Sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) have consistently demonstrated a clinically significant reduction of cardiovascular mortality. However, their safety in clinical practice is ...still incompletely characterized, and post-marketing monitoring is required considering the expected increase in clinical use. Different analyses of international spontaneous reporting systems, known as disproportionality analyses (DAs), have highlighted the occurrence of ketoacidosis, amputations, acute renal failure and skin toxicity.
In this viewpoint, we critically appraise these pharmacovigilance data on SGLT2-Is, with the aim of supporting clinicians in proper interpretation of these studies, and discussing their risk-benefit profile. To this aim, we offer a broad perspective on basic technical aspects subtending DAs of spontaneous reporting databases (describing peculiarities of the Food and Drug Administration Adverse Event Reporting System), their common and evolving uses, key pitfalls in presenting study results (in terms of “risk” or “association”) and relevant strategies to account for major confounders. This will also facilitate reviewers and editors in proper evaluation of DAs, and prompt pharmacovigilance experts in converging towards a set of minimum requirements in standardization of design, performance and reporting of DAs. A consensus on quality assessment of DAs will finally establish their transferability to clinical practice. It is anticipated that DAs cannot be used per se as a standalone approach to assess a drug-related risk and cannot replace clinical judgment in the individual patient.
Background
Apart from the underlying cardiovascular (CV) risk associated with migraine, both triptans and ergotamines can induce vasoconstriction and potentially increase the risk of serious ischemic ...events. Because of the low frequency of such events in eligible patients, randomized controlled trials are not exhaustive to assess the drug-related CV risk. Observational studies are, therefore, an essential source of information to clarify this matter of concern.
Aim
The aim of this study was to systematically review the available published observational studies investigating the risk of serious CV events in triptan or ergotamine users, as compared to unexposed migraineur controls.
Methods
We systematically searched MEDLINE and EMBASE electronic databases for cohort or case-control studies up to December 1, 2013. Studies retrieved from CDSR, DARE and HTA databases of the Cochrane Library were used for snowballing. Studies investigating the risk of any CV outcome in patients with a migraine diagnosis and exposed to triptans or ergotamines were considered for inclusion. Selection of studies, data extraction, and risk of bias assessment were conducted independently by two reviewers. Pooled odds ratios (ORs) with 95% confidence interval (95% CI) were computed using a random-effects model for studies and outcomes judged eligible for quantitative data synthesis.
Results
From a total of 3370 citations retrieved, after duplicate removal and screening, only four studies met the inclusion criteria (three nested case-control analyses and one retrospective cohort study). These studies investigated the risk of different CV outcomes associated with either the recency or the intensity of exposure to the studied drugs. As for the intensity of use, the pooled OR of serious ischemic events was 2.28 (95% CI 1.18–4.41; I2 = 0%) for ergotamine use (two studies), whereas for triptans (three studies) it was 0.86 (95% CI 0.52–1.43; I2 = 24.5%). Recent use of ergotamines was not significantly associated with any CV outcome (only one available study). Two studies investigated the risk of stroke related to recent triptan use: the first study reported an OR of 0.90 (0.64–1.26), and the second one suggested an increased risk of 2.51 (1.10–5.71). In this case, because of the high degree of heterogeneity, results were not pooled.
Conclusions
To date, few comparative observational studies have investigated the CV safety of migraine-specific drugs in clinical practice. Evidence gathered here suggests that intense consumption of ergotamines may be associated with an increased risk of serious ischemic complications. As for triptans, available studies do not suggest strong CV safety issues, although no firm conclusions can be drawn. In particular, evidence on stroke risk is conflicting. However, if an increase of the absolute stroke risk in recently exposed patients does actually exist, it must be small. Overall, residual uncontrolled confounding factors reduce the confidence in the risk estimates collected from the included studies. Further investigations are needed to better define the risk for rare but serious CV events related to triptan and ergotamine use for treatment of migraine.
The aging population has increased concerns about the affordability, quality, and nature of long-term care for older people, emphasizing the role of nursing homes. Unlike acute hospital and primary ...care, there is a lack of drug consumption data in long-term care to understand regional or national healthcare policies.
