Background

Licorice, through the effects of glycyrrhizic acid (GA), raises blood pressure (BP). The World Health Organization has suggested that 100 mg GA/d would be unlikely to cause adverse effects, but of 13 previously published studies none have been randomized and controlled and independently quantified the GA content.

Objective

Our aim was to analyze the effects on home BP of a daily licorice intake containing 100 mg GA.

Methods

Healthy volunteers were randomly assigned to start with either licorice or a control product in a nonblinded, 2 × 2 crossover study. Home BP was measured daily, and blood samples were collected at the end of each 2-wk period.

Results

There were 28 participants and no dropouts. The median age was 24.0 y (interquartile range 22.8–27.0 y). During the licorice compared with control intake period, the systolic home BP increased [mean difference: 3.1 mm Hg (95% confidence interval [CI]: 0.8, 5.4 mm Hg) compared with −0.3 mm Hg (95% CI: −1.8, 1.3 mm Hg); P = 0.018] and renin and aldosterone were suppressed [mean change: −30.0% (95% CI: −56.7%, −3.3%) compared with 15.8% (95% CI: −12.8%, 44.4%); P = 0.003; and −45.1% (95% CI: −61.5%, −28.7%) compared with 8.2% (95% CI: −14.7%, 31.1%); P <0.001, respectively]. In the quartile of participants with the most pronounced suppression of renin and aldosterone, N-terminal prohormone of brain natriuretic peptide concentration increased during the licorice compared with control period [mean change: 204.1% (95% CI: −11.6%, 419.7%) compared with 72.4% (95% CI: −52.2%, 197.1%); P = 0.016].

Conclusions

We found licorice to be more potent than previously known, with significant increases in BP, after a daily intake of only 100 mg GA. Thus, the safe limit of intake of this substance might need to be reconsidered.

Hypertension is the most common preventable cause of premature all-cause mortality, primarily from cardiovascular disease (CVD). Individuals with dysglycemia, including prediabetes and diabetes, are at increased risk. Licorice intake raises blood pressure (BP) through the effects of glycyrrhizic acid (GA), but the true limit of safe intake is uncertain. Home BP has several benefits over BP measured at a clinic, including a higher predictive value for CVD. By combining office and home BP, it is possible to diagnose masked hypertension (MH), in which home but not office BP is elevated, and white coat hypertension (WCH), in which office but not home BP is elevated. The aim of this thesis was to advance our knowledge on home BP in relation to dysglycemia, markers of CVD, and licorice intake.  

The first 3 papers used data from the Linköping cohort of the prospective Swedish CArdioPulmonary bioImage Study (SCAPIS). Study IV was a randomized controlled cross-over study. Data was obtained from questionnaires, blood samples and office and home BP measurements. In studies I-III, pulse wave velocity (PWV), coronary artery calcium score (CACS), and carotid artery plaques as markers of CVD were also included.  

In Study I, we examined 5025 men and women aged 50-64 years old for the relation between dysglycemia and home BP. Both the systolic office and home BP measurements were positively as-sociated with dysglycemia. Participants with dysglycemia vs normoglycemia more often had MH. The findings were in line with previous research and strengthened the association between dysglycemia and MH.  

In Study II, we examined the associations between MH and markers of CVD in 4122 individuals without BP-lowering treatment. Of participants, 4.2% had MH, and these were more often men and had higher BMI than those with normotension. Participants with MH also had higher odds for CACS ≥100, an as-sociation which has previously been suggested as a trend.

In Study III, we examined the relation between soluble P-se-lectin (sP-selectin) as a measure of thrombotic activity, plasma high-sensitivity C-reactive protein (hsCRP) as a measure of inflammation, and home BP in 4548 participants. Both markers were higher in each hypertension phenotype compared with sustained normotension. The quartile of participants with the highest sP-se-lectin values had higher odds for CACS ≥100 and carotid artery plaques. The association between sP-selectin and sustained hyper-tension was novel and not affected by adjustments for hsCRP.  

In Study IV, 28 healthy participants aged 18-30 years old were evaluated for the effects of a daily intake of licorice containing 100 mg of GA compared with a control product for 2 weeks. During the licorice intake period, the systolic home BP increased with 3.1 mmHg, and the suppression of serum aldosterone and plasma renin levels indicated that this was due to the licorice intake.  

In conclusion, this thesis further strengthens the idea that both home and office BP measurements have values beyond that of the other, and that home BP may be most valuable in individuals with dysglycemia and obesity, and in men. Finally, licorice may be more potent than previously known, suggesting the need for increased awareness. 

