Metformin and Cancer: Solutions to a Real-World Evidence Failure.

The quest to repurpose metformin, an antidiabetes drug, as an agent for cancer prevention and treatment, which began in 2005 with an observational study that reported a reduction in cancer incidence among metformin users, generated extensive experimental, observational, and clinical research. Experimental studies revealed that metformin has anticancer effects via various pathways, potentially inhibiting cancer cell proliferation. Concurrently, multiple nonrandomized observational studies reported remarkable reductions in cancer incidence and outcomes with metformin use. However, these studies were shown, in 2012, to be affected by time-related biases, such as immortal time bias, which tend to greatly exaggerate the benefit of a drug. The observational studies that avoided these biases did not find an association. Subsequently, the randomized trials of metformin for the treatment of type 2 diabetes and as adjuvant therapy for the treatment of various cancers, advanced or metastatic, did not find reductions in cancer incidence or outcomes. Most recently, the largest phase 3 randomized trial of metformin as adjuvant therapy for breast cancer, which enrolled 3,649 women with a 5-year follow-up, found no benefit for disease-free survival or overall survival with metformin. This major failure of observational real-world evidence studies in correctly assessing the effects of metformin on cancer incidence and outcomes was caused by preventable biases which, surprisingly, are still prominent in 2022. Rigorous approaches for observational studies that emulate randomized trials, such as the incident and prevalent new-user designs along with propensity scores, avoid these biases and can provide more accurate real-world evidence for the repurposing of drugs such as metformin.

Selective serotonin reuptake inhibitors and the risk of type 2 diabetes mellitus in youths.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have been associated with type 2 diabetes mellitus (T2DM) in youths, possibly via 5-HT2C, H1 receptors and serotonin transporter (SERT). SSRIs have similar affinity for SERT but variable affinity for 5-HT2C and H1. This study assessed whether SSRIs with strong affinity for 5-HT2C and H1 (relative to SERT) were associated with T2DM risk compared with weak-affinity SSRIs. METHODS: Using the UK Clinical Practice Research Datalink, we assembled a cohort of patients aged 5-24, newly prescribed a strong-affinity SSRI (citalopram, escitalopram, fluoxetine) or weak affinity (paroxetine, sertraline, fluvoxamine) between 1990 and 2019. We controlled for confounding using standardized mortality ratio weighting, estimated from calendar time-specific propensity scores. We used weighted Cox proportional hazards models to estimate hazard ratios (HRs) of incident T2DM with 95 % confidence intervals (CIs). RESULTS: The cohort included 347,368 new users of strong-affinity SSRIs and 131,359 of weak-affinity SSRIs. Strong-affinity SSRIs were not associated with an increased T2DM risk compared with weak-affinity SSRIs (incidence rate 2.8 vs 2.7 per 1000 person-years; HR 1.03, 95 % CI 0.85-1.25). T2DM risk did not vary with duration of use, age or sex. However, the HR was numerically higher in youths with normal or low weight (HR 1.30, 95 % CI 0.85-1.98) and with prior antipsychotic use (HR 1.62, 95 % CI 0.83-3.18). LIMITATIONS: Median duration of SSRI use, in line with real-world SSRI prescribing, was relatively short. CONCLUSION: T2DM risk did not differ between strong- and weak-affinity SSRIs, providing reassurance for clinicians when choosing between SSRIs in youths.

Atorvastatin lowers serum calcium levels in lithium-users: results from a randomized controlled trial.

