Cardiovascular and diabetes management

This was a Saturday Healthed programme in Brisbane covering three linked fireside and lecture blocks: midlife women’s cardiovascular risk and menopausal hormone therapy (MHT), secondary-prevention lipid management with residual risk, and when SGLT2 inhibitors are the better early option in type 2 diabetes. Names below follow Otter and the stage introductions — surnames that sounded garbled are not invented.

1. Menopause, MHT and cardiovascular risk

Professor Charlotte framed a myths-and-facts chat with Professor Rod/Rob (O&G). The opening question: why is women’s cardiovascular risk lower during reproductive life, then rises?

Menopause itself — not only age

Risk rises with age for everyone, but several studies show menopause adds risk beyond chronological age. Framingham followed a Massachusetts town for decades (nearly 3,000 women) after Roosevelt’s untreated hypertensive stroke death in 1945 highlighted how little was then known. Swan (Study of Women Across the Nation) and New South Wales 45 and Up data published more recently were cited: if usual Australian menopause age is about 51–53, each year earlier menopause raised CVD risk by about 3%. That meant roughly ~36% higher risk after premature menopause and ~15% after early menopause — and later menopause looked protective by the same arithmetic.

How estrogen protects vessels

• Lipids: estrogen tends to lower LDL. HDL concentration may be unchanged, but Swan data were cited that HDL’s cholesterol efflux capacity falls — so “same HDL number” can still mean worse atheroma risk.
• Rapid vessel effects: estrogen supports nitric oxide synthase; without estrogen, more endothelin-1 vasoconstriction.
• Longer-term genomic effects: more endothelial cell growth with estrogen; more smooth-muscle growth without it — net shift toward atherosclerosis when estrogen is absent.

Perimenopause is when the surrogates move

Swan follow-up (thousands of women, now into older age) showed body composition and metabolic changes accelerate around the final menstrual period: visceral and total fat accumulation rises from about two years before to two years after; LDL rises from about a year before to a year after then plateaus; metabolic syndrome rate accelerates and does not really slow; carotid intima-media thickness rate jumps about a year before the final period for ~two years. Things go wrong while hormones are fluctuating — not only when estrogen is at rock bottom. FSH may matter for endothelium, but they stressed that remains uncertain.

Observational hope vs WHI reality

Decades of observational work (Lipid Research Clinic, Leisure World, Nurses’ Health Study) mostly suggested benefit when hormones started near symptoms / final period. Framingham’s self-reported angina endpoint was flagged as a weak outlier — women’s ischaemic symptoms often differ from classic angina, and reflux can be mislabelled.

Women’s Health Initiative tested whether hormones reduce CVD in allegedly healthy postmenopausal women. Surrogates looked promising (less upper-body adiposity and insulin resistance, less type 2 diabetes, lower LDL — though triglycerides rose on oral hormones; coronary calcium lower after >5 years estrogen alone). Hard endpoints: with conjugated estrogen + MPA there was more stroke and PE during the intervention; no clear increase in CHD/MI; all-cause mortality unchanged; absolute risks lower in ages 50–59. After long follow-up, CV risks returned toward baseline. Estrogen-alone pointed more to the progestogen problem (synthetic MPA binding androgen/glucocorticoid receptors). Long-term follow-up of women 50–59 who took estrogen alone for ~7 years then were followed ~20 years showed fewer CHD/MI events (~11 fewer per 10,000 women per year) — modest, not “earth-shattering.”

Prescribing for symptoms when CVD is present or possible

Can women with established CVD take MHT for bothersome vasomotor symptoms? Rod: yes, mostly — after careful clinical assessment and risk estimation. Charlotte cautioned that the Australian CVD risk calculator gives five-year risk and can label a 45-year-old “low risk” while lifetime risk is high. High BP, high LDL and overweight still need action even if the five-year number looks calm. The calculator asks ethnicity, First Nations status, mental illness, premature family CVD, CAC, renal disease — but misses obstetric history (preeclampsia, GDM, preterm birth, recurrent miscarriage / stillbirths) and often under-weights COPD (COPD patients more often die of heart attack than of COPD itself — same pattern as CKD).

Micronised progesterone: well absorbed vaginally (same molecule as IVF vaginal product); night dosing if oral because of sedation (100 mg mornings → sleepy all day). Alternate-day vaginal use may be enough for endometrial effect — side-effect differences vs oral not fully settled. Synthetic progestogens differ from progesterone mainly via receptor binding.

Summary they gave: estrogen has multiple CV-protective mechanisms; starting when arteries are younger/healthier may help later CHD and mortality — but they do not support MHT for primary or secondary CV prevention yet. Assess CVD risk before starting when disease is suspected.

2. Lipid management, LDL targets and residual risk

Associate Professor Karam Kostner (UQ / Mater cardiology, preventive lipids) with GP educator Ralph walked a secondary-prevention case: Mr R, 65, hypertension, ACS a year ago with stents, premature family history (father AMI 58; brother later), tried atorvastatin 40 then rosuvastatin 20 for myalgia, now on ezetimibe 10 mg, perindopril 10 mg, aspirin 100 mg — LDL swinging around ~3.6. Not a cardiologist’s happy place.

