous sex hormones that resulted in adverse changes in body fat, lipids, and lipoproteins, as well as structural and functional measures of overall vascular health.

 These revelations have led the American Heart Association (AHA) to release a scientific statement addressing the implications of menopausal transitioning on CVD in women.

The last AHA guidelines addressing CVD prevention in women were released in 2011. In the time since then much more has been discovered about the complexities of the menopausal transition (MT) with major implications on CV risk for women in midlife. The primary hormonal changes experienced through the five stages of the MT involve estradiol and follicle-stimulating hormone levels. Typically, estradiol levels begin to fall before the final menstrual period while levels of follicle-stimulating hormone rise.

 While these changes may lead to the symptoms women experience during the MT, researchers have found that the symptoms themselves may herald ominous CV changes.

Symptoms women commonly experience during the MT include hot flashes and night sweats, mood changes, sleep and cognitive disturbances, genitourinary, and sleep function changes. Hot flashes and night sweats are examples of vasomotor symptoms that may occur in conjunction with higher body fat composition and are associated with cigarette smoking, depression and lower educational level.

 Vasomotor disturbances may also be responsible for some measure of increased CV risk.

Five characteristics of menopause have been found to influence CV risk. Studies have shown that women who experience menopause at less than 45 years of age experience exhibit significantly higher cardiovascular risk when compared to those who are older. Data from the Framingham Heart Study showed that earlier menopause was associated with increased CVD but also that high cholesterol, systolic blood pressure, and diastolic blood pressure led to earlier menopause.

 This points to a clear association between preexisting CV risk factors and the MT leading to decreased CV health.

The second characteristic is type of menopause. Some studies showed that the risk for CHD was higher if menopause was caused by surgical removal of the ovaries when no estrogen therapy was prescribed.5 This theory was modified when it was found that the timing of surgical menopause was important. Surgical removal of the ovaries at a young age increased the risk of CHD while removal at the time of normal menopause did not.

The third characteristic is the stage of menopause where it appears that the most deleterious changes in blood pressure and intima-medial arterial thickening occur during the later stages of menopause.

 Endogenous estradiol levels have also been shown to affect CV risk with higher levels being associated with lower progression of carotid narrowing over time.

Finally, the previously mentioned vasomotor symptoms of menopause correlate to reduced flow-mediated dilation and greater aortic calcification independent of other CVD risk factors or hormonal levels.

In addition to lifestyle behavior modification in the form of weight loss and smoking cessation, the evidence suggests a role for menopausal hormone therapy (MHT).

 It appears that initiating MHT before the age of 60 or within less than 10 years since menopause confers a CV risk-benefit while later initiation may increase risk.

 Treatment with MHT may also mitigate other comorbidities by promoting lean body mass and lower body mass index as well as decreased levels of fasting glucose. Once started stopping MHT increased the risk of CVD in menopausal women.

Finally, while data for primary and secondary prevention of atherosclerotic disease and improved survival with lipid-lowering interventions is lacking, there may be a role for such therapy during the MT.

It is clear that the MT is a uniquely impactful facet of a woman’s cumulative cardiovascular risk deserving of close attention. Clinicians need to recognize the changes that occur and armed with the knowledge in the scientific statement, educate patients, tailor interventions, and provide the treatment women need to navigate this unique time. Through encouragement of lifestyle changes, management of other risk factors for CVD, and patient-specific approaches to MHT women can realize increased quality of life, reduced CV risk, and potentially a longer and more satisfying life.

Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, et al; on behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart dis- ease and stroke statistics—2019 update: a report from the American Heart Association [published correction appears in 

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Samar R. El Khoudary, Brooke Aggarwal, Teresa M. Beckie, et al. Menopause transition and cardiovascular disease risk: implications for timing of early prevention. A scientific statement from the American heart association. 

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Articles

Dr. Gregory Weiss offers perspective on a recent guideline update from the American Heart Association outlining strategies to best manage risk of cardiovascular disease in women entering menopause. 