BACKGROUND: Although lithium is considered the gold-standard treatment for bipolar disorder (BD), it is associated with a variety of major endocrine and metabolic side effects, including parathyroid hormone (PTH) dependent hypercalcemia. Aside from surgery and medication discontinuation, there are limited treatments for hypercalcemia. This paper will assess data from a randomized controlled trial (RCT). METHODS: This is a secondary analysis of an RCT that explored the effects of atorvastatin (n = 27) versus placebo (n = 33) on lithium-induced nephrogenic diabetes insipidus (NDI) in patients with BD and major depressive disorder (MDD) using lithium (n = 60), over a 12-week period. This secondary analysis will explore serum calcium levels and thyroid stimulating hormone (TSH) measured at baseline, week 4, and week 12. RESULTS: At 12-weeks follow-up while adjusting results for baseline, linear regression analyses found that corrected serum calcium levels were significantly lower in the treatment group (mean (M) = 2.30 mmol/L, standard deviation (SD) = 0.07) compared to the placebo group (M = 2.33 mmol/L, SD = 0.07) (ß = - 0.03 (95% C.I.; - 0.0662, - 0.0035), p = 0.03) for lithium users. There were no significant changes in TSH. CONCLUSION: In lithium users with relatively normal calcium levels, receiving atorvastatin was associated with a decrease in serum calcium levels. Although exciting, this is a preliminary finding that needs further investigation with hypercalcemic patients. Future RCTs could examine whether atorvastatin can treat PTH dependent hypercalcemia due to lithium and other causes.

Long-term clinical outcomes of oral antidiabetic drugs as fixed-dose combinations: A nationwide retrospective cohort study.

AIM: To compare treatment patterns and clinical outcomes of single-pill fixed-dose combination (FDC) and two-pill combination (TPC) therapies using real-world data. METHODS: We conducted a nationwide retrospective cohort study using South Korea's healthcare database (2002-2015). We identified two cohorts of incident patients with type 2 diabetes who initiated FDC or TPC therapy within 4 months of their first prescription for metformin or sulphonylurea. We examined persistence and adherence patterns and the clinical outcome of a composite endpoint of death or hospitalization for acute myocardial infarction, heart failure or stroke and compared the differences in treatment patterns and clinical outcomes using Cox models. RESULTS: Of 5143 and 10 973 patients who initiated FDC and TPC therapy, respectively, we identified 5143 patient pairs after propensity score matching. The FDC group exhibited greater median time to treatment discontinuation (163 vs. 146 days), and proportion of days covered at 12 months (mean 0.60 vs. 0.57, P < .0001) and at 24 months (0.53 vs. 0.51, P = .014) than the TPC group. The FDC group, compared with the TPC group, had reduced risks of the composite clinical outcome (hazard ratio 0.86, 95% confidence intervals 0.77-0.97) and hospitalization for stroke (0.80, 0.67-0.96). CONCLUSION: FDC therapy may provide favourable cardiovascular benefits, especially reducing the risk of hospitalization for stroke, and has better medication adherence among patients with type 2 diabetes.

The association of long-acting insulin analogue use versus neutral protamine Hagedorn insulin use and the risk of major adverse cardiovascular events among individuals with type 2 diabetes: A population-based cohort study.

AIMS: To compare the risk of cardiovascular outcomes associated with long-acting insulin analogues versus neutral protamine Hagedorn (NPH) insulin among patients with type 2 diabetes. MATERIALS AND METHODS: We conducted a population-based retrospective cohort study using the UK Clinical Practice Research Datalink Aurum, linked with hospitalization and vital statistics data. Patients with type 2 diabetes who initiated basal insulin treatment between 2002 and 2018 were included in the study. Exposure was defined as current use of long-acting insulin analogues or NPH insulin, defined using a time-varying approach. The primary outcome was major adverse cardiovascular events (MACE; a composite endpoint of myocardial infarction, ischaemic stroke and cardiovascular death). We used a marginal structural Cox proportional hazards model to estimate the hazard ratio (HR) and 95% confidence interval (CI) for MACE with current use of long-acting insulin analogues versus NPH insulin, and in secondary analyses, by long-acting insulin molecule. RESULTS: Our cohort included 57 334 patients. A total of 3494 MACE occurred over a mean follow-up of 1.6 years (incidence rate 37.4, 95% CI 36.2 to 38.7 per 1000 person-years). Long-acting insulin analogues were associated with a decreased risk of MACE compared to NPH insulin (HR 0.89, 95% CI 0.83 to 0.96). CONCLUSIONS: Current use of long-acting insulin analogues is associated with a modestly reduced risk of MACE compared to current use of NPH insulin among patients with type 2 diabetes. This study could have important implications for drug plan managers and guideline-writing committees for recommendations of insulin treatment for type 2 diabetes.

