Indication bias or protopathic bias? Faillie, Jean‐Luc
BJCP. British journal of clinical pharmacology/British journal of clinical pharmacology,
October 2015, Volume:
80, Issue:
4
Journal Article
Main effects and suspected adverse reactions secondary to inhibition of sodium-glucose transporter 2 (SGLT2) by gliflozins.
Display omitted
Sodium-glucose transporter 2 (SGLT2) inhibitors, also known ...as gliflozins, are a new class of orally active drugs used in the management of type 2 diabetes. By inhibiting the SGLT responsible for the reabsorption of glucose from the kidney, their use aims primarily to induce glycosuria and, as a consequence, lower glycemic levels. However, their specific mechanism of action involves other pharmacodynamic consequences including potentially harmful adverse reactions. This manuscript reviews the physiological and pharmacological background behind inhibition of SGLTs, and discusses the pharmacological aspects of the safety of gliflozins.
Aim
Sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2i) have been commercialized in France for type 2 diabetes since April 2020 and later for heart and renal diseases. Given the recent developments ...in treating diabetes and the widening of SGLT‐2i indications, we aimed to study changes in the use of glucose‐lowering drugs in France and to characterize SGLT‐2i new users.
Methods
We performed a nationwide utilization study using the French health insurance database. Trends in incidence and prevalence of glucose‐lowering drug use were assessed by a repeated cross‐sectional study in 2019 and 2021. A cohort study of incident SGLT‐2i users was then conducted to describe patient characteristics and the strategy for treating diabetes.
Results
The prevalence of SGLT‐2i use gradually reached 0.1% in the third quarter of 2021 and increased more significantly to 0.2% thereafter. SGLT‐2i became the second most prescribed glucose‐lowering drug class after metformin at the end of 2021 (0.1%). Among the cohort of 125 387 SGLT‐2i new users (mean age 65.0 years; 60.1% of men), 87.6% presented a diabetic comorbidity. The patient profile changed over the study period with an increasing proportion of patients with cardiovascular (28.7% in 2020 vs. 40.2% in 2021) or renal (7.7% in 2020 vs. 11.8% in 2021) comorbidities at initiation. The main combinations used at SGLT‐2i initiation were metformin (12.5%) and metformin plus dipeptidyl peptidase‐4 inhibitors (8.1%). One‐year probability of SGLT‐2i persistence was estimated to be 55%.
Conclusion
The expansion of indications for SGLT‐2i and the broadening of the target population make it essential to assess the reasons for discontinuation and review their safety profile.
According to previous reports, diabetes seems to be a risk factor which worsens the serious clinical events caused by COVID-19. But is diabetes per se a risk factor that increases the probability of ...getting the virus? This paper will discuss this point. There are not many research data on antidiabetic drugs in this context. The potential influence of glucose-lowering agents on the severity of COVID-19 has not been described yet. Dipeptidylpeptidase-4 (DPP-4) is a cell surface protein ubiquitously expressed in many tissues and it is also a soluble molecule found in serum/plasma fluids. DPP-4 is involved in infection of cells by some viruses. This paper reviews data about the use of DPP-4 inhibitors and others diabetes drugs on COVID-19 patients. As such, no available evidence has yet suggested that glucose-lowering drugs - including those targeting DPP4-related pathways - produce any significant harm or benefit in the context of human infections. However, insulin must remain the first-choice agent in the management of critically ill-hospitalized patients, while it is recommended to suspend other agents in unstable patients. This paper provides related French and international recommendations for people with diabetes who got infected by COVID-19 and upholds that infections may alter glucose control and may require additional vigilance.
