In July of 2023, the European Medicines Agency announced that it was conducting a formal review into reports that the use of these drugs could increase the risk for suicide and suicidal thoughts. This was based on The Icelandic Medicines Agency receiving reports of up to 150 people who took the drugs and experienced suicidal thoughts or self-injury.
This was surprising since there was no signal of this potential adverse effect in the randomized trial data. However, since randomized trials have strict inclusion criteria to exclude people with psychological issues at baseline, trial safety data may not observe concerns about psychiatric safety risks.
As such, the other approach is to look at real world data. To this end, a study published in JAMA medicine have reported this.1
In the study, investigators identified everyone in Sweden and Denmark who started taking semaglutide or liraglutide (N = 124 517) for diabetes from 2013 to 2021. Use of SGLT2 inhibitor (N = 174 036) at the same time but not GLP-1 therapy was used as a control group.
In any case, 124 517 adults were prescribed Ozempic or an Ozempic-like drug, and 174 036 started taking an SGLT2 inhibitor. Interestingly, those who were prescribed Ozempic were more likely to be using or to have previously used antidepressants and to have had an outpatient visit for a psychiatric diagnosis. Analysis was undertaken via a propensity score analysis to adjust for confounders. The study showed that 77 new Ozempic users died from suicide (6 out of 10 000 people) as did 71 new SGLT2 inhibitor users (4 out of 10 000 people). While there was a slight increase risk with GLP-1, the margin of error is very large. Crucially, when death from suicide and nonfatal self-harm were combined, GLP-1 receptor agonists appear to be protective (HR, 0.83; 95% CI, 0.07–0.97), while no difference was noted between GLP-1 and SGLT2 inhibitor on new psychiatric disorder.
In my opinion therefore, the outcome is equivocal and that there is no significant association between Ozempic and suicide. These findings are reassuring but further monitoring and surveillance is needed to monitor its safety.
Previous studies have shown clear benefits of lifestyle intervention for the prevention of type 2 diabetes. Since then advances in gene technology have allowed researchers to identify more than 500 genetic variants that predispose individuals to type 2 diabetes. However, lifestyle factors are also important determinants of increased risk of developing type 2 diabetes. Whether type 2 diabetes can be prevented by lifestyle changes among individuals carrying numerous genetic variants that predispose them to type 2 diabetes however is not known. To clarify this, a new study from the University of Eastern Finland is the first to show that a healthy diet and regular exercise reduce the risk of type 2 diabetes even in individuals with a high genetic risk.1
The T2D-GENE trial was a three-year lifestyle intervention that involved 973 men with the Metabolic Syndrome, aged 50–75 years, body mass index ≥25 kg/m2, fasting plasma glucose 5.6–6.9 mmol/L and haemoglobin A1c < 48 mmol/mol. Genetic risk was determined based on 76 gene variants known to predispose to type 2 diabetes. There were 2 intervention groups, a low (n = 315) and high genetic risk for Type 2 Diabetes (n = 313), and the remaining participants served as a control group. Men in the intervention group were provided with a 3-year group-based intervention with access to a web portal focused on healthy diet and physical activity. The corresponding population-based control groups have low (n = 196) and high (n = 149) genetic risk for Type 2 Diabetes and received general health advice similar to the intervention group.
Men participating in the lifestyle intervention increased their intake of dietary fibre, improved the quality of fats in their diet and increased their consumption of vegetables, fruits and berries.
The intervention significantly lowered the risk of Type 2 Diabetes among the participants with a high genetic risk for T2D by 70%, whereas in the low genetic risk group the effect was not significant. The intervention effect was not significantly different between the high and low genetic risk groups (p = .135). The intervention significantly prevent the worsening of glucose levels and decreased weight both in the low and high genetic risk groups.
The study therefore was the first to show that individuals with a high genetic risk for T2D benefitted from a simple group-based intervention programme focusing on healthy diet and physical activity.
Tirzepatide is a novel, dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) analogue. Studies have shown superiority of Tirzepatide compared with Semaglutide, a once weekly GLP-1 agonist in reducing HbA1c and weight, but whether these metabolic improvements lead to improvements in cardiovascular and kidney outcomes remains unclear. Semaglutide meanwhile has been shown to reduce cardiovascular events and reduce risk of heart failure progression in patients with or without type 2 diabetes.1, 2 There is currently no studies which have directly compared tirzepatide with GLP-1 RAs.
In view of this, the publication in the journal JAMA Network Open comparing the cardio-renal benefits of Tirzepatide versus Semaglutide in people with type 2 diabetes is welcoming.3
This was retrospective cohort study using US Collaborative Network of TriNetX data and collected clinical information of individuals with type 2 diabetes aged 18 years. Patients with stage 5 chronic kidney disease or kidney failure at baseline; myocardial infarction or ischemic or hemorrhagic stroke within 60 days of drug initiation were excluded. The primary outcome was all-cause mortality, and secondary outcomes included major adverse cardiovascular events (MACEs), the composite of MACEs and all-cause mortality, kidney events, acute kidney injury, and major adverse kidney events.
14 834 patients treated with tirzepatide and 125 474 treated with GLP-1 RA were analysed. Mean age was 58.1 years. After a median follow-up of 10.5 months, 95 patients (0.6%) in the tirzepatide group and 166 (1.1%) in the GLP-1 RA group died. Tirzepatide treatment was associated with a 42% lower risk of all-cause mortality, 20% lower risk of Major Adverse Cardiovascular events (MACE) and 24% reduced risk of combined all-cause mortality and MACE. Kidney events was also reduced by 48%, acute kidney injury by 22% and major adverse kidney events by 46% with Tirzepatide compared with Semaglutide. Perhaps unexpectedly, treatment with tirzepatide was also associated with greater decreases in glycated haemoglobin (treatment difference, −0.34 percentage points) and body weight (treatment difference, −2.9 kg compared with semaglutide. An interaction test for subgroup analysis revealed consistent results when stratified by estimated glomerular filtration rate, glycated haemoglobin level, body mass index, concurrent therapies and comorbidities.
