| 1. |
- Ali, Mohammed K., et al.
(författare)
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Obesity‐associated metabolites in relation to type 2 diabetes risk : A prospective nested case‐control study of the CARRS cohort
- 2022
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 24:10, s. 2008-2016
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To determine whether obesity-associated metabolites are associated with type 2 diabetes (T2DM) risk among South Asians.Materials and methods: Serum-based nuclear magnetic resonance imaging metabolomics data were generated from two South Asian population-based prospective cohorts from Karachi, Pakistan: CARRS1 (N = 4017) and CARRS2 (N = 4802). Participants in both cohorts were followed up for 5 years and incident T2DM was ascertained. A nested case-control study approach was developed to select participants from CARRS1 (Ncases = 197 and Ncontrols = 195) and CARRS2 (Ncases = 194 and Ncontrols = 200), respectively. First, we investigated the association of 224 metabolites with general obesity based on body mass index and with central obesity based on waist-hip ratio, and then the top obesity-associated metabolites were studied in relation to incident T2DM.Results: In a combined sample of the CARRS1 and CARRS2 cohorts, out of 224 metabolites, 12 were associated with general obesity and, of these, one was associated with incident T2DM. Fifteen out of 224 metabolites were associated with central obesity and, of these, 10 were associated with incident T2DM. The higher level of total cholesterol in high-density lipoprotein (HDL) was associated with reduced T2DM risk (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.53, 0.86; P = 1.2 × 10-3 ), while higher cholesterol esters in large very-low-density lipoprotein (VLDL) particles were associated with increased T2DM risk (OR 1.90, 95% CI 1.40, 2.58; P = 3.5 × 10-5 ).Conclusion: Total cholesterol in HDL and cholesterol esters in large VLDL particles may be an important biomarker in the identification of early development of obesity-associated T2DM risk among South Asian adults.
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| 2. |
- Alsalim, Wathik, et al.
(författare)
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Persistent whole day meal effects of three dipeptidyl peptidase-4 inhibitors on glycaemia and hormonal responses in metformin-treated type 2 diabetes
- 2020
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 22:4, s. 590-598
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Dipeptidyl peptidase-4 (DPP-4) inhibition has effects on both fasting and postprandial glucose. However, the extent of this effect over the whole day and whether different DPP-4 inhibitors have the same effects have not been established. We therefore explored the whole day effects of three different DPP-4 inhibitors versus placebo on glucose, islet and incretin hormones after ingestion of breakfast, lunch and dinner in subjects with metformin-treated and well-controlled type 2 diabetes. Methods: The study was single-centre and crossover designed, involving 24 subjects [12 men, 12 women, mean age 63 years, body mass index 31.0 kg/m2, glycated haemoglobin 44.7 mmol/mol (6.2%)], who underwent four test days in random order. Each whole day test included ingestion of standardized breakfast (525 kcal), lunch (780 kcal) and dinner (560 kcal) after intake of sitagliptin (100 mg) or vildagliptin (50 mg twice), or saxagliptin (5 mg) or placebo. Results: Compared with placebo, DPP-4 inhibition reduced glucose levels, increased beta-cell function (insulin secretory rate in relation to glucose), suppressed glucagon, increased intact glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) but suppressed total GLP-1 and GIP after all three meals. The effects were sustained throughout the daytime period with similar changes after each meal and did not differ between the DPP-4 inhibitors. Conclusions: DPP-4 inhibition has persistent daytime effects on glucose, islet and incretin hormones with no difference between three different DPP-4 inhibitors.
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| 3. |
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| 4. |
- Asker, Mohammed, et al.