Effectiveness and Safety of Apixaban versus Rivaroxaban in Patients with Atrial Fibrillation and Type 2 Diabetes Mellitus.

AIMS: To evaluate the effectiveness and safety of apixaban versus rivaroxaban among patients with nonvalvular atrial fibrillation (NVAF) and type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: Using the United Kingdom's Clinical Practice Research Datalink linked to the Hospital Episode Statistics repository, and the Office for National Statistics database, we identified a cohort of patients with NVAF and T2DM newly treated with apixaban or rivaroxaban between 2013 and 2020. Propensity scores with standardized mortality ratio weighting were used to control for confounding. We used weighted Cox proportional hazards models to estimate separately the hazard ratios (HRs) with 95% confidence intervals (CIs) of ischemic stroke, major bleeding, and major adverse limb events associated with the use of apixaban compared with rivaroxaban. We also evaluated whether the risk was modified by age, sex, duration of diabetes, microvascular and macrovascular complications of diabetes, nephropathy, CHA2DS2-VASc and HAS-BLED scores, and by dose (standard vs. low dose). RESULTS: The cohort included 11,561 apixaban and 8,265 rivaroxaban users. Apixaban was associated with a similar risk of stroke (HR: 0.99, 95% CI: 0.79-1.23), and a 32% reduced risk of major bleeding (HR: 0.68, 95% CI: 0.59-0.78), compared with rivaroxaban. The risk of major adverse limb events was similar between apixaban and rivaroxaban (HR: 0.75, 95% CI: 0.54-1.04). Overall, the risk of ischemic stroke and major bleeding was consistent in stratified analyses. CONCLUSION: Among patients with NVAF and T2DM, apixaban was associated with a similar risk of stroke and a lower risk of major bleeding compared with rivaroxaban.

The association between glycaemic control during hospitalization and risk of adverse events: A retrospective cohort study.

INTRODUCTION: Hyperglycaemia is common during hospitalization; glycaemic targets in non-critical care settings have not been well studied. We assessed associations between inpatient glycaemic control and adverse events. METHODS: We conducted a retrospective cohort study on non-critically ill medical patients hospitalized in a tertiary care hospital between 2015 and 2018. Mean glycaemia during the first four days of hospitalization was categorized as 4.0-7.0 mmol/L, 7.1-10.0 mmol/L and >10.0 mmol/L. The primary outcome was a composite of adverse events including mortality, infections, acute kidney injury, thromboembolic and cardiovascular events. The secondary outcome was hypoglycaemia, defined as any glycaemia <4.0 mmol/L. Logistic regression was used to assess adverse events, and a Cox proportional hazards model was used to estimate hypoglycaemia risk. RESULTS: Our cohort included 1,368 patients, of whom 407 (29.8%) experienced an adverse event. We did not find associations between glycaemia of 4.0-7.0 mmol/L (adjusted odds ratio [OR]: 0.88, 95% confidence interval [CI]: 0.63-1.23) or glycaemia of >10.0 mmol/L (adjusted OR: 0.98, 95% CI: 0.75-1.28) and the occurrence of adverse events, compared to a glycaemia of 7.1-10.0 mmol/L. Glycaemia of >10.0 mmol/L was associated with an increased risk of hypoglycaemia (adjusted hazard ratio [HR]: 1.72, 95% CI: 1.21-2.45). Hypoglycaemia was associated with adverse events (adjusted OR 1.85, 95% CI 1.31-2.60). CONCLUSIONS: Neither glycaemia of 4.0-7.0 mmol/L nor glycaemia of >10.0mmol/L during non-critical care hospitalization was associated with increased adverse events. Glycaemia of >10.0 mmol/L was associated with increased hypoglycaemia, likely due to aggressive glucose lowering. These findings highlight the need for further studies to discern optimal inpatient glycaemic targets.