Förhöjt blodtryck (hypertoni) är den huvudsakliga orsaken till förtida död, främst genom hjärtkärlsjukdom. Flera mekanismer och riskfaktorer som kan förklara hypertoni har identifierats. Individer med förhöjt blodsocker, inklusive diabetes och dess förstadier, lö-per ökad risk för hjärtkärlsjukdom, och förhöjt blodsocker samexisterar ofta med hypertoni. Lakritsintag höjer blodtrycket genom dess beståndsdel glycyrrhizinsyra (GA), och även om både Europeiska unionen och Världshälsoorganisationen har föreslagit att ett intag av upp till 100 mg per dag sannolikt är säkert att förtära för de flesta individer, är den gränsnivån osäker.  

Jämfört med blodtryck som mäts på mottagningen av medicinskt utbildad personal har hemblodtryck flera fördelar, inklusive starkare koppling till framtida hjärtkärlsjukdom. Genom att kombinera mottagnings- och hemblodtryck går det att diagnosticera maskerad hypertoni (MH), då hemblodtrycket är förhöjt trots normalt mottagningsblodtryck, och vitrockhypertoni (WCH), då mottagningsblodtrycket men inte hemblodtrycket är förhöjd. Syftet med denna avhandling var att vidare utforska hemblodtryck i relation till förhöjt blodsocker, markörer för hjärtkärlsjukdom, och lakritsintag.  

Avhandlingens fyra arbeten baseras på två studier. I de första tre arbetena analyserades data från Linköpings-kohorten i the Swedish CArdioPulmonary bioImage Study (SCAPIS), en prospektiv studie av män och kvinnor i åldrarna 50-64 år. I det sista arbetet analyserades data från en lottad överkorsningsstudie. Data i studierna bestod av enkätsvar, blodprover, samt mottagnings- och hemblodtrycksmätningar. I studie I-III ingick även pulsvågshastighet, kalkhalt i kranskärlen vid skiktröntgen (CACS) och plack-förekomst i halspulsådrorna vid ultraljudsundersökning som markörer på hjärtkärlsjukdom.  

I det första delarbetet undersökte vi data för 5025 individer avseende blodtryck och förhöjt blodsocker. Både mottagnings- och hemblodtryck var associerat med förhöjt blodsocker. Deltagare med förhöjt blodsocker hade oftare MH jämfört med de med normalt blodsocker, och skillnaden mellan mottagnings- och hemblodtrycket var omvänt associerat med långtidsblodsocker. Fynden var i linje med tidigare forskning, och stärkte kända kopplingar mellan MH och förhöjt blodsocker. Förklaringarna till detta samband är okända, men möjliga sådana inkluderar selektiva effekter av blodtryckssänkande läkemedel hos individer med förhöjt blodsocker, samsjukligheter såsom fetma, och aktivering av det sympatiska nervsystemet.  

I det andra delarbetet analyserade vi förekomst av och associationer för MH hos 4122 individer utan pågående blodtryckssänkande läkemedelsbehandling. Av dessa hade 4.2% MH, och dessa var oftare män och hade högre BMI än de med normalt blodtryck. Deltagare med MH hade också högre pulsvågshastighet och oftare förhöjt CACS. Associationen mellan MH och markörer för hjärt-kärlsjukdom var tidigare känd och styrktes av våra resultat.  

I det tredje delarbetet undersökte vi 4548 deltagare avseende två blodprovsmarkörer: en för blodplättsaktivitet, lösligt P-selektin i blodet, och en för inflammation, högkänsligt C-reaktivt protein (hsCRP). Både P-selektin och hsCRP var högre vid hypertoni, oavsett typ, jämfört med vid normalt blodtryck. Den kvartil av deltagarna som hade högst P-selektin hade oftare WCH och hypertoni både hemma och på mottagningen, jämfört med normalt blodtryck, och oftare förhöjt CACS och plack i halspulsådrorna. Associationen mellan P-selektin och högt blodtryck både hemma och på mottagningen var inte tidigare känd, och påverkades inte av justering för hsCRP, vilket antydde att den inte enbart förklarades av inflammation.  

I det fjärde och sista delarbetet inkluderas 28 friska individer i åldrarna 18 till 30 år. I en överkorsningsstudie bad vi deltagarna att dagligen under 2 veckor inta antingen lakrits med ett innehåll av 100 mg GA eller en kontrollprodukt utan lakrits. Deltagarna undersöktes med avseende på hemblodtryck, liksom hormonnivåer i blodet. Under lakrits- jämfört med kontrollperioden steg det systoliska hemblodtrycket med 3,1 mmHg, och hormonnivåerna påverkades på ett sätt som talade för att GA påverkade blodtrycket.  