Physician Perspective: AHA Guidelines on Managing CVD Risk During Menopause

This year clinicians and researchers across all disciplines of medicine have witnessed many firsts. As we navigate a perilous landscape dominated by the global COVID-19 pandemic, we have seen an extraordinary adaptation in the academic community. Science, medicine, and humanity itself must go on.

In keeping with this idea, the American Heart Association (AHA) has just completed its first virtual annual meeting from which the global academic community has introduced the latest research and insight in the field of cardiovascular science. In light of the incredible strain the pandemic has had on the global economy we present four sessions from the AHA Scientific Sessions 2020 highlighting the cost versus benefit of the latest drugs that treat type II diabetes mellitus that are also known to reduce cardiovascular (CV) risk.

On November 13th, 2020, Joseph Azuri, MD, and colleagues from Tel Aviv, Israel presented, in session P2007, a comparison between empagliflozin, an inhibitor of the sodium-glucose cotransporter 2 (SGLT2) and oral semaglutide, the first oral glucagon-like peptide 1 (GLP-1) receptor agonist. In keeping with the AHA strategic goal of reducing cardiovascular mortality by 20% these two drugs have been shown to significantly reduce the incidence of CV mortality in patients with type 2 diabetes mellitus and known CVD.

In light of the potential cost burden adding a new drug to a diabetes treatment regimen creates, Azuri sought to determine which drug would be most cost-effective while still reducing CV risk in type 2 diabetics. The research team went on to calculate the cost needed to treat (CNT) and prevent one case of CV mortality using either drug. They found the annual costs for empagliflozin and semaglutide were $4,572 and $6,680, respectively.

 In light of the similarity between the drugs with regards to efficacy and CV risk reduction, Azuri’s team recommends empagliflozin as the more cost-effective treatment.

In a second session on November 13th, 2020, P2013, Azuri and colleagues went on to compare three popular GLP-1 receptor agonists. With regards to semaglutide, dulaglutide, and liraglutide, the American Diabetes Association recommends providing one of these GLP-1 therapies to patients with type 2 diabetes and established CVD regardless of glycemic control.

 Concerned about the staggering costs associated with these new drugs Azuri sought to compare the 3 drugs for cost-effectiveness.

Azuri again calculated the annual cost needed to prevent one major adverse cardiovascular event (MACE) utilizing each of the three drugs in patients with type 2 diabetes and established CVD. The relative costs were $557,000 for semaglutide, $1,179,360 for liraglutide and $1,605,904 for dulaglutide.2 The research team concluded that, for secondary prevention of MACE in patients with type 2 diabetes and established CVD, semaglutide provides more value than the other two medications.

In session P1146 on November 13th, a colleague of Azuri’s, Ronen Arbel, PhD, further breaks down the cost effectiveness of two different preparations of the GLP-1 drug semaglutide. With an oral preparation of semaglutide now available, Arbel imagined that patients may prefer it over a subcutaneous injection for prevention of MACE in patients with type 2 diabetes.

Following the previous model, Arbel calculated the average annual cost for both preparations needed to prevent one MACE. The research team found that the average costs per year were $641,823 and $855,040 for the subcutaneous and oral preparations respectively.

 They further looked at the cost relationship between the two preparations and the endpoints of MACE versus cardiovascular mortality (CVM) alone. They concluded that the subcutaneous preparation of semaglutide was more cost-effective for the prevention of MACE in patients with type 2 diabetes but that for the prevention of CVM the oral preparation provided a significantly better monetary value.

Finally, in session MP463, also on November 13th, Arbel and colleagues looked at the cost-effectiveness of icosapent ethyl, a prescription omega-3 fatty acid supplement known to aid in prevention of MACE in patients with hypertriglyceridemia. The team looked specifically at the difference in cost when used for secondary prevention in diabetic patients with known CVD and for primary prevention in those with risk factors for CVD.

Arbel analyzed the cost of icosapent ethyl to prevent one MACE per year when prescribed for either primary or secondary prevention. The average cost of icosapent ethyl annually was $874,500 versus $206,965 when used for primary and secondary prevention respectively.