Levothyroxine and the risk of adverse pregnancy outcomes in women with subclinical hypothyroidism: a systematic review and meta-analysis.

BACKGROUND: Levothyroxine replacement therapy may decrease the risk of adverse pregnancy outcomes among women with subclinical hypothyroidism (SCH). The aim of this study is to conduct a systematic review and meta-analysis to examine the risk of adverse pregnancy, perinatal, and early childhood outcomes among women with SCH treated with levothyroxine. METHODS: A systematic literature search was conducted using Ovid-Medline, Ovid-EMBASE, Pubmed (non-Medline), Ebsco-CINAHL Plus with full text and Cochrane Library databases. Randomized controlled studies (RCTs) and observational studies examining the association between treatment of SCH during pregnancy and our outcomes of interest were included. Studies that compared levothyroxine treatment versus no treatment were eligible for inclusion. Data from included studies were extracted and quality assessment was performed by two independent reviewers. RESULTS: Seven RCTs and six observational studies met our inclusion criteria. A total of 7342 individuals were included in these studies. RCTs demonstrated several sources of bias, with lack of blinding of the participants or research personnel; only one study was fully blinded. In the observational studies, there was moderate to serious risk of bias due to lack of adjustment for certain confounding variables, participant selection, and selective reporting of results. Pooled analyses showed decreased risk of pregnancy loss (RR: 0.79; 95% CI: 0.67 to 0.93) and neonatal death (RR: 0.35; 95% CI: 0.17 to 0.72) associated with levothyroxine treatment during pregnancy among women with SCH. There were no associations between levothyroxine treatment and outcomes during labour and delivery, or cognitive status in children at 3 or 5 years of age. CONCLUSION: Treatment of SCH with levothyroxine during pregnancy is associated with decreased risks of pregnancy loss and neonatal death. Given the paucity of available data and heterogeneity of included studies, additional studies are needed to address the benefits of levothyroxine use among pregnant women with SCH.

Corrigendum to "A Case of Severe Acute Kidney Injury Exacerbated by Canagliflozin in a Patient with Type 2 Diabetes".

[This corrects the article DOI: 10.1155/2019/8639629.].

SGLT-2 inhibitors and the risk of hospitalization for community-acquired pneumonia: A population-based cohort study.

PURPOSE: Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) have been associated with an increased risk of genitourinary tract infections. Through similar biological mechanisms, they may also increase the risk of community-acquired pneumonia. Our objective was to compare the rate of hospitalization for community-acquired pneumonia (HCAP) with SGLT-2i compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) among patients with type 2 diabetes. METHODS: We used the United Kingdom's Clinical Practice Research Datalink Gold, linked to hospitalization data, to construct a cohort of patients with type 2 diabetes. Using a time-dependent Cox proportional hazards model, we estimated the adjusted hazard ratio (HR) for HCAP with current use of SGLT-2i versus DPP-4i. RESULTS: Among 29 896 patients, 705 HCAPs occurred over a mean follow-up of 1.7 years (SD: 1.2). Incidence rates for SGLT-2i and DPP-4i users were 6.2 (95% confidence interval [CI]: 3.7, 10.2) and 17.8 (95% CI: 15.3, 20.7) per 1000 person-years, respectively. Current use of SGLT-2i was associated with a decreased risk of HCAP compared to current use of DPP-4i (adjusted HR: 0.48, 95% CI: 0.28, 0.82). However, a comparison of SGLT-2i versus glucagon-like peptide-1 receptor agonists (GLP-1 RA) found no difference in risk of HCAP (adjusted HR: 0.94, 95% CI: 0.44, 1.89). CONCLUSIONS: SGLT-2i are associated with a decreased rate of HCAP compared to DPP-4i, but not when compared to GLP-1 RA, among patients with type 2 diabetes.

Type 2 diabetes mellitus and risk of community-acquired pneumonia: a systematic review and meta-analysis of observational studies.