Sammanfattningsvis stärker studiernas resultat kunskapen om att blodtrycksmätning både på mottagningen och i hemmet är värdefullt både var för sig och tillsammans, och att hemblodtryck är särskilt värdefullt hos individer med förhöjt blodsocker eller övervikt, samt hos män. Slutligen visade sig små mängder lakrits påverka kroppen mer än tidigare känt, och ökad medvetenhet och bättre etikettering av lakritsprodukter kan vara befogad.  

Background: Orthostatic hypotension (OH) is more common in the elderly, and associated with increased mortality. However, its implications in 85-year-olds are not known.

Methods: In the prospective observational cohort study Elderly in Linköping Screening Assessment (ELSA 85), 496 individuals in Linköping, Sweden, were followed from age 85 years with cognitive assessments. Blood pressure (BP) was measured supine and after 1, 3, 5, and 10 minutes of standing. Participants with a BP fall of ≥20 mmHg systolic or ≥10 mmHg diastolic after 1 or 3 minutes were classified as classical continuous or classical transient OH depending on whether the BP fall was sustained or not, at subsequent measurements. Those with a BP fall of the same magnitude, but only after 5 or 10 minutes were classified as delayed OH.

Results: Of participants, 329 took part in BP measurements and were included. Of these, 156 (47.4%) had classical OH (113 [34.3%] continuous classical, 38 [11.6%] transient classical), and 15 (4.6%) had delayed OH. Cognitive assessments were not markedly different between groups. After 8.6 years, 195 (59.3%) of the participants had died, and delayed vs no OH was associated with twice the risk of all-cause mortality, HR 2.15 (95% CI 1.12-4.12). Transient classical OH was associated with reduced mortality, HR 0.58 (95% CI 0.33-0.99), but not after multiple adjustments, and continuous classical OH was not associated with mortality.

Conclusion: OH may have different implications for morbidity and mortality in 85-year-olds compared with younger populations.

The duration of treatment for which a physician may prescribe a medicine, ‘prescription duration’, is often dispensed at the pharmacy on multiple occasions of shorter time periods, ‘dispensing duration’. These durations vary significantly between and within countries. In Australia, the quantity of medication supplied at each dispensing has recently been extended from 30 to 60 days for a selection of medicines used for chronic health conditions, such as diabetes and hypertension. Dispensing durations vary between countries, with 30, 60 or 90 days being the most common—with 90 days aligning with the recommendation of the 2023 Global Report on Hypertension from the World Health Organization. The full impact of shorter vs longer prescription durations on health costs and outcomes is unknown, but current evidence suggests that 90-day dispensing could reduce costs and improve patient convenience and adherence. More rigorous research is needed.

Background: Soluble P-selectin (sP-selectin) and high-sensitivity C-reactive protein (hsCRP) have previously been associated with hypertension, but the relation with out-of-office blood pressure (BP) and coronary artery calcification score is unknown. We aimed to examine the relationship between sP-selectin, hsCRP and home BP, as well as coronary artery calcification score and carotid artery plaques.

Methods: In the Swedish CArdioPulmonary bioImage Study (SCAPIS), 5057 randomly selected participants were evaluated with office and home BP using the semi-automatic Omron M10-IT device. For this cross-sectional study, participants with sP-selectin <4 standard deviations above mean and hsCRP <5 mg/l, representing low-grade inflammation, were included. Using generalized linear models, these inflammatory markers were evaluated in relation to BP classifications, as well as coronary artery calcification score and carotid artery plaques.

Results: Of participants, 4548 were included in the analyses. The median age was 57.2 (53.4–61.2) years, and 775 (17.0%) reported taking medication for hypertension. Participants in the highest quartile of sP-selectin [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.40–1.98, P < 0.001] and hsCRP [OR 2.25, (95% CI 1.89–2.60), P < 0.001] were more likely to have sustained hypertension. Participants in the highest quartile of hsCRP were also more likely to have masked hypertension, OR (95% CI) 2.31 (1.72–3.10), P < 0.001 and carotid artery plaques, OR (95% CI) 1.21 (1.05–1.38), P = 0.007.

Conclusion: Increased sP-selectin and hsCRP were independently associated with sustained hypertension. These findings indicate an association between hypertension and platelet activity, as expressed by sP-selectin.

