TABLE 1.

History of cardiovascular effects of drugs used for weight loss

Agent	Year(s)	History of cardiovascular effects
Dinitrophenol	1930s	Affected mitochondrial oxidative phosphorylation to induce weight loss, and was associated with elevated body temperature [27,39].
Amphetamines	1950s	Linked to increased risk of hypertension and pulmonary hypertension [29].
Phentermine	1959 till present	The European Commission withdrew marketing authorization for all weight-loss drugs (phentermine, amfepramone, and mazindol) from the market due to unfavourable risk-to-benefits ratio. The licence was withdrawn and then subsequently reinstated several times [38], but a decision in 2002 by the European Court of First Instance overturned previous decisions to withdraw marketing authorizations for phentermine [37]. Phentermine is eligible for marketing authorization, but would require an updated application to be submitted.
Fenfluramine and dexfenfluramine	Fenfluramine: 1973–1997; dexfenfluramine: 1996–1997	Fenfluramine or dexfenfluramine used in combination with phentermine until fenfluramine and dexfenfluramine were withdrawn from the market in September 1997 due to links to pulmonary hypertension and valvulopathy [28,30–33].
Aminorex	1965–1968	An amphetamine analogue, withdrawn due to risks of pulmonary hypertension [27].
Sibutramine	1997–2010	Norepinephrine and serotonin-reuptake inhibitor was approved for treating obesity in the US and in Europe. Due to increased SBP, DBP, and pulse, caution was recommended in people with poorly controlled hypertension or history of cardiovascular arterial disease, stroke, or arrhythmia hyperthermia [27,39].
		Findings from the Sibutramine cardiovascular Outcomes Trial (SCOUT) of 10 000 overweight/obese patients with a history of coronary or peripheral vascular disease or stroke, and other risk factors, showed: 16% increase in risk of non-fatal myocardial infarction or non-fatal stroke, cardiovascular death, or resuscitated cardiac arrest with sibutramine vs. placebo, which caused US and European market withdrawal in October 2010 [35]; modest weight loss in patients participating in the SCOUT study was associated with reductions in cardiovascular mortality over 4–5 years of follow-up [10].
Phenylpropanolamine	2000	Withdrawn from the US market due to increased risk of haemorrhagic stroke [27].
Ephedrine	2004	Withdrawn from the US market due to adverse cardiovascular effects [27].
Rimonabant	2006–2008	Oral cannabinoid receptor antagonist/inverse agonist, gained approval in Europe in 2006 (but not in the US due to psychiatric safety concerns), was studied for possible long-term benefits for reducing cardiovascular risk in people with cardiovascular disease [34].
		The Comprehensive Rimonabant Evaluation Study of CV Endpoints and Outcomes (CRESCENDO) trial was prematurely discontinued due to European Health Authorities withdrawing rimonabant from the market (due to psychiatric risks) [27].

CV, cardiovascular.