(författare)
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Peripherally restricted oxytocin is sufficient to reduce food intake and motivation, while CNS entry is required for locomotor and taste avoidance effects
- 2023
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 25:3, s. 856-877
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesOxytocin (OT) has a well-established role in reproductive behaviours; however, it recently emerged as an important regulator of energy homeostasis. In addition to central nervous system (CNS), OT is found in the plasma and OT receptors (OT-R) are found in peripheral tissues relevant to energy balance regulation. Here, we aim to determine whether peripheral OT-R activation is sufficient to alter energy intake and expenditure.Methods and ResultsWe first show that systemic OT potently reduced food intake and food-motivated behaviour for a high-fat reward in male and female rats. As it is plausible that peripherally, intraperitoneally (IP) injected OT crosses the blood-brain barrier (BBB) to produce some of the metabolic effects within the CNS, we screened, with a novel fluorescently labelled-OT (fAF546-OT, Roxy), for the presence of IP-injected Roxy in CNS tissue relevant to feeding control and compared such with BBB-impermeable fluorescent OT-B-12 (fCy5-OT-B-12; BRoxy). While Roxy did penetrate the CNS, BRoxy did not. To evaluate the behavioural and thermoregulatory impact of exclusive activation of peripheral OT-R, we generated a novel BBB-impermeable OT (OT-B-12), with equipotent binding at OT-R in vitro. In vivo, IP-injected OT and OT-B-12 were equipotent at food intake suppression in rats of both sexes, suggesting that peripheral OT acts on peripheral OT-R to reduce feeding behaviour. Importantly, OT induced a potent conditioned taste avoidance, indistinguishable from that induced by LiCl, when applied peripherally. Remarkably, and in contrast to OT, OT-B-12 did not induce any conditioned taste avoidance. Limiting the CNS entry of OT also resulted in a dose-dependent reduction of emesis in male shrews. While both OT and OT-B-12 proved to have similar effects on body temperature, only OT resulted in home-cage locomotor depression.ConclusionsTogether our data indicate that limiting systemic OT CNS penetrance preserves the anorexic effects of the peptide and reduces the clinically undesired side effects of OT: emesis, taste avoidance and locomotor depression. Thus, therapeutic targeting of peripheral OT-R may be a viable strategy to achieve appetite suppression with better patient outcomes.
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| 5. |
- Balintescu, A., et al.
(författare)
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Glycaemic control and sepsis risk in adults with type 1 diabetes
- 2023
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 25:7, s. 1942-1949
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To study the association between glycated haemoglobin (HbA1c) and sepsis in adults with type 1 diabetes, and to explore the relationship between HbA1c and mortality among individuals who developed sepsis.Materials and Methods: We included 33 549 adult individuals with type 1 diabetes recorded in the Swedish National Diabetes Register between January 2005 and December 2015. We used multivariable Cox regression and restricted cubic spline analyses to study the relationship between HbA1c values and sepsis occurrence and association between HbA1c and mortality among those with sepsis.Results: In total, 713 (2.1%) individuals developed sepsis during the study period. Com-pared with the HbA1c reference interval of 48-52 mmol/mol (6.5-6.9%), the adjusted hazard ratio for sepsis was: 2.50 [95% confidence interval (CI) 1.18-5.29] for HbA1c <43 mmol/mol; 1.88 (95% CI 0.96-3.67) for HbA1c 43-47 mmol/mol; 1.78 (95% CI 1.09-2.89) for HbA1c 53-62 mmol/mol; 1.86 (95% CI 1.14-3.03) for HbA1c 63-72 mmol/mol; 3.15 (95% CI 1.91-5.19) for HbA1c 73-82 mmol/mol; and 4.26 (95% CI 2.53-7.16) for HbA1c >82 mmol/mol. On multivariable restricted cubic spline analy-sis, we found a J-shaped association between HbA1c and sepsis risk, with the lowest risk observed at HbA1c of approximately 53 mmol/mol. We found no association between HbA1c and mortality among those individuals who developed sepsis.Conclusions: In our nationwide observational study of adult individuals with type 1 diabetes we found a J-shaped relationship between HbA1c and risk of sepsis, with the lowest risk at HbA1c levels about 53 mmol/mol (7.0%). HbA1c was not associ-ated with mortality in individuals affected by sepsis.
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| 6. |
- Birkeland, Kåre I., et al.
