In a recent forum organized by the Hong Kong Society for Medical Healthcare Management and AstraZeneca, chaired by Dr. James Wong Yu Man, specialists and general practitioners from across Guangdong and Hong Kong met in Hong Kong to share their experiences and insights on novel treatments for cardiovascular and metabolic diseases. The meeting included lectures by expert endocrinologist Dr. Norman Chan and cardiologist Dr. Duncan Ho, a discussion moderated by Dr. Chong Man Yuk, preceded by an afternoon visit to the new Cardiology and Intervention Laboratory of Union Hospital in Shatin, Hong Kong. As Dr. Wong remarked, the meeting aims to create more opportunities for cooperation between Mainland and Hong Kong physicians, provide the best treatment for patients, improve treatment outcomes and quality of life, and broaden the basis for clinical research.
Updates in Management of Diabesity
By Dr. Norman Chan
Honorary Associate Professor, The Chinese University of Hong Kong “Not two T2DM patients are the same, because their cardiovascular disease risk profiles are very different.”
Diabesity management: While modest obesity can already lead to various health problems, and most type 2 diabetes mellitus (T2DM) patients are obese to varying degrees, treatment for T2DM should be customized for individual patients. Excess sugar is stored in the liver, affects insulin secretion, leads to the development of fatty liver disease, and increases the risks for cardiovascular diseases. Doctors’ role in facilitating health management become more importance as disease emerges, particularly since patients often only then attend to their health condition.
Glucagon-like peptide-1 receptor agonists (GLP1-RA): Traditional oral anti-diabetic medications (OAD) such as sulfonylurea and insulin increases weight, and are directed at post-prandial blood sugar levels. Drugs that can lower weight and control pre-prandial blood sugar levels would be beneficial. The American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) guidelines [1,2] have moved forward the use of GLP1-RA and sodium-glucose co-transporter-2 inhibitor (SGLT2i) after metformin. The GLP1-RA mimics the action of incretin that is normally produced in the small-intestine when blood sugar level is high. It signals 1) b-cells to produce more insulin 2) alpha cells to reduce glucagon production, 3) the stomach to slow down food transport to the intestine, and 4) the brain to lower appetite, thereby leading to weight loss. The new GLP1-RA exenatide weekly injection improves from the old daily formulation by using a microsphere technology that extends the drug’s release in the body. In the DURATION-6 trial, it showed less gastrointestinal (GI) side effects than another GLP1-RA liraglutide  . In the DURATION-8 trial, weekly exenatide and the SGLT2i dapagliflozin each led to -1.6% and -1.4% HbA1c reduction, and -2% when used in combination. In terms of weight loss, weekly exenatide and dapagliflozin each led to -1.5kg and -2.2kg weight reduction, and -3.4 kg when used together.
Case-sharing: To date, Dr. Chan has had 404 patients on SGLT2i and 25 on weekly GLP1-RA, of which 16 have been using the two in combination. Dr. Chan shared the case of a young, obese T2DM smoker patient with fatty liver and dyslipidaemia (in Nov 2013: 37 years old, 97.4kg, BMI at 33 and HbA1c 6.1%, who already lost 11 kg from exercise and diet before presentation). The patient, originally on metformin alone, was put on single tablet saxagliptin/metformin, but in Sep 2015, rebounded back to 103kg, with HbA1c increased to 8.4%, and the patient was put on dapagliflozin. In Mar 2017, FibroScan showed high controlled attenuation parameter (CAP) score of 298 dB/m and high fibrosis score of 8.8 kPa suggestive of early fibrosis. The patient was willing to add-on weekly injectable exenatide. Since Sep 2015, the patient achieved a 7kg weight reduction, with HbA1c stably maintained at <7%, which improved his diabetic condition as well as the associated cardiovascular disease (CVD) risks.
Conclusion: Dr. Chan suggested that GLP1-RA is suitable for use as monotherapy or add-on therapy to other OADs, and, in certain T1DM patients, for reducing insulin dose (but not for complete switching, due to the risk of ketoacidosis). However, GLP1-RA should not be administered to newly-diagnosed T2DM patients, and insulin reduction should be conducted with care.
