Diabetes is a risk factor for dementia, but whether antidiabetic medication decreases the risk is unclear. We examined the association between antidiabetic medication and dementia.
We performed a ...nested case-control study within a cohort of all 176 250 patients registered with type 2 diabetes in the Danish National Diabetes Register between 1995 and 2012. This population was followed for dementia diagnosis or anti-dementia medication use until May 2018. Using risk-set sampling, each dementia case (n = 11 619) was matched on follow-up time and calender year of dementia with four controls randomly selected among cohort members without dementia (n = 46 476). Ever use and mean daily defined dose of antidiabetic medication was categorized in types (insulin, metformin, sulfonylurea and glinides combined, glitazone, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP1) analogs, sodium-glucose transport protein 2 (SGLT2) inhibitors and acarbose).
Conditional logistic regression models were fitted to calculate odds ratios (ORs) for dementia associated with antidiabetic medication use, adjusting for potential confounders.
Use of metformin, DPP4 inhibitors, GLP1 analogs, and SGLT2 inhibitors were associated with lower odds of dementia after multible adjustments (ORs of 0.94 (95% confidence interval (CI): 0.89-0.99), 0.80 (95% CI 0.74-0.88), 0.58 (95% CI: 0.50-0.67), and 0.58 (95% CI: 0.42-0.81), respectively), with a gradual decrease in odds of dementia for each increase in daily defined dose. Analyses of the most frequent treatment regimes did not show any synergistic effects of combined treatment.
Use of metformin, DPP4 inhibitors, GLP1 analogs and SGLT2 inhibitors was associated with lower risk of dementia in patients with diabetes.
Depression and cardiovascular diseases (CVDs) are common diseases and associated in a bidirectional manner.
To examine whether a bidirectional association between CVD and depression could be ...explained by shared risk factors, misclassification of disease measures or non-response.
A total of 10 population-based cohorts including 93 076 men and women (mean age 54.4 years, s.d. = 9.2) and an additional 10 510 men (mean age 51.2 years, s.d. = 0.3) were followed for subsequent depression, ischaemic heart disease (IHD) and stroke in the Danish National Patient Registry from health examinations between 1982 and 2015 and until end of follow-up in 2017-2018. Exposures were physicians' diagnoses of IHD, stroke, depression or self-reported chest pain, depression, use of antidepressant medication and the Major Depression Inventory at the time of study entry in the Metropolit study. Associations were analysed using Cox proportional hazard regression with disease as time-dependent variables.
IHD and stroke were associated with subsequent depression (hazard ratio (HR) for IHD: 1.79, 95% CI 1.43-2.23 and HR for stroke: 2.62, 95% CI 2.09-3.29) and the associations were present in both men and women. Adjustment for the shared risk factors socioeconomic status, lifestyle, body mass index, statin use and serum lipids did not change the risk estimates. Furthermore, depression was associated with higher risk of subsequent IHD (HR = 1.63, 95% CI 1.36-1.95) and stroke (HR = 1.94, 95% CI 1.63-2.30). The associations were also present when the analyses were based on self-reported disease measures or restricted to include non-responders.
The bidirectional association between CVD and depression was not explained by shared risk factors, misclassification or non-response.
The long-term effects of electroconvulsive therapy (ECT) on the risk of stroke are unknown. We examined the association between ECT and risk of incident or recurrent stroke. A cohort of 174 534 ...patients diagnosed with affective disorder between 2005 and 2016 in the Danish National Patient Registry were followed for stroke until November 2016. The association between ECT and stroke was analysed using Cox regression with multiple adjustment and propensity-score matching on sociodemographic and clinical variables. In 162 595 patients without previous stroke, 5781 (3.6%) were treated with ECT. The total number of patients developing stroke during follow-up was 3665, of whom 165 had been treated with ECT. In patients <50 years, ECT was not associated with stroke (adjusted hazard ratio (HR) = 1.29, 95% CI 0.87-1.93). In patients ≥50, ECT was associated with a lower risk of stroke (adjusted HR = 0.69, 95% CI 0.57-0.89), but this estimate was likely influenced by competing mortality risk. Of 11 939 patients with a history of stroke, 228 (1.9%) were treated with ECT. During follow-up, 2330 (19.5%) patients had a recurrence, of which 26 were patients treated with ECT. ECT was not associated with risk of a new event (HR = 0.69, 95% CI 0.46-1.00; P = 0.05). ECT is not associated with an elevated risk of incident or recurrent stroke.Declaration of interestNone.