Aims: To evaluate whether dog ownership from the time of type 2 diabetes diagnosis improved glycaemic control, increased achievement of major guideline treatment goals or reduced the risk of all-cause death.

Methods: Patients diagnosed with type 2 diabetes were followed by linkage of four Swedish national registers covering diabetes, dog ownership, socioeconomics, and mortality. Linear regression was used to estimate the mean yearly change in glycated haemoglobin (HbA1c). Cox survival analysis and logistic regression were used to analyse associations between dog ownership and all-cause death and achievement of treatment goals, respectively.

Results: Of 218,345 individuals included, 8,352 (3.8%) were dog-owners. Median follow-up was 5.2 years. Dog-owners had worse yearly change in HbA1c, and were less likely to reach HbA1c, low-density lipoprotein (LDL), and systolic blood pressure (SBP) treatment goals than non-dog-owners (adjusted odds ratios [95% CI] of 0.93 [0.88–0.97], 0.91 [0.86–0.95], and 0.95 [0.90–1.00], respectively). There was no difference in the risk of all-cause death (adjusted hazard ratio [95% CI] 0.92 [0.81–1.04], dog owners versus not).

Conclusion: Owning a dog when diagnosed with diabetes did not lead to better achievement of treatment goals or reduced mortality, but was in fact associated with a smaller reduction in HbA1c and reduced likelihood of achieving treatment goals.

Background: Masked hypertension is associated with cardiovascular disease (CVD). However, previous large studies have not used the same device to measure office and home blood pressure (BP) and adhered to current home BP measurement recommendations of the European Society of Hypertension. We aimed to characterize masked hypertension and explore its relation to manifestations of CVD.

Methods: A randomly selected cohort of 5057 participants aged 50–64 years from the Swedish CardioPulmonary BioImage Study (SCAPIS) was evaluated with office and home BP using the semi-automatic Omron M10-IT oscillometric device. Additional analyses included pulse wave velocity (PWV) and coronary artery calcium score (CACS).

Results: Of participants, 4122 did not have current antihypertensive treatment, and were thus included in our analyses. Of these, 2634 (63.9%) had sustained normotension, and 172 (4.2%) had masked hypertension. Participants with masked hypertension vs. sustained normotension were more often men (66.9 vs. 46.2%, P < 0.001). Those with masked hypertension had higher mean PWV [9.3 (95% confidence interval, 95% CI 9.1–9.5) vs. 8.3 (95% CI 8.2–8.4) m/s, P < 0.001] and odds ratio for CACS at least 100 [1.65 (95% CI 1.02–2.68), P = 0.040]. These associations were similar in a posthoc analysis of masked hypertension and sustained normotension, matched for age, sex and systolic office BP.

Conclusion: Masked hypertension was associated with markers of CVD. This suggests that home BP is a better predictor of risk, even when the recordings are performed with the same measurement device, in a population-based setting with randomized recruitment.

Background

Cigarette smoking is a major risk factor for cardiovascular disease. In type 2 diabetes mellitus (T2D), medications such as antihypertensives and statins can reduce the increased cardiovascular risk. The aim of this study was to evaluate the impact of cigarette smoking on major adverse cardiovascular event (MACE) and all-cause mortality in patients with T2D in a relatively well treated Swedish cohort.

Methods

Seven hundred and sixty-one patients with T2D aged 55–66 years were followed in the prospective observational CArdiovascular Risk factors in patients with DIabetes – a Prospective study in Primary care (CARDIPP) study. Baseline data included blood samples of markers of dysglycemia and inflammation, blood pressure as well as questionnaire responses regarding cigarette smoking. Participants were followed for incidence of MACE and all-cause mortality.

Results

Of the included 663 participants, the mean age was 60.6 (SD 3.1) years and 423 (63.8%) were men. Levels of C-reactive protein and vitamin D, as well as the proportion of participants treated with antihypertensives, acetylic salicylic acid, statins, and diabetes medications, were similar between smokers and nonsmokers. Median follow-up time was 11.9 (Q1–Q3 10.8–12.7) years. Cigarette smoking was associated with all-cause mortality [hazard ratio 2.24 (95% confidence interval, 95% CI 1.40–3.56), P < 0.001], but not MACE [hazard ratio 1.30 (95% CI 0.77–2.18), P = 0.328].

Conclusion

In patients with T2D, cigarette smoking was not associated with an increased risk of MACE. This raises the question of whether cardioprotective drugs in individuals with T2D to some degree mitigate the cardiovascular harm of smoking, even though they do not affect other dire consequences of smoking.