What to look at on the lipid report

• LDL cholesterol is the practical GP target — trials and guidelines are LDL-centric.
• Non-HDL and ApoB are useful risk markers for enthusiasts; for day-to-day simplicity, LDL is enough.
• HDL is a risk marker (very low ~0.5–0.6 suggests reverse-transport problems). Raising HDL with drugs has not shown CV benefit; lifestyle that raises HDL helps for other reasons.
• All LDL is “bad” in the preventive-cardiology framing they used — long exposure drives arterial disease. Small-dense LDL marketing was dismissed as not useful for GPs.

Familial combined hyperlipidemia vs FH

Mr R’s high cholesterol and triglycerides pattern fits familial combined hyperlipidemia — said to be present in roughly 40% of coronary-care presentations. Pancreatitis risk rises when triglycerides exceed ~10; diabetes, alcohol, hypothyroidism, hormones (link back to the menopause talk), and very high saturated-fat / ketogenic patterns can push levels up. It is polygenic — no single genetic test. Treat the LDL hard regardless.

Familial hypercholesterolemia is different: ~1 in 250 Australians, high LDL (often >4–5) with early family disease. Dutch Lipid score >6 can support FH without a mutation found; many true FH have scores of 3–4; elevated Lp(a) can inflate the cholesterol pool. Dutch score mainly helps the high-LDL + early-family phenotype (and drug access), not combined hyperlipidemia.

Lp(a) is not inside your LDL number

LDL reports cholesterol in the LDL fraction; Lp(a) is a separate, highly atherogenic, genetic particle. Testing often costs $50–70 out of pocket unless in a public Queensland pathway. Use it to reclassify intermediate risk and treat other factors more aggressively (similar logic to a calcium score). Best prediction combines traditional factors + CAC + Lp(a). A large Lp(a)-lowering trial (pelacarsen) press release overnight relative to the talk had failed its primary endpoint — so for now Lp(a) remains a risk marker; lowering it has not yet proven hard-outcome benefit in that first large trial.

Combination early, targets lower

Ezetimibe is cheap (~$10 private), effective with a low-dose statin or PCSK9, and has outcome data in combinations. Authority friction for ezetimibe has eased. Queensland public discharge planning discussed recommending high-intensity statin plus ezetimibe from the start when admission LDL is high after ACS — same cost/side-effect envelope as statin alone, two metabolic pathways blocked, better chance of a low LDL target. International practice and emerging Australian Heart Foundation guidance were said to be moving that way. Message: after ACS, combination often makes sense irrespective of the first outpatient result; lower LDL is better.

Secondary-prevention target discussed as 1.4 (many still thinking 1.8). European-style very high risk (polyvascular, recurrent events, multivessel, FH) may aim <1. Imaging and outcome trials: lower LDL → more soft-plaque regression / less progression. Genetics (PCSK9 loss-of-function) and multi-year trials: very low or even near-undetectable LDL without neurocognitive harm signal — “no such thing as too low” for high-risk patients. Primary prevention / newly menopausal women with rising LDL do not all need 1.4 — 1.8 can be acceptable when arteries have not had lifelong bombardment.

Statin intolerance and PCSK9

Real-world intolerance ~10% (trials lower because they exclude prior intolerance, older patients, fibrate users). Rechallenge often fails to reproduce pain (~1 in 3). Practical ladder: try pravastatin; or very low rosuvastatin three times weekly + daily ezetimibe (~30–40% LDL drop); then PCSK9. Never stop tolerated ezetimibe/statin when starting PCSK9 — LDL rebounds and you lose additive benefit. Evolocumab every 2 weeks (most data) vs inclisiran every 6 months (adherence-friendly). PBS criteria discussed: significant vascular disease with LDL >1.8; FH primary prevention with LDL >5; enhancement factors including diabetes age ≥60 after ACS. Under-prescribed; GPs can prescribe in conjunction with a specialist. If LDL 1.7 on max tolerated oral therapy and not PBS-eligible, private PCSK9 (~$4,000/year) only if the patient can afford it.

Diet, EPA, fibrates, inflammation

• Mediterranean / vegetarian heart-healthy but modest LDL effect; portfolio diet (nuts, plant sterols, soy, fibre, etc.) can cut LDL ~30–35%.
• Triglycerides respond more to weight loss, alcohol reduction, less saturated fat, omega-3.
• Icosapent ethyl / Vascepa (highly concentrated EPA 4 g/day): REDUCE-IT relative risk reduction ~25%, NNT ~21 in high-risk patients already on statin ± ezetimibe with TG >1.7 — PBS streamlined authority discussed; under-used. Slight AF and minor bleeding risk — caution with DAPT or NOAC + antiplatelet. Benefit independent of how far TG falls. Other fish oils lower TG; this was the one with hard CV outcome data (EPA vs DHA debate flagged as too long for the slot).
• Fibrates: FIELD was a “positive-negative” trial — soft on hard CV endpoints, better on microvascular outcomes. Main 2026 roles: TG >10 (pancreatitis prevention) or diabetic residual dyslipidaemia when microvascular worry dominates. For heart-focused residual risk after ACS with TG 1.9, prefer EPA over fenofibrate if choosing one.
• Bile-acid resins: largely obsolete for lipids vs ezetimibe; pruritus niche.
• Colchicine / selective anti-inflammatories: mixed; traditional risk factors still dominate.
• Obesity as independent risk; GLP-1 RA for CV risk if patient will pay privately; SGLT2 in non-diabetics — “icing,” after TG/LDL basics.