This study aimed to describe medication consumption by older adults and expenditure in Italian nursing homes (NHs).
Data on drug consumption and costs from the administrative medicine informational flows that detect medicines packages supplied to patients in health facilities and NHs were used. Data on the characteristics of the healthcare residence were from the Italian Health Ministry. Records for the year 2019, selecting the nursing homes exclusively providing elderly or mixed (elderly and disabled) were used.
In 2019, the total expenditure on medicines in NHs amounted to 25.38 million euros, the average cost to 1.30 and the expenditure per bed to 436.18 euros. Cardiovascular drugs were the highest-consuming therapeutic class (177.0 defined daily doses-DDDs/100 days of NH stay; 22.2% of total) followed by drugs acting on the alimentary tract and metabolism (167.6% and 21.0%) and blood drugs (160.4% and 20.1%). The treatment of hypertension and heart failure was widely the most frequently used, with the consumption being driven mainly by furosemide and ramipril. Antiulcer drugs were used on average in more than half of the days of NH stay (58.5 DDDs/100 days of NH stay), representing a therapeutic category for which deprescribing initiatives are recommended. On average, almost all patients received a dose of benzodiazepines, antipsychotics and antidepressants (37.6, 35.9, and 17.7 DDDs/100 days of NH stay, respectively), confirming the high prevalence of use for these medicines. Antibiotics reached 6.8 DDDs/100 days of NH stay.
The availability of data in this specific setting allows the identification of the main interventions toward improving appropriateness and represents a challenge for drug utilization research. Data from this study suggest that proton pump inhibitors (PPIs), benzodiazepines and antibacterials can be areas of improving prescribing appropriateness.
In this paper, we present a pharmacophore for QT-prolonging drugs, along with a 3D QSAR (CoMFA) study for a series of very structurally variegate HERG K(+) channel blockers. The blockade of HERG K(+) ...channels is one of the most important molecular mechanisms through which QT-prolonging drugs increase cardiac action potential duration. Since QT prolongation is one of the most undesirable side effects of drugs, we first tried to identify the minimum set of molecular features responsible for this action and then we attempted to develop a quantitative model correlating the 3D stereoelectronic characteristics of the molecules with their HERG blocking potency. Having considered an initial set of 31 QT-prolonging drugs for which the HERG K(+) channel blocking activity was measured on mammalian transfected cells, we started the construction of a theoretical screening tool able to predict whether a new molecule can interact with the HERG channel and eventually induce the long QT syndrome. This in silico tool might be useful in the design of new drug candidates devoid of the physicochemical features likely to cause the above-mentioned side effect.
We assessed post-marketing safety of sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) by analyzing adverse events (AEs) reported in international pharmacovigilance databases.
Eudravigilance, ...WHO-Vigibase (as of Feb 25, 2017) and the FDA Adverse Event Reporting System (FAERS, from 2004 to 2016 second quarter) were queried to extract AEs recording SGLT2-Is as suspect. Disproportionality analyses (case/non-case method) were performed in FAERS by calculating the reporting odds ratios (RORs) from System Organ Classes (SOCs) to Preferred Terms (PTs) (precise clinical entities). Potential signals were defined by statistically-significant ROR (lower limit of the 95% confidence interval – LL95%CI – >1) undetected by literature analysis (as of December 2016).
SGLT2-Is were recorded in 7972, 19,775, 11,137 reports (Eudravigilance, WHO-Vigibase and FAERS, respectively); in FAERS, statistically significant ROR emerged for the following SOCs: “infections and infestations” (N = 2162; LL95%CI = 3.25), “metabolism and nutrition disorders” (2278; 1.36), “renal and urinary disorders” (1665; 2.31), “reproductive system and breast disorders” (471; 4.85), “skin and subcutaneous tissue disorders” (1136; 1.52). Skin toxicity emerged as potential signal (e.g., rash, photosensitivity, urticaria as PTs), both for SGLT2-Is as a class and as individual drugs. Severe adverse skin events (81 reports, 7% of the skin cases) mainly occurred in females aged 18–65 using SGLT2-Is as single antidiabetic regimen.