Diarrhoea is an adverse drug reaction of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril + valsartan. It was also described with olmesartan and more recently with other angiotensin ...receptor blockers. The study was performed to compare diarrhoea reports in pharmacovigilance databases with sacubitril + valsartan and valsartan. The study used reports of diarrhoea with the ARNI sacubitril + valsartan registered: first in the French PharmacoVigilance Database (FPVD) and second in Vigibase®, the WHO Global Individual Case Safety Report database. After description of the main characteristics, disproportionality analyses were performed. Results are reported as reporting odds ratios (ROR) with 95% confidence interval. We found 29 reports of diarrhoea with sacubitril + valsartan in the FPVD and 686 in Vigibase®. With sacubitril + valsartan, diarrhoea occurred more frequently in males around 70 years with a median delay of 3 days. With valsartan, diarrhoea occurred more frequently in females around 68 years with a median delay of 0.5 days. In the FPVD, a significant association was found with sacubitril + valsartan in comparison with valsartan alone before (ROR = 8.78 5.19–14.85) and after (ROR = 11.19 5.89–21.25) exclusion of concomitant drugs known to be associated with diarrhoea. A significant association was also found in Vigibase® after adjustment on age, sex, reporter and its location (ROR = 1.31 1.14–1.50). Diarrhoea reported with sacubitril + valsartan has marked differences in gender, delay of occurrence and frequency of reporting in comparison with diarrhoea with valsartan. From a pharmacodynamic point of view, these results suggest a specific role of sacubitril in diarrhoea.
Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and dipeptidyl peptidase‐4 (DPP‐4) inhibitors might increase the risk of intestinal obstruction, but real‐world evidence for this severe adverse ...event is lacking. Thus, the objective of this study was to determine whether GLP‐1 RAs and DPP‐4 inhibitors are associated with an increased risk of intestinal obstruction compared with sodium‐glucose cotransporter‐2 (SGLT‐2) inhibitors. We used the United Kingdom Clinical Practice Research Datalink and linked databases to assemble two new‐user, active comparator cohorts (2013–2019). The first included 25,617 and 67,261 GLP‐1 RA and SGLT‐2 inhibitor users, respectively. The second included 131,927 and 40,615 DPP‐4 inhibitor and SGLT‐2 inhibitor users, respectively. Propensity score fine stratification weighted Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of intestinal obstruction requiring hospitalization. GLP‐1 RAs were associated with an increased risk of intestinal obstruction compared with SGLT‐2 inhibitors (1.9 vs. 1.1 per 1,000 person‐years, respectively; HR: 1.69, 95% CI: 1.04–2.74). The highest HR was observed after 1.6 years of use (HR: 3.48, 95% CI: 1.79–6.79). DPP‐4 inhibitors were also associated with an increased risk (2.7 vs. 1.0 per 1,000 person‐years; HR: 2.59, 95% CI: 1.52–4.42), with the highest HR observed after 1.8 years of use (HR: 9.53, 95% CI: 4.47–20.30). The number needed to harm after 1 year of use was 1,223 and 603 for GLP‐1 RAs and DPP‐4 inhibitors, respectively. In this large real‐world study, GLP‐1 RAs and DPP‐4 inhibitors were associated with an increased risk of intestinal obstruction.
Aims
In the last French study in 2007, the incidence of hospital admissions (HAs) related to adverse drug reactions (ADRs) was 3.6%. The objective was to assess the current ADR‐HA incidence in France ...and to describe both its characteristics and preventability.
Methods
A prospective multicentre study was conducted among randomly selected French public hospital medical wards (April–July 2018). Patients admitted during a week period were included. ADR‐HA cases were collected by the French Regional Pharmacovigilance Centres network. An independent committee validated potential cases and ADR preventability.
Results
ADR‐HA incidence was 8.5% (95% confidence interval CI: 7.6–9.4%), increasing with age (3.3% 95%CI: 1.8–5.5% ≤16 y vs. 10.6% 95%CI: 9.3–12.0% ≥65 y). The most common ADRs were haemorrhagic events (8.8%), haematological disorders (6.5%), acute renal failure (6.3%), fluid and electrolyte disorders (6.0%), and falls (5.2%). New drugs were involved: targeted therapies (22.8% of antineoplastics), direct oral anticoagulants (29.6% of antithrombotics) and incretin‐based drugs (20.0% of antidiabetics). ADRs were preventable in 16.1% of cases because the drugs involved had not been used in accordance with monographies, package leaflets or other therapeutic guidelines. The main situations of noncompliance addressed either dose or duration of use (27.9%), warning (23.2%), use precaution (18.6%) and inappropriate self‐medication or misuse by patients (11.6%).