(författare)
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Heart failure and chronic kidney disease manifestation and mortality risk associations in type 2 diabetes : A large multinational cohort study
- 2020
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 22:9, s. 1607-1618
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Tidskriftsartikel (refereegranskat)abstract
- Aims To examine the manifestation of cardiovascular or renal disease (CVRD) in patients with type 2 diabetes (T2D) initially free from CVRD as well as the mortality risks associated with these diseases.Methods Patients free from CVRD were identified from healthcare records in England, Germany, Japan, the Netherlands, Norway and Sweden at a fixed date. CVRD manifestation was defined by first diagnosis of cardiorenal disease, or a stroke, myocardial infarction (MI) or peripheral artery disease (PAD) event. The mortality risk associated with single CVRD history of heart failure (HF), chronic kidney disease (CKD), MI, stroke or PAD was compared with that associated with CVRD-free status.Results Of 1 177 896 patients with T2D, 772 336 (66%) were CVRD-free and followed for a mean of 4.5 years. A total of 137 081 patients (18%) developed a first CVRD manifestation, represented by CKD (36%), HF (24%), stroke (16%), MI (14%) and PAD (10%). HF or CKD was associated with increased cardiovascular and all-cause mortality risk: hazard ratio (HR) 2.02 (95% confidence interval [CI] 1.75-2.33) and HR 2.05 (95% CI 1.82-2.32), respectively. HF and CKD were separately associated with significantly increased mortality risks, and the combination was associated with the highest cardiovascular and all-cause mortality risk: HRs 3.91 (95% CI 3.02-5.07) and 3.14 (95% CI 2.90-3.40), respectively.Conclusion In a large multinational study of >750 000 CVRD-free patients with T2D, HF and CKD were consistently the most frequent first cardiovascular disease manifestations and were also associated with increased mortality risks. These novel findings show these cardiorenal diseases to be important and serious complications requiring improved preventive strategies.
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| 7. |
- Birkeland, Kare I., et al.
(författare)
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Lower cardiorenal risk withsodium-glucosecotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes without cardiovascular and renal diseases : A large multinational observational study
- 2021
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 23:1, s. 75-85
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Tidskriftsartikel (refereegranskat)abstract
- Aims We compared the new use of sodium-glucose cotransporter-2 inhibitor (SGLT2i) versus dipeptidyl peptidase-4 inhibitor (DPP4i) and the risk of cardiorenal disease, heart failure (HF) or chronic kidney disease (CKD), in patients with type 2 diabetes without a history of prevalent cardiovascular and renal disease, defined as cardiovascular and renal disease (CVRD) free, managed in routine clinical practice. Materials and methods In this observational cohort study, patients were identified from electronic health records from England, Germany, Japan, Norway, South Korea and Sweden, during 2012-2018. In total, 1 006 577 CVRD-free new users of SGLT2i or DPP4i were propensity score matched 1:1. Unadjusted Cox regression was used to estimate hazard ratios (HRs) for outcomes: cardiorenal disease, HF, CKD, stroke, myocardial infarction (MI), cardiovascular and all-cause mortality. Results Baseline characteristics were well balanced between the treatment groups (n = 105 130 in each group) with total follow-up of 187 955 patient years. Patients had a mean age of 56 years, 43% were women and they were indexed between 2013 and 2018. The most commonly used agents were dapagliflozin (91.7% of exposure time) and sitagliptin/linagliptin (55.0%), in the SGLT2i and DPP4i, groups, respectively. SGLT2i was associated with lower risk of cardiorenal disease, HF, CKD, all-cause and cardiovascular mortality; HR (95% confidence interval), 0.56 (0.42-0.74), 0.71 (0.59-0.86), 0.44 (0.28-0.69), 0.67 (0.59-0.77), and 0.61 (0.44-0.85), respectively. No differences were observed for stroke [0.87 (0.69-1.09)] and MI [0.94 (0.80-1.11)]. Conclusion In this multinational observational study, SGLT2i was associated with a lower risk of HF and CKD versus DPP4i in patients with type 2 diabetes otherwise free from both cardiovascular and renal disease.
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| 8. |
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| 9. |
- Brieditis, Emelie, et al.