BACKGROUND: People with type 2 diabetes are at greater risk for infections than those without type 2 diabetes. Our objective was to examine the association between type 2 diabetes and the risk of community-acquired pneumonia (CAP). METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, CINAHL, ProQuest theses and dissertations, Global Health, the Global Index Medicus of the World Health Organization, and Google Scholar. We included observational studies published in English or French between Jan. 1, 1946 (start of MEDLINE) and July 18, 2020. Two independent reviewers extracted data and assessed quality using the ROBINS-I tool. DerSimonian-Laird random-effects models were used to pool estimates of the association between type 2 diabetes and CAP. RESULTS: Our systematic review included 15 articles, reporting on 13 cohort studies and 4 case-control studies (14 538 968 patients). All studies reported an increased risk of pneumonia among patients with type 2 diabetes, and all were at serious risk of bias. When estimates were pooled across studies, the pooled relative risk was 1.64 (95% confidence interval [CI] 1.55-1.73); although there was a substantial amount of relative heterogeneity (I 2 94.2), the amount of absolute heterogeneity was more modest (T2 0.008). The relative risk was 1.70 (95% CI 1.63-1.77, I 2 85.2%, T2 0.002) among cohort studies (n = 13), and the odds ratio was 1.54 (95% CI 1.14-2.09, I 2 92.7%, T2 0.07) among case-control studies (n = 4). INTERPRETATION: Type 2 diabetes may be associated with an increased risk of CAP; however, the available evidence is from studies at serious risk of bias, and additional, high-quality studies are needed to confirm these findings. PROSPERO REGISTRATION: CRD42018116409.

Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Below-Knee Amputation: A Multicenter Observational Study.

OBJECTIVE: Reports of amputations associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors have been inconsistent. We aimed to compare the risk of below-knee amputation with SGLT2 inhibitors versus dipeptidyl peptidase 4 (DPP-4) inhibitors among patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This multicenter observational study used administrative health care databases from seven Canadian provinces and the U.K. Incident SGLT2 inhibitor users were matched to DPP-4 inhibitor users using a prevalent new-user design and time-conditional propensity scores. Cox proportional hazards models were used to estimate site-specific adjusted hazard ratios (HR) and corresponding 95% CIs of incident below-knee amputation for SGLT2 inhibitor versus DPP-4 inhibitor users. Random effects meta-analyses were used to pool the site-specific results. RESULTS: The study cohort included 207,817 incident SGLT2 inhibitor users matched to 207,817 DPP-4 inhibitor users. During a mean exposed follow-up time of 11 months, the amputation rate was 1.3 per 1,000 person-years among SGLT2 inhibitor users and 1.5 per 1,000 person-years among DPP-4 inhibitor users. The adjusted HR of below-knee amputations associated with SGLT2 inhibitor use compared with DPP-4 inhibitor use was 0.88 (95% CI 0.71-1.09). Similar results were obtained in stratified analyses by specific SGLT2 inhibitor molecule. CONCLUSIONS: In this large multicenter observational study, there was no association between SGLT2 inhibitor use and incident below-knee amputations among patients with type 2 diabetes compared with DPP-4 inhibitor use. While these findings provide some reassurance, studies with a longer duration of follow-up are needed to assess potential long-term effects.

Subclinical hypothyroidism and the risk of cancer incidence and cancer mortality: a systematic review.