 The team found that the cost needed to treat was four times higher in the primary prevention group when compared to the secondary prevention group concluding that prescribing icosapent ethyl for diabetic patients with known CVD is significantly more cost effective.

We as clinicians often overlook the cost of the therapies we prescribe focusing solely on the most effective and proven treatments for our specific patients. These reports show that, when given choices between equally efficacious treatments, cost can play a significant role in our decision making and should. Of final note, we should all consider the enormous monetary amounts reported above. Reread those annual costs and consider the relative burdens such numbers place on patients and the health care system overall. A discussion for another time.

In a recent column Gregory Weiss, MD, uses studies from AHA Scientific Sessions 2020 to compare the cost-effectiveness of antihyperglycemic agents for reducing cardiovascular events. 

Comparing Cost-Effectiveness of Antihyperglycemic Agents with Cardiovascular Benefit

Empagliflozin leads to substantial reductions in liver fat in patients with type 2 diabetes mellitus (T2DM).

Empagliflozin also leads to a significant decrease in the liver function test alanine aminotransferase (ALT).

Levels of aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) were also reduced, although not significantly with empagliflozin treatment in patients T2DM.

Non-alcoholic fatty liver disease (NAFLD) is a build up of fat on the liver, but not related to drinking alcohol.

Mabrish Mithal, MD, of Medanta-The Medicity Hospital in Delhi, India states, “NAFLD can progress to [non-alcoholic steatohepatitis, NASH], and subsequently to cirrhosis and even cancer of the liver, potentially fatal conditions. NAFLD is particularly common in diabetes. Medications to treat NAFLD/NASH are sorely needed.”

Empagliflozin is a sodium glucose cotransporter-2 (SGLT-2) inhibitor that has been shown in rodent models to reduce liver fat. Empagliflozin and other SGLT-2 inhibitors are used to lower blood sugar in adults with T2DM.

Dr. Mithal and colleagues from Medanta-The Medicity Hospital hoped to determine if empagliflozin could reduce liver fat in T2DM patients with NAFLD; they presented their E-LIFT trial as a 

 at the ENDO 2018 annual meeting in Chicago, Illinois.

The E-LIFT trial is a single-center, prospective, open-label, randomized controlled trial looking at 50 patients with T2DM and NAFLD. Subjects were randomized to receive standard treatment for T2DM plus empagliflozin or standard treatment without empagliflozin. The primary outcome was liver fat change over 20 weeks.

Empagliflozin combined with standard treatment reduced the amount of liver fat more than standard treatment alone (4%; p<.0001).

At the end of 20 weeks MRI-derived proton density fat fraction was 11.3% vs 16.2% at baseline in the empagliflozin group (P<.0001) and 15.5% vs 16.4%, respectively, in the standard-treatment group (P=.057).

ALT, AST, and GGT were lowered in the empagliflozin group (–10.9 IU/L, P=0.005, –7.7 IU/L; P=.212 and –11 IU/L; P=.057 respectively). 

There were no significant differences between fasting plasma glucose and HbA1C between the empagliflozin and control groups at 20 weeks (p=0.850; HbA1C, p=0.880 respectively).

Adding empagliflozin to standard treatment for T2DM significantly reduced liver fat at 20 weeks compared to standard treatment alone.

No significant differences between groups were found with regards to HbA1c or fasting glucose levels.

“While our findings do not prove that empagliflozin will help treat NAFLD or prevent NASH, the initial results are promising and open up the possibility that empagliflozin may provide additional benefits for patients with diabetes,” Dr. Mithal stated. 

Kuchay MS, Krishan S, Mishra SK, Mithal A. 

Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT trial).

 Paper presented at The Endocrine Society Annual Meeting (ENDO 2018); March 2018; Chicago, IL.

Empagliflozin shown to significantly reduce liver fat in patients with T2DM, according to a new study. 

Gregory M. Weiss, M.D.

Articles

Physician Perspective: AHA Guidelines on Managing CVD Risk During Menopause

Comparing Cost-Effectiveness of Antihyperglycemic Agents with Cardiovascular Benefit

The Skinny on Reducing Liver Fat with Empagliflozin in Type 2 Diabetes