Novel Treatments for Post-MI Diabetes Patients
By Dr. Duncan Ho
Honorary Consultant Cardiologist, Hong Kong Sanitorium & Hospital “In extending double-anti platelet therapy, we select patients who will receive the greatest benefits.”
“Small” steps: Dr. Ho began by quoting from the moon landing that “That’s one small step for man, one giant leap for mankind”, noting that treatments for acute coronary syndrome (ACS) and acute myocardial infarction (AMI) have progressed in many “small” steps. Main treatments in the past were nitroglycerin, morphine, warfarin, and elective percutaneous coronary intervention (PCI). Nowadays, treatments include statin, aspirin, stenting, angioplasty, thrombolysis and primary PCI. Benefits aggregate over the years.
Anti-platelet therapy: For preventing blood clots, besides aspirin, there are currently three available P2Y12 inhibitors: clopidogrel, prasugrel and ticagrelor. Prasugrel is not as commonly used, due to risks in patients with old age or a history of stroke(s). Clopidogrel, which requires activation via liver metabolism, might not give sufficient “balloon time” for PCI. Due to differences in liver metabolism, its efficacy might vary across patients. Data showed that at 2 hours after administration, only 16% of patients on clopidogrel achieved a 70% inhibition of platelet aggregation (IPA). Unlike clopidogrel, ticagrelor is an active drug and appears to be more potent and stable. It binds reversibly to platelets, which results in a shorter half-life and a shorter discontinuation time for avoiding bleeding (e.g. before surgery).
New evidences: The European Society of Cardiology (ESC) 2015 and American Heart Association (AHA) 2016 guidelines both recommended using ticagrelor 90 mg over clopidogrel for ACS and primary PCI [6,8] , in regards to evidences from the following studies: in the PLATO study that compared 180 mg ticagrelor vs. 300 mg clopidogrel in 18,624 ACS patients, recurrent myocardial infarction (MI) and cardiovascular (CV) deaths at 1 year were reduced by 16% (HR=0.84 (95%CI: 0.75-0.95), p=0.005) and 21% (HR=0.79 (95%CI: 0.69–0.91), p=0.001). A Sweden observational cohort study of 45,073 ACS patients over 3 years also observed similar outcomes for a composite endpoint of CV deaths, MI or stroke (HR=0.85 (95%CI: 0.78-0.93)).
DAPT duration: The risks of recurrence MI or death for post-MI survivors are 20% within the 1st year, and, for those who are event-free after 1 year, another 20% within 3 years Since only about half of recurrent MIs occur at the original vessel, anti-platelet agents might be beneficial in addition to local stenting in providing more systemic protection. The DAPT Study showed that antiplatelet therapy for a period of 12-30 months after initial MI conferred benefits: event rates (a composite of death, myocardial infarction, or stroke) of thienopyridine (clopidogrel or prasugrel) vs. placebo were 4.3% vs. 5.9%, HR=0.71 (95%CI: 0.59-0.85), p<0.001. Subsequent analysis by a “DAPT score” showed that those with additional risk factors benefited much more (4.9% vs. 7.6%, p=0.001) vs. the lower risk group (3.7% vs. 3.8%, p=0.73). Dr. Ho would tailor the best therapy for patients based on individual conditions: factors that might increase the risk of MI recurrence, including smoking, T2DM, prior PCI (especially saphenous vein graft (SVG) PCI), heart failure (HF) and/or left ventricular ejection fraction (LVEF) <30%, the patient’s blood flow and blood vessel conditions (e.g. thinness), are weighed against the patient’s bleeding risk, such as old age.
High-risk patients: For high-risk post-MI patients, the PEGASUS trial for 21,162 patients (aged >50 with a history of spontaneous MI 1-3 years prior to enrolment and at least one additional atherothrombosis risk factor) showed that using 90 mg or 60 mg BID ticagrelor vs. placebo reduced CV death, MI or stroke by 15% (HR=0.85 (95%CI: 0.75-0.96), p=0.008) and 16% (HR=0.84 (95% CI 0.74–0.95), p=0.004). Although major bleeding increased (2.3% vs. 1.1%, p<0.01), fatal bleeding was similar (0.25% vs. 0.26%, p=1.00).