Conclusion
In France, ADR‐HA incidence dramatically increased over the last decade. A significant proportion was related to new pharmacological classes and considered as preventable. These findings should lead to in‐depth thought on preventive actions on at‐risk drug classes.
Since pandemic start, patients may have faced difficulties in accessing to care and treatment. This study aimed at assessing the impact of COVID-19 pandemic and its control measures on the use of ...drugs indicated in cardiovascular prevention and diabetes mellitus in France. From 09/17/2018 to 09/20/2020, a repeated cohort analysis was performed using the French nationwide health insurance databases. The pandemic impact was assessed using time-series analyses and unobserved components model for the weekly number of patients with (i) drug dispensing, (ii) ongoing treatment, (iii) treatment initiation, (iv) treatment disruption. Overall, 14,822,132 patients with cardiovascular drug dispensings and 3,231,618 with antidiabetic ones were identified. After a sharp spike in the amount of dispensings in the week the first national lockdown was announced, the period was marked by decreased levels and trends. Altogether, the estimated impact of the pandemic on dispensings appeared limited over the lockdown period (1–3% lack in dispensings). During lockdown, the weekly numbers of treatment disruptions remained stable whereas a significant decrease in treatment initiations was observed for almost all drug classes (e.g. β-blockers initiations: − 8.9%). Conversely, the post-lockdown period showed increases in treatment disruptions especially for antihypertensive and lipid lowering drugs (e.g. statins disruptions: + 4.9%). The pandemic and associated measures had a significant impact on cardiovascular and antidiabetic drugs use in France, mostly consisting in decreases of treatment initiations over lockdown and increases in treatment disruptions afterwards. Both could result in increased morbimortality that remains to be assessed.
The use of dipeptidyl-peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues-a group of drugs used in the management of type 2 diabetes mellitus-may be associated with an ...increased risk of bile duct and gallbladder disease. To date, no observational study has assessed this possible association.
To determine whether the use of DPP-4 inhibitors and GLP-1 analogues is associated with an increased risk of incident bile duct and gallbladder disease in patients with type 2 diabetes.
A population-based cohort study linked the United Kingdom Clinical Practice Research Datalink with the Hospital Episodes Statistics database, yielding a cohort of 71 369 patients, 18 years or older, initiating an antidiabetic drug (including oral and injectable agents) between January 1, 2007, and March 31, 2014.
Current use of DPP-4 inhibitors and GLP-1 analogues (alone or in combination therapy) compared with current use of at least 2 oral antidiabetic drugs.
Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs of incident bile duct or gallbladder events (cholelithiasis, cholecystitis, cholangitis) causing hospitalization, comparing current use of DPP-4 inhibitors and GLP-1 analogues with current use of at least 2 oral antidiabetic drugs.
During 227 994 person-years of follow-up, 853 of the 71 369 patients were hospitalized for bile duct and gallbladder disease (incidence rate per 1000 person-years, 3.7; 95% CI, 3.5-4.0). Current use of DPP-4 inhibitors was not associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (3.6 vs 3.3 per 1000 person-years; adjusted HR, 0.99; 95% CI, 0.75-1.32). In contrast, the use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (6.1 vs 3.3 per 1000 person-years; adjusted HR, 1.79; 95% CI, 1.21-2.67). In a secondary analysis, GLP-1 analogues were also associated with an increased risk of cholecystectomy (adjusted HR, 2.08; 95% CI, 1.08-4.02).
The use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease. Physicians should be aware of this potential adverse event when prescribing these drugs.
PDF