Among antidiabetics, SGLT2-Is are associated with higher reporting of infections, metabolism, renal and reproductive AEs, corroborating clinical trial evidence. Their large reporting patterns and the unexpected signal of skin toxicity justify active vigilance by clinicians and “real-time” monitoring by pharmacovigilance experts.
•Multi-database pharmacovigilance analysis was performed to assess post-marketing safety of SGLT2-Is.•The majority of adverse events were predictable from pre-approval clinical evidence.•The unexpected signal of skin toxicity warrants active monitoring in the real-world.•Large analytical safety studies are needed for risk quantification.
In patients with diabetes, disease per se, co-morbidities and drugs, including novel agents acting on the incretin system, have all been associated with pancreatitis with controversial data. We ...investigated the publicly available FDA Adverse Event Reporting System (FDA_AERS) database to gain insight into the possible association between antidiabetic agents and pancreatitis. To this aim, a case/non-case method was retrospectively performed on the FDA_AERS database (2004–2009 period). Cases were defined as reports of pancreatitis according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology. All other reports associated with antidiabetics were considered non-cases. The Reporting Odds Ratio (RORs), with corresponding 95% confidential interval (CI) and Mantel–Haenszel corrected
P
value, was calculated as a measure of disproportionality, with subsequent time-trend analysis. We retrieved 86,938 reports related to antidiabetics, corresponding to 159,226 drug-report combinations: 2,625 cases and 156,601 non-cases. Disproportionality was found only for exenatide (number of cases, 709; ROR, 1.76; 95% CI, 1.61–1.92;
P
MH
< 0.001) and sitagliptin (128; 1.86; 1.54–2.24; <0.001). For exenatide, significant disproportionality appeared in the first quarter of 2008 (ROR, 1.24; 95% CI, 1.10–1.40;
P
MH
< 0.001), soon after the FDA alert; for sitagliptin in the second quarter of 2008 (1.41; 1.05–1.90; 0.021). This temporal analysis found a striking influence of relevant FDA warnings on reporting of pancreatitis (the so-called notoriety bias) and is, therefore, recommended to avoid transforming a pharmacovigilance signal of alert automatically into an alarm. The precise quantification of the risk of pancreatitis associated with antidiabetics deserves assessment through specific disease-based registries.
Antidopaminergic gastrointestinal prokinetics (bromopride, clebopride, domperidone, levosulpiride and metoclopramide) have been exploited clinically for the management of motor disorders of the upper ...gastrointestinal tract, including functional dyspepsia, gastric stasis of various origins and emesis. The prokinetic effect of these drugs is mediated through the blockade of enteric (neuronal and muscular) inhibitory D2 receptors. The pharmacological profiles of the marketed compounds differ in terms of their molecular structure, affinity at D2 receptors, ability to interact with other receptor systems 5-hydroxytryptamine-3 (5-HT3) and 5-HT4 receptors for metoclopramide; 5-HT4 receptors for levosulpiride) and ability to permeate the blood-brain barrier (compared with the other compounds, domperidone does not easily cross the barrier). It has been suggested that the serotonergic (5-HT4) component of some antidopaminergic prokinetics may enhance their therapeutic efficacy in gastrointestinal disorders, such as functional dyspepsia and diabetic gastroparesis. The antagonism of central D2 receptors may lead to both therapeutic (e.g. anti-emetic effect due to D2 receptor blockade in the area postrema) and adverse (including hyperprolactinaemia and extrapyramidal dystonic reactions) effects. As the pituitary (as well as the area postrema) is outside the blood-brain barrier, hyperprolactinaemia is a side-effect occurring with all antidopaminergic prokinetics, although to different extents. Extrapyramidal reactions are most commonly observed with compounds crossing the blood-brain barrier, although with some differences amongst the various agents. Prokinetics with a high dissociation constant compared with that of dopamine at the D2 receptor (i.e. compounds that bind loosely to D2 receptors in the nigrostriatal pathway) elicit fewer extrapyramidal signs and symptoms. A knowledge of central and peripheral D2 receptor pharmacology can help the clinician to choose between the antidopaminergic prokinetics to obtain a more favourable risk/benefit ratio.
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