While this is a retrospective study with its usual caveat and limitations – namely allocation bias and residual confounders, evidence from this study provide novel and preliminary evidence of the effectiveness of Tirzepatide when used in routine clinical practice compared with Semaglutide. I look forward to evidence of cardio-renal benefits of Tirzepatide in a randomized clinical trial setting, especially when compared with high dose Semaglutide at 2.4 mg once weekly.
Obstructive sleep apnoea (OSA) is highly prevalent in patients with obesity with or without type 2 diabetes. Data from the American diabetes Association reported that around 40% of patients with obesity have OSA. Continuous Positive Airway pressure (CPAP) is an effective and the most-used intervention for OSA, but many patients may not be able to tolerate the device or stop using it. Tirzepatide a dual GLP-1 GIP agonist has been shown to induce significant weight loss and improve glycaemic control in people with type 2 diabetes. Whether the weight loss induced by Tirzepatide could positively affect the severity and improve outcome in people with OSA however remains unclear.
To clarify this, SURMOUNT-OSA was undertaken. This was a combination of two phase 3, multi-center, randomized, double-blind, parallel, placebo-master protocol studies, comparing the efficacy and safety of tirzepatide to placebo in adults living with moderate-to-severe obstructive sleep apnea and obesity who were unable or unwilling to use CPAP (Study 1) and those who were and planned to stay on CPAP therapy during the duration of the trial (Study 2). The trials randomized 469 participants from 60 sites across 9 countries, in a 1:1 ratio to receive tirzepatide maximum tolerated dose 10 mg or 15 mg or placebo. The primary objective of both studies was to demonstrate that tirzepatide is superior in change in apnea-hypopnea index (AHI) from baseline at 52 weeks as compared to placebo. The study was published online in the New England J of Medicine.1
Patients were enrolled if they had moderate-to-severe OSA, defined as more than 15 events per hour (using the AHI and a body mass index of 30 kg/m2 or greater. In study 1, 114 individuals received tirzepatide and 120 received placebo. For study 2, 119 patients received tirzepatide and 114 received placebo. All participants received regular lifestyle counselling sessions about nutrition and were instructed to reduce food intake by 500 kcal/day and to engage in at least 150 min/week of physical activity.
At baseline, 65%–70% of participants had severe OSA, with more than 30 events/hour on the AHI scale and a mean of 51.5 events/h in study 1 and 49.5 in study 2.
By 1 year, patients taking tirzepatide had 27–30 fewer events/hour compared with 4–6 fewer events/hour for those taking placebo. Up to half of those who received tirzepatide in both trials had less than 5 events/h or 5–14 AHI events/h and an Epworth Sleepiness Scale score of 10 or less. This translate to around 40%–50% of patient who were no longer required to use CPAP therapy for the management of their OSA. Patients who received tirzepatide also reported fewer daytime and night-time disturbances, as measured using the Patient-Reported Outcomes Measurement Information System Short Form scale for Sleep-Related Impairment and Sleep Disturbance. Patients in the tirzepatide group also had a decrease in systolic blood press
Previous evidence have reported an risk of retinopathy progression following rapid reduction of Hba1c level (~2.5%) with Semaglutide.1 At risk patients were those who had high baseline HbA1c, long diabetes duration or had evidence of significant diabetic retinopathy prior to treatment initiation. A recent study have raised new evidence linking Semaglutide with an increased risk of developing, nonarteritic anterior ischemic optic neuropathy, an uncommon condition that can cause vision loss.2
This was a retrospective data base analysis involving 16 827 patients at Massachusetts Eye and Ear in Boston. Despite the large number, their analysis only focuses on 710 patients with type 2 diabetes (194 of whom had been prescribed semaglutide) and 979 patients with overweight or obesity (361 prescribed semaglutide). The researchers compared patients prescribed semaglutide with those prescribed a medication other than a GLP-1 agent. They matched patients by factors such as age and sex and whether they had hypertension, obstructive sleep apnea, or coronary artery disease. Cumulative incidence of nonarteritic anterior ischemic optic neuropathy (NAION) were assessed during 36 months of follow-up.
The study showed that Semaglutide use was associated with a 4.3 fold increased risk for NAION in patients with type 2 diabetes and 7.6 fold increased risk in patients with overweight or obesity. Among patients with type 2 diabetes, the cumulative incidence of NAION over 36 months was 8.9% for those prescribed semaglutide versus 1.8% among those taking non-GLP-1 medications. For patients with overweight or obesity, the cumulative incidence of NAION over 36 months was 6.7% for the semaglutide cohort versus 0.8% for those in the other group.
The study has significant limitations. First it is a retrospective study. As such evidence derived from this may not be fully adjusted for residual confounders. Specifically, the study did not adjust for baseline or cumulative HbA1c or diabetes duration—two important factors which determine risk of retinopathy progression. The results were driven by a relatively small number of NAION cases in the patients exposed to semaglutide. The study does not establish that semaglutide directly causes NAION, but rather provide an association which needs to be tested in larger clinical trials or a post-market analysis of all GLP-1 RA drugs. The generalizability of the study is also unclear since the study was undertaken from patients which attend a specialist eye hospital. Interestingly, since risk of NAION was also seen in people without Type 2 diabetes, the potential mechanism for increased risk of NAION is unlikely to be driven by rapid lowering of HbA1c levels as reported in SUSTAIN-6.1
In clinical practise, the evidence form this study, in my opinion should not detract the continued use of semaglutide—given its well-recognized benefits in improv
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