(författare)
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Vulvovaginal candidiasis and type 2 diabetes : A nationwide retrospective cohort study
- 2024
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Ingår i: Diabetes, Obesity and Metabolism. - 1462-8902. ; 26:9, s. 4043-4051
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To examine whether vulvovaginal candidiasis (VVC) precedes type 2 diabetes and to quantify the possible time period between VVC and subsequent diabetes. Material and Methods: We conducted a nationwide retrospective primary healthcare study including 1 838 929 women aged 35–65 years in Sweden (2007–2018). Cox regression models were used to examine associations between VVC and type 2 diabetes, while controlling for possible confounders. Propensity-score-weighted analysis was also conducted. Results: The incidence rate of diabetes per 1000 person-years was 3.06 (95% confidence interval [CI] 3.05–3.08) in women without preceding VVC and 4.05 (95% CI 3.86–4.24) in women with preceding VVC. The incidence rate was particularly high in women aged 55 years and older with VVC: 9.56 (95% CI 8.01–11.11). Women with VVC had a hazard ratio (HR) of 1.41 (95% CI 1.28–1.55) for diabetes compared to women without VVC in the multivariable-adjusted model. The corresponding HR was 1.63 (95% CI 1.53–1.74) in propensity-score-weighted analysis. Women with prior VVC also seemed to have a stronger risk of diabetes with older age, particularly after the age of 55 years. The mean (range) time between VVC and subsequent diabetes was 0.57 (0–2) years, depending on the age of the woman. Conclusion: We found temporal associations between VVC and diabetes. The findings demonstrate that the presence of VVC may indicate a future diagnosis of diabetes, especially in women aged 55 years and older. This knowledge could be valuable for clinicians when treating women with VVC.
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| 10. |
- Cariou, Bertrand, et al.
(författare)
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Effect of tirzepatide on body fat distribution pattern in people with type 2 diabetes
- 2024
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Ingår i: Diabetes, obesity and metabolism. - : WILEY. - 1462-8902 .- 1463-1326.
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Tidskriftsartikel (refereegranskat)abstract
- AimsTo describe the overall fat distribution patterns independent of body mass index (BMI) in participants with type 2 diabetes (T2D) in the SURPASS-3 MRI substudy by comparison with sex- and BMI-matched virtual control groups (VCGs) derived from the UK Biobank imaging study at baseline and Week 52. MethodsFor each study participant at baseline and Week 52 (N = 296), a VCG of >= 150 participants with the same sex and similar BMI was identified from the UK Biobank imaging study (N = 40 172). Average visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (aSAT) and liver fat (LF) levels and the observed standard deviations (SDs; standardized normal z-scores: z-VAT, z-aSAT and z-LF) were calculated based on the matched VCGs. Differences in z-scores between baseline and Week 52 were calculated to describe potential shifts in fat distribution pattern independent of weight change. ResultsBaseline fat distribution patterns were similar across pooled tirzepatide (5, 10 and 15 mg) and insulin degludec (IDeg) arms. Compared with matched VCGs, SURPASS-3 participants had higher baseline VAT (mean [SD] z-VAT +0.42 [1.23]; p < 0.001) and LF (z-LF +1.24 [0.92]; p < 0.001) but similar aSAT (z-aSAT -0.13 [1.11]; p = 0.083). Tirzepatide-treated participants had significant decreases in z-VAT (-0.18 [0.58]; p < 0.001) and z-LF (-0.54 [0.84]; p < 0.001) but increased z-aSAT (+0.11 [0.50]; p = 0.012). Participants treated with IDeg had a significant change in z-LF only (-0.46 [0.90]; p = 0.001), while no significant changes were observed for z-VAT (+0.13 [0.52]; p = 0.096) and z-aSAT (+0.09 [0.61]; p = 0.303). ConclusionIn this exploratory analysis, treatment with tirzepatide in people with T2D resulted in a significant reduction of z-VAT and z-LF, while z-aSAT was increased from an initially negative value, suggesting a possible treatment-related shift towards a more balanced fat distribution pattern with prominent VAT and LF loss.
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| 11. |
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| 12. |
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| 13. |
- Da Silva, Julien, et al.