3. When are SGLT2 inhibitors the better option?

Dr Ted Woo (RPA Diabetes Centre endocrinology; Otter also “Ted Bu”) argued against the magazine narrative that GLP-1s are the only diabetes answer. Supply shortages followed off-label popularity. Look at guidelines instead.

Guidelines and PBS put SGLT2 early

• RACGP type 2 primary-care pathway: metformin first; then SGLT2 listed ahead of GLP-1 in the dark-blue second/third-line preference (not alphabetical — DPP-4 would win alphabetically).
• ADS specialist pathway: after metformin, SGLT2 next whether or not cardiac/kidney disease is evident; GLP-1 if SGLT2 contraindicated/not tolerated.
• ADA: SGLT2 often first-line (even before metformin) for HF or CKD; GLP-1 equal mainly when ASCVD dominates.
• PBS revision April 2025: SGLT2 + metformin can be first-line for type 2 with established or high CV risk (multiple risk factors; Indigenous origin noted), regardless of HbA1c. GLP-1 sits after SGLT2 intolerance or inadequate control — not first.

Outcome data they summarised

EMPA-REG OUTCOME: empagliflozin vs placebo reduced 3-point MACE; ~40% lower CV death; ~35% fewer HF hospitalisations; ~40% less new nephropathy — first diabetes drug to show CV-death superiority in that design. Dapagliflozin broadly similar for MACE/HF/renal though CV-death alone differed. Dedicated HF trials: benefit in both HFrEF and HFpEF — first agents to move the HFpEF “graveyard.” Dedicated kidney trials (e.g. EMPA-KIDNEY): ~50% slower eGFR decline, with and without diabetes.

Don’t save them for “later”

SGLT2s were built as glucose-lowering drugs. Vs sitagliptin in uncomplicated type 2, higher-dose empagliflozin lowered HbA1c more. Weight: typically ~2–3 kg; with higher baseline weight and longer follow-up, averages around 5 kg — ~90% from fat mass (calories lost as urinary glucose). Mortality curves in EMPA-REG widened more in younger patients. EMPA-KIDNEY extrapolation: starting at eGFR 20 delayed dialysis ~1.9 years; starting near eGFR 85 without albuminuria extrapolated to ~26 years delay — never too late, and never too early.

When not to use

• Type 1 diabetes — DKA risk; mainly non-GP specialists err here.
• Pregnancy, preconception, GDM, breastfeeding.
• Prior recurrent genital fungal infection, Fournier’s gangrene, unexplained DKA (precipitated DKA may allow restart after education).
• Hypersensitivity; not indicated on dialysis (renal units sometimes use without clear extra harm in his framing).

UTIs: randomised trials/meta-analyses have not shown increased UTI with SGLT2s — genital thrush is the infection signal. UTIs are common in diabetes; coincidence is easy to misattribute.

Both SGLT2 and GLP-1 when you can

Not either/or. PBS diabetes rules push switch rather than dual listing — practical workarounds discussed: put GLP-1 on the diabetes PBS path and find HF or renal PBS criteria for SGLT2 (clinical HF; low enough eGFR / high enough ACR), or private SGLT2 (~$50; splitting tablets mentioned as a cost hack to approximate prior PBS co-pay). Hypoglycaemia risk of metformin + SGLT2 is very low.

Case Matthew: 58, accountant, 6 years type 2 on metformin, HbA1c 6.7%, BMI 28, controlled HTN/dyslipidaemia, family CHD, ex-smoker, Australian 5-year CV risk 10% (high). Old PBS blocked SGLT2 because A1c <7%; new rules allow SGLT2 + metformin first-line for high CV risk regardless of A1c — empagliflozin 10 mg or dapagliflozin 10 mg daily as examples named on stage.

Clinic takeaways

1. Menopause is a CV risk amplifier — especially if early. Treat vasomotor symptoms after risk assessment; prefer transdermal as risk rises. Do not sell MHT as proven heart prevention.
2. Five-year calculators under-tell lifetime risk in midlife women — still fix BP, LDL, weight; ask obstetric and COPD history the tool misses.
3. LDL first, combination early after ACS — statin + ezetimibe; escalate to PCSK9; keep tolerated orals on. Target ~1.4 in secondary prevention as discussed.
4. Residual risk: TG >1.7 and Lp(a) as markers; high-dose EPA where PBS-eligible; fibrates mainly for TG >10 or microvascular niches.
5. SGLT2 early in type 2 for glucose, weight, HF phenotypes, and kidney protection — don’t wait for complications; combine with GLP-1 via HF/renal or private pathways when dual diabetes listing blocks you.

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