Diabetes type 2 is associated with depression, but the impact of antidiabetic drugs is not clear. The objective was to analyze the association between diabetes type 2, antidiabetic drugs, and ...depression.
This register-based study included 116.699 patients with diabetes type 2 diagnosed from 2000 to 2012 and an age, gender, and municipality matched reference group of 116.008 individuals without diabetes. All participants were followed for a diagnosis of depression or prescription of antidepressant medication. Based on this, a case-control study was nested within the cohort, using risk set sampling. Antidiabetic medication was categorized into insulin, metformin, sulfonylureas and glinides combined, glitazones, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP1) analogs, sodium-glucose transport protein 2 (SGLT2) inhibitors and acarbose. The association between diabetes and depression was analyzed using Cox proportional hazards regression, whereas conditional logistic regression was used to analyze the association between use of antidiabetic drugs and depression.
Patients with diabetes had higher risk of depression compared to individuals without diabetes (hazard ratio 1.14 (95% confidence interval 1.14–1.15)). Low doses of metformin, DPP4 inhibitors, GLP1 analogs, and SGLT2 inhibitors were associated with lower risk of depression in patients with diabetes compared to non-users, with the lowest risk for sodium-glucose transport protein 2 inhibitor users (odds ratio 0.55 (0.44–0.70)). Use of insulin, sulfonylurea and high doses of metformin were associated with higher risk of depression.
Patients with diabetes had increased risk of depression. However, users of specific antidiabetic drugs had lower risk of depression compared to non-users.
•Danish patients with diabetes type 2 had a 14% higher risk of later depression.•Use of metformin, DPP4 inhibitors, GLP1 analogs, and SGLT2 inhibitors were associated with lower depression risk.•Higher doses of insulin and sulfonylurea were associated with higher risk of depression.
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•Reduced ATP or oxygen availability is common in depression models, human depression, and depression risk factors.•Capillary dysfunction can cause tissue hypoxia, even when blood ...supply is inconspicuous.•Tissue hypoxia triggers inflammation, affecting capillary function in other organs.•Inflammatory cytokines and tissue hypoxia interfere with neurotransmitter synthesis.•Early life stress may predispose to depression and other diseases in later life by damaging the splanchnic microcirculation.•Capillary function and neurogenic blood flow affect brain oxygenation, and whether functional neuroimaging truly detects changes in neuronal activity.
Are energy demands too high, or our energy resources either too low or inappropriately prioritized, as we develop stress and/or depression? We review evidence of dysregulated cellular energy homeostasis and energy depletion in stress and depression, identifying factors that might limit energy substrate availability. Resetting of cellular energy-sensors, splanchnic hypoxia, and catecholamine effects on blood viscosity emerge as mechanisms that might disrupt normal energy homeostasis, accelerate cell injury, and cause depression-like symptoms in severe or prolonged stress. In particular, a vicious cycle of capillary dysfunction, cellular hypoxia, and inflammation emerges as a mechanism, by which prolonged stress might accelerate the development of diseases, including depression, in later life. Oxygen is a substrate for both serotonin- and ATP-synthesis, and the review therefore analyzes evidence of reduced oxygen availability in neurological diseases with high incidence of depression.
Blood supply and oxygen availability are also keys to the inference of neuronal activity by functional neuroimaging. We review how neurotransmitters interfere with blood flow regulation, affecting interpretations of neuroimaging studies in stress and depression.
Highlight • IL-6 and hsCRP were not associated with specific depressive symptoms, but high hsCRP was associated with decreased psychomotor speed in patients with major depression.
The authors investigated the frequency and determinants of long-term use and risk of dose escalation of benzodiazepines and benzodiazepine-related drugs (benzodiazepine receptor agonists, or BZRAs).
...All adults ages 20-80 years living in Denmark on January 1, 2000 (N=4,297,045) were followed for redeemed prescriptions of BZRAs in the Danish National Prescription Registry from January 1, 2000, to December 31, 2020. For each drug class, we calculated long-term use for more than 1 or 7 years, and dose escalation measured as increase in dose to a level above the recommended level. Associations were examined using logistic regression.