(författare)
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Real-world performance of the MiniMed™ 670G system in Europe
- 2021
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Ingår i: Diabetes, obesity and metabolism. - : Wiley-Blackwell Publishing Inc.. - 1462-8902 .- 1463-1326. ; 23:8, s. 1942-1949
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The MiniMed™ 670G system has been available in Europe since October 2018. Herein, the system's real-world performance in individuals with diabetes is evaluated.MATERIALS AND METHODS: Data uploaded October 2018 to July 2020 by individuals living in Europe were aggregated and retrospectively analyzed. The mean Glucose Management Indicator (GMI), percentage of time spent within (TIR), below (TBR) and above (TAR) glycemic ranges, system use and insulin consumed in users with ≥10 days of SG data after initial Auto Mode start were determined. Another analysis based on suboptimally- (GMI >8.0%) and well-controlled (GMI <7.0%) glycemia pre-Auto Mode initiation was also performed.RESULTS: Users (N=14,899) spent a mean of 81.4% of the time in Auto Mode and achieved a mean GMI of 7.0±0.4%, TIR of 72.0±9.7%, TBR <3.9 mmol/L of 2.4±2.1% and TAR >10 mmol/L of 25.7±10%, after initiating Auto Mode. When compared to pre-Auto Mode initiation, GMI reduced by 0.3±0.4% and TIR increased by 9.6±9.9% (p<0.0001 for both). Significantly improved glycemic control was observed irrespectively of pre-Auto Mode GMI level <7.0% or >8.0%. While total daily dose of insulin increased for both groups, a greater increase was observed in the latter: an increase due primarily to increased basal insulin delivery. In contrast, basal insulin decreased slightly in well-controlled users.CONCLUSIONS: Most MiniMed™ 670G system users in Europe achieved TIR >70% and GMI <7% while minimizing hypoglycemia, in a real-world environment. These international consensus-met outcomes were enabled by automated insulin delivery meeting real-time insulin requirements adapted to each individual user.
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| 14. |
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| 15. |
- Frías, Juan P., et al.
(författare)
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Long-term effects of dapagliflozin plus saxagliptin versus glimepiride on a background of metformin in patients with type 2 diabetes: Results of a 104-week extension to a 52-week randomized, phase 3 study and liver fat MRI substudy
- 2022
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1463-1326 .- 1462-8902. ; 24:1, s. 61-71
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To report the results of a 104-week extension to a 52-week study in which dapagliflozin plus saxagliptin (DAPA+SAXA) improved glycaemic control, liver fat and metabolic variables compared with glimepiride (GLIM) in participants with type 2 diabetes (T2D) receiving background metformin. Materials and methods: This extension to a 52-week global, multicentre, parallel-group, active-controlled, double-blind study (NCT02419612) continued randomized participants (1:1) on DAPA+SAXA (10/5 mg) plus placebo, or GLIM (1-6 mg) plus placebo, once daily. Eligible participants were aged ≥18 years, had T2D (glycated haemoglobin [HbA1c] 58.5-91.3 mmol/mol [7.5%-10.5%]), and a body mass index of 20.0 to 45.0 kg/m2, and were receiving metformin (MET; ≥1500 mg/d). Key outcomes were: requirement for treatment intensification, based on HbA1c ≥53 mmol/mol (7%); achieving therapeutic glycaemic response; and changes in adipose tissue and liver fat on magnetic resonance imaging in a substudy. Results: Overall, 382 participants entered and 338 completed the 104-week extension period (MRI substudy, n = 82). The need for treatment intensification during the 156-week period was lower for DAPA+SAXA+MET (37.0%) than GLIM+MET (55.6%; hazard ratio 0.52, 95% confidence interval [CI] 0.39-0.68; P < 0.001). At week 156, 21.4% of DAPA+SAXA+MET versus 11.7% of GLIM+MET participants achieved therapeutic glycaemic response (HbA1c <53 mmol/mol; odds ratio 2.1, 95% CI 1.23-3.42; P = 0.006). DAPA+SAXA+MET led to greater adjusted mean reductions from baseline in liver fat and visceral and subcutaneous adipose tissue volumes versus GLIM+MET at week 122 (least-squares mean difference from GLIM+MET −4.89%, −0.41 L and −0.44 L, respectively; nominal P values ≤ 0.008). Safety was consistent with that of the monocomponents. Conclusions: Overall, glycaemic control, metabolic benefits and efficacy were better maintained with DAPA+SAXA+MET than with GLIM+MET in T2D.
