Of dengue, diabetes, heart failure, myocardial infarctions and such like. Interesting updates.

Well folks here is another step taken by the medical profession for improving patient care. There is a tetravalent vaccine for dengue fever. I hope it reaches the third world countries soon. Here is a reminder from a current trial.

Dengue is a pandemic-prone viral disease, the incidence of which has increased by a factor of 30 over the past 50 years. Nearly half of the world’s population lives in dengue-endemic areas in more than 100 countries worldwide, where approximately 390 million cases of dengue virus infection are estimated to occur each year. Dengue can range from asymptomatic infection to severe disease with a mortality rate of 20% if untreated. Four serotypes of dengue virus (DENV-1 through DENV-4) frequently cocirculate in areas in which the disease is endemic. Although infection provides decades of protective immunity against the infecting serotype, secondary infection with a different serotype increases the risk of severe disease.

A tetravalent dengue vaccine based on a yellow fever virus “backbone,” CYD-TDV (Dengvaxia, Sanofi Pasteur), has been licensed in several countries on the basis of a 56 to 61% vaccine efficacy against virologically confirmed dengue among children in Asia and Latin America. CYD-TDV is associated with an increased risk of severe dengue and dengue leading to hospitalization in seronegative persons, which has led to recommendations that it be provided only to persons with evidence of past infection. This leaves a substantial unmet need.

A new tetravalent dengue vaccine candidate, TAK-003 (Takeda), is based on a live attenuated DENV-2 virus that provides the genetic backbone for all four of the viruses in the vaccine, which were originally designed and constructed by scientists at the Division of Vector-Borne Diseases of the Centers for Disease Control and Prevention (CDC). The DENV-2 strain (TDV-2) is based on an attenuated laboratory-derived virus, DEN-2 primary dog kidney (PDK)–53. The other three virus strains (TDV-1, TDV-3, and TDV-4) are chimeras that were generated by replacing the premembrane and envelope genes of TDV-2 with those from wild-type DENV-1, DENV-3, and DENV-4 strains.

TAK-003 was efficacious against symptomatic dengue in countries in which the disease is endemic. (Funded by Takeda Vaccines; TIDES ClinicalTrials.gov number, NCT02747927. opens in new tab.)

Here is the reference.

Efficacy of a Tetravalent Dengue Vaccine in Healthy Children and Adolescents
List of authors. Shibadas Biswal, M.D., Humberto Reynales, M.D., Ph.D., Xavier Saez-Llorens, M.D., Pio Lopez, M.D., Charissa Borja-Tabora, M.D., Pope Kosalaraksa, M.D., Chukiat Sirivichayakul, M.D., Veerachai Watanaveeradej, M.D., Luis Rivera, M.D., Felix Espinoza, M.D., LakKumar Fernando, M.D., Reynaldo Dietze, M.D., et al., for the TIDES Study Group* N Engl J Med 2019; 381:2009-2019 DOI: 10.1056/NEJMoa1903869

Dapaglifozin in patients with heart failure.

What price SGLT2 in diabetes with a failing heart? Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a new group of oral medications used for treating type 2 diabetes The drugs work by helping the kidneys to lower blood glucose levels. SGLT2 inhibitors have been approved for use as a treatment for diabetes since 2013. They are taken once a day with or without food.

The following drugs belong to the SGLT2 inhibitors class (trade name first, generic name in brackets):

Forxiga (Dapagliflozin), Invokana (Canagliflozin), Jardiance (Empagliflozin)
SGLT2 inhibitors work by preventing the kidneys from reabsorbing glucose back into the blood. This allows the kidneys to lower blood and the excess glucose in the blood is removed from the body via urine. Major hypoglycemia is rare, as is diabetic ketoacidosis, and both of these adverse events occurred only in patients with diabetes. The postulated mechanisms of action of SGLT2 inhibition and neprilysin inhibition are distinct.

In patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.

Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124. opens in new tab.)

Thus SGLT2 have a different mode of action to the first line drugs used in the treatment of diabetes which are based on the presence of insulin, the need to increase insulin or sensitise the receptors to insulin. They are also safe to use in heart failure. In the trial dapagliflozin was as effective in the 55% of patients without type 2 diabetes as in those with diabetes. This demonstration of the cardiovascular benefits of an SGLT2 inhibitor in patients without diabetes provides support for prior suggestions that such treatment has beneficial actions other than glucose lowering.

Here is the reference.

Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
List of authors.
John J.V. McMurray, M.D., Scott D. Solomon, M.D., Silvio E. Inzucchi, M.D., Lars Køber, M.D., D.M.Sc., Mikhail N. Kosiborod, M.D., Felipe A. Martinez, M.D., Piotr Ponikowski, M.D., Ph.D., Marc S. Sabatine, M.D., M.P.H., Inder S. Anand, M.D., Jan Bělohlávek, M.D., Ph.D., Michael Böhm, M.D., Ph.D., Chern-En Chiang, M.D., Ph.D., et al., for the DAPA-HF Trial Committees and Investigators

N Engl J Med 2019; 381:1995-2008. DOI: 10.1056/NEJMoa1911303

Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction

Experimental and clinical evidence support the role of inflammation in atherosclerosis and its complications. Colchicine is an inexpensive, orally administered, potent anti inflammatory medication that was initially extracted from the autumn crocus and has been used for centuries. Its mechanism of action is through the inhibition of tubulin polymerization and microtubule generation and, possibly, effects on cellular adhesion molecules, inflammatory chemokines, and the inflammasome. Colchicine is currently indicated for the treatment of gout, familial Mediterranean fever, and pericarditis.

Two trials have already been conducted to reduce inflammation by inhibition of interleukin-1β by the injectable monoclonal antibody canakinumab. This led to a 15% lower risk of cardiovascular events than was observed with placebo in the Canakinumab Anti inflammatory Thrombosis Outcomes Study (CANTOS) but also led to a slightly higher incidence of fatal infections. Canakinumab has not been approved for cardiovascular use. The administration of methotrexate did not affect cardiovascular outcomes or plasma markers of inflammation in the Cardiovascular Inflammation Reduction Trial (CIRT).

Here is the reference. List of authors. Jean-Claude Tardif, M.D., Simon Kouz, M.D., David D. Waters, M.D., Olivier F. Bertrand, M.D., Ph.D., Rafael Diaz, M.D., Aldo P. Maggioni, M.D., Fausto J. Pinto, M.D., Ph.D., Reda Ibrahim, M.D., Habib Gamra, M.D., Ghassan S. Kiwan, M.D., Colin Berry, M.D., Ph.D., José López-Sendón, M.D.

November 16, 2019DOI: 10.1056/NEJMoa1912388

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I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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