BACKGROUND: Thyroid hormone has been shown to be involved in carcinogenesis via its effects on cell proliferation pathways. The objective of this study is to determine the association between subclinical hypothyroidism (SCH) and the risk of incident cancer and cancer mortality via systematic review. METHODS: A systematic search was performed on Medline and Pubmed to identify relevant studies. Randomized controlled trials, and observational studies assessing SCH or its treatment and the risk of incident cancer or cancer mortality were identified. RESULTS: A total of 7 cohort and 2 case-control studies met our inclusion criteria. In general, these studies were of medium to good quality. Overall, studies revealed no association between SCH and breast and prostate cancer. One study found that untreated SCH may be associated with an increased risk of colorectal cancer (adjusted odds ratio [OR]: 1.16; 95% confidence interval [CI]: 1.08-1.24). One study showed an increased risk in thyroid cancer incidence (adjusted OR: 3.38; 95% CI: 2.05-5.59) associated with elevation of a thyroid stimulating hormone (TSH) of > 1.64mIU/L. Two studies found an increase in cancer mortality among patients with SCH compared to euthyroid individuals; in contrast one study found no association between subclinical hypothyroidism and cancer mortality among aging men. CONCLUSION: The number of studies examining thyroid dysfunction and cancer risk and mortality is limited. Future studies assessing the association between thyroid dysfunction and cancer risk and mortality are needed, which will further address the need to treat subclinical hypothyroidism.

Comparative cardiovascular and hypoglycaemic safety of glimepiride in type 2 diabetes: A population-based cohort study.

AIM: To assess the incidence of cardiovascular and hypoglycaemic adverse events associated with glimepiride compared with other second-generation sulphonylureas among patients with type 2 diabetes in a real-world clinical setting. MATERIALS AND METHODS: We identified all sulphonylurea initiators between 1998 and 2017 in the UK Clinical Practice Research Datalink. Using a prevalent new-user design, glimepiride initiators were matched 1:4 with initiators of other second-generation sulphonylureas on calendar time, prior sulphonylurea use, and time-conditional high-dimensional propensity score. Cox proportional hazards models yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for myocardial infarction, ischaemic stroke, severe hypoglycaemia, cardiovascular death, and all-cause mortality. RESULTS: Among 66 032 sulphonylurea new users, 6438 initiated glimepiride and were matched to up to 20 582 initiators of other second-generation sulphonylureas. During a mean follow-up of 1.3 years, glimepiride was associated with a similar incidence of myocardial infarction (HR 0.99, 95% CI 0.75-1.30) and ischaemic stroke (HR 0.96, 95% CI 0.72-1.27) compared with other second-generation sulphonylureas, while there was a non-significant trend towards a higher incidence of severe hypoglycaemia (HR 1.24, 95% CI 0.92-1.68). Glimepiride was also associated with a lower incidence of all-cause mortality (HR 0.77, 95% CI 0.67-0.89), and a non-significant but similar trend for cardiovascular death (HR 0.83, 95% CI 0.65-1.05). CONCLUSIONS: Glimepiride was associated with a lower incidence of all-cause mortality compared with other second-generation sulphonylureas.

A Case of Severe Acute Kidney Injury Exacerbated by Canagliflozin in a Patient with Type 2 Diabetes.

BACKGROUND: Sodium glucose cotransport (SGLT)-2 inhibitors are the newest class of antihyperglycemic agents used as second- or third-line treatment in the management of type 2 diabetes. Although the use of SGLT-2 inhibitors has not been shown to cause nephrotoxicity, there have been case reports of SGLT-2 inhibitor use being associated with acute kidney injury. CASE PRESENTATION: A 72-year-old woman with a history of type 2 diabetes and no known chronic renal insufficiency presented to the emergency room with a 3-day history of nausea, vomiting, and increased somnolence. She was found to have potassium level of 7.4 (normal: 3.5-5.5) mmol/L and a markedly elevated creatinine level at 1154 (normal: 45-95) µmol/L. Imaging of the abdomen and pelvis did not reveal any findings of obstruction. Urine microscopy showed many granular casts. In the absence of other causes for her clinical presentation, the patient was diagnosed with acute kidney injury secondary to ischemic acute tubular necrosis, with canagliflozin use likely an important contributing factor. CONCLUSIONS: Physicians should inform patients to stop the use of SGLT-2 inhibitors when patients are unable to maintain hydration or during acute illness. Use of SGLT-2 inhibitors in managing type 2 diabetes should be done with caution among more vulnerable populations, including individuals with cognitive impairment and the elderly.