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| 16. |
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| 17. |
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| 18. |
- Goedecke, Julia H., et al.
(författare)
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Waist circumference thresholds predicting incident dysglycaemia and type 2 diabetes in Black African men and women
- 2022
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 24:5, s. 918-927
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To determine the waist circumference (WC) thresholds for the prediction of incident dysglycaemia and type 2 diabetes (T2D) in Black South African (SA) men and women and to compare these to the advocated International Diabetes Federation (IDF) Europid thresholds.Materials and Methods: In this prospective study, Black SA men (n = 502) and women (n = 527) from the Middle-aged Sowetan Cohort study who had normal or impaired fasting glucose at baseline (2011-2015) were followed up until 2017 to 2018. Baseline measurements included anthropometry, blood pressure and fasting glucose, HDL cholesterol and triglyceride concentrations. At follow-up, glucose tolerance was assessed using an oral glucose tolerance test. The Youden index was used to determine the optimal threshold of WC to predict incident dysglycaemia and T2D.Results: In men, the optimal WC threshold was 96.8 cm for both dysglycaemia and T2D (sensitivity: 56% and 70%; specificity: 74% and 70%, respectively), and had higher specificity (P < 0.001) than the IDF threshold of 94 cm. In women, the optimal WC threshold for incident dysglycaemia was 91.8 cm (sensitivity 86%, specificity 37%) and for T2D it was 95.8 cm (sensitivity 85%, specificity 45%), which had lower sensitivity, but higher specificity to predict incident dysglycaemia and T2D than the IDF threshold of 80 cm (sensitivity: 97% and 100%; specificity: 12% and 11%, respectively)).Conclusions: We show for the first time using prospective cohort data from Africa that the IDF Europid WC thresholds are not appropriate for an African population, and show that African-specific WC thresholds perform better than the IDF Europid thresholds to predict incident dysglycaemia and T2D.
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| 19. |
- Green, Jennifer B., et al.
(författare)
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Sex differences in the complications, care and clinical outcomes of patients with type 2 diabetes in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL)
- 2023
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Ingår i: Diabetes, obesity and metabolism. - : WILEY. - 1462-8902 .- 1463-1326. ; 25:6, s. 1473-1484
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To examine sex differences in the characteristics and outcomes in participants with type 2 diabetes (T2D), with or without cardiovascular disease (CVD), randomized to once-weekly exenatide (EQW) or placebo in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).Materials and Methods: Baseline characteristics were summarized and compared by sex. Cox proportional hazards regression models were used for clinical outcomes, including the primary composite outcome of cardiovascular (CV) death, non-fatal myocardial infarction or non-fatal stroke (MACE3). Models including sex-by-treatment interaction were used to evaluate differences in effects of EQW.Results: Overall, 5603 women and 9149 men were followed for a median of 3.2 years. Women were younger (mean 61.4 vs. 62.2 years, P < .001) and had a shorter duration of diabetes (mean 12.9 vs. 13.2 years, P = .039) and less coronary artery disease (35.2% vs. 61.0%, P < .001) than men, but also a less favourable metabolic risk profile and lower use of cardioprotective medications. MACE3 occurred in 9.1% of women and 13.5% of men, corresponding to 2.82 versus 4.40 events/100 participant-years (adjusted hazard ratio 0.80, 95% CI: 0.70-0.93, P = .003). There was no difference in MACE3 with EQW compared with placebo, or evidence of heterogeneity of treatment effect by sex.Conclusions: This analysis of a large population of individuals with T2D, with or without established CVD, identified between-sex differences in clinical characteristics and care. Despite having worse management of CV risk factors, women had significantly lower rates of important CV events not attributable to the effects of study treatment.
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| 20. |
- Hals, Ingrid K., et al.
(författare)
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A 1-year pilot study of intralymphatic injections of GAD-alum in individuals with latent autoimmune diabetes in adults (LADA) with signs of high immunity: No safety concerns and resemblance to juvenile type 1 diabetes
- 2023
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Ingår i