Conclusion: Dr. Ho concluded that 1) ticagrelor 90 mg DAPT as first-line over clopidogrel DAPT for >12 months is recommended by international guidelines; 2) there seems to be emerging evidences that non-stented area recurrent MI rates would be reduced through long-term DAPT; 3) for certain high-risk patient types (e.g. post-MI, high CVD risk factors, etc.), long-term DAPT for >12 months (ticagrelor 60 mg + aspirin) beyond 1 year can be considered.
Have you used GLP1-RA on non– or borderline-T2DM patients?
Dr. Chan: in Hong Kong, physicians have administered GLP1-RA to patients with “hidden” T2DM, such as those with impaired glucose tolerance (IGT; with fasting glucose of 7.8 – 11.1 mmol/L). While weekly GLP1-RA has a good adverse event profile, physicians should be careful using it on patients if only for weight loss.
What is your choice of antiplatelet therapy for i) elective PCI and ii) simple PCI?
Dr. Ho: clopidogrel and ticagrelor each has advantages and disadvantages. Although ticagrelor is more potent, it is taken twice daily and sometimes leads to dyspnea. Dr. Ho would prefer ticagrelor for bioresorbable polymeric stents (BPS), whereas for 3-4mm stents, patient’s total number of pills/day (including other medications) may also be considered.
What is most difficult about post-MI management?
Dr. Ho: first, it depends on how fast the MI patient arrived at the hospital, which, if late, would result in complications such as tardy arrhythmia; second, other concurrent conditions such as HF and low LVEF might later lead to sudden death. General practitioners can be helpful in ensuring compliance and facilitating lifestyle adjustments.
Has there been any discontinuation of weekly GLP1-RA due to skin injection nodules?
Dr. Chan: skin nodules happen in about every 5 to 6 of my patients. They nodules can be relieved with alcohol rubs, and tend to disappear over time. Patients were comfortable to continue the drug.
Would cost be an issue for continuing DAPT beyond 1 year?
Dr. Ho: one must balance risks with benefits. Considerations to continue DAPT should be given to patients with additional risk factors. Conversely, for these patients, if not continuing the therapy, valid reasons should be also have been thought through.
While most T2DM patients are obese to varying degrees, with associated CVD risks, treatment for T2DM should be customized for individual patients. The benefits of the weekly GLP1-RA include stable glycemic control, weight loss and low risks of hypoglycemia or other adverse events. Dr. Chan shared the case of a young, obese T2DM smoker patient (37 years old; 103kg) with fatty liver and dyslipidaemia. Using GLP1-RA and SGLT2i combination over 2 years, the patient achieved a 7kg weight loss, with HbA1c maintained at <7%, which improved his diabetic condition as well as the associated CVD risks.
For post-MI management, ticagrelor 90 mg DAPT as first-line over clopidogrel DAPT for >12 months is recommended by international guidelines. There seems to be emerging evidences that non-stented area recurrent MI rates would be reduced through long-term DAPT. For certain high-risk patient types (e.g. post-MI, high CVD risk factors, etc.), long-term DAPT for >12 months (ticagrelor 60 mg + aspirin) beyond 1 year can be considered.
- American Diabetes Association. Diabetes Care 2017; 40: S1-135.
- Garber AJ, et al. Endocr Pract 2017; 23: 207-38.
- Kim D, et al. Diabetes Care 2007; 30: 1487-93.
- Buse JB, et al. Lancet 2013; 381: 117-24.
- Frías JP, et al. Lancet Diabetes Endocrinol 2016; 4: 1004-16.
- Roffi M, et al. Eur Heart J 2016; 37: 267-315.
- Gurbel PA, et al. Circulation 2009; 120: 2577-85.
- Levine GN, et al. J Am Coll Cardiol 2016; 68: 1082-115.
- Wallentin L, et al. N Engl J Med 2009; 361: 1045-57.
- Sahlén A, et al. J Am Coll Cardiol 2016; 67: 471.
- Jernberg T, et al. Eur Heart J 2015; 36: 1163-70.
- Stone GW, et al. N Engl J Med 2011; 364: 226-35.
- Mauri L, et al. N Engl J Med 2014; 371: 2155-66.
- Yeh RW, et al. JAMA 2016; 315: 1735-49.
- Bonaca MP, et al. N Engl J Med 2015; 372: 1791-800.