The authors identified 950,767 incident BZRA users, of whom 15% and 3% became long-term users for more than 1 or 7 years, respectively. These percentages were highest for individuals who initiated Z-drugs (17.8% and 4%). Among the 5% of BZRA users who had at least 3 years of continuous use, there was no indication of dose escalation, as the median dose remained relatively stable. However, 7% (N=3,545) of BZRA users escalated to doses above the recommended level. Psychiatric comorbidity, especially substance use disorder, was associated with higher risk of long-term use and dose escalation.
A limited portion of the population that received BZRA prescriptions were classified as continuous users, and only a small proportion of this group escalated to doses higher than those recommended in clinical guidelines. Thus, this study does not, under the current regulations, support the belief that BZRA use frequently results in long-term use or dose escalation.
We examined the influence of comorbid sleep disorder on the association between type 2 diabetes (T2D) and risk of incident depression.
The study population (N = 232,489) was based on all individuals ...registered aged ≥40 years with a T2D diagnosis between January 1, 2000 to December 31, 2012 in the Danish National Diabetes Register and a matched reference population. The risk of incident depression (diagnosis or anti-depressant medication) following T2D and possible effect modification of comorbid sleep disorder was estimated using adjusted Cox proportional hazards regression. Sleep disorder was defined as a diagnosis of insomnia, hypersomnia or sleep-wake schedule disorders or use of sleep medication (z-drugs or melatonin) in the Danish National Patient Registry or the Danish National Prescription Registry.
At study entry, 15.3 % of the participants had a sleep disorder. During follow-up, 2.6 % were diagnosed with depression and 32.1 % received antidepressant medication. The unadjusted hazard ratio (HR) for depression was 1.54 (95%CI 1.52–1.56) for patients with diabetes, which attenuated to 1.50 (1.48–1.52) after adjustment for sleep disorders, which further attenuated to 1.27 (1.26–1.29) in the model further adjusted for psychiatric and somatic comorbidities. The analyses of T2D and sleep disorder as independent and combined variables compared with none of the conditions on risk of depression, showed a HR of 1.27 (95 % CI 1.19–1.35) for T2D without sleep disorder, 1.46 (95 % CI 1.33–1.59) for sleep disorders without T2D, and 1.49 (95%CI 1.37–1.63) for both conditions.
T2D and sleep disorders were independently associated with subsequent risk of depression and individuals with both conditions experienced the greatest relative risk. Sleep disorders neither explained nor amplified the relation between diabetes and depression.
•Type 2 diabetes and sleep disorders were independent risk factors for depression.•Patients with both conditions had the highest risk of depression.•Sleep neither explained nor amplified the relation between diabetes and depression.
To evaluate the risk of falls and fractures in users of benzodiazepines, Z-drugs, or melatonin.
We followed 699,335 adults with a purchase of benzodiazepines, Z-drugs, or melatonin in the Danish ...National Prescription Registry between 2003 and 2016 for falls and fractures in the Danish National Patient Registry between 2000 and 2018. A self-controlled case-series analysis and conditional Poisson regression were used to derive incidence rate ratios (IRR) of falls and fractures during six predefined periods.
In total 62,105 and 36,808 adults, respectively, experienced a fall or fracture. For older adults, the risk of falls was highest during the 3-month pre-treatment period (IRR
, 4.22 (95% confidence interval, 3.53-5.05), IRR
, 3.03 (2.59-3.55)) compared to the baseline (>1 year before initiation). The risk continued to be higher in the later treatment periods. Contrarily, in men and women aged 40-69 years, the risk was only higher in the 3-month pre-treatment period. The incidence of falls among young men and women was slightly lower after initiation of sedating medication (treatment period, IRR
, 0.66 (0.50-0.86), IRR
, 0.65 (0.51-0.83)). Analyses with fractures as outcome yielded similar results.
Although falls and fractures occur more often in persons using sedative-hypnotic medication, the higher risk of falls and fractures in the pre-treatment period relative to the period directly after treatment, suggests that this association is better explained by other factors that elicited the prescription of this medication rather than the adverse effects of the sedative-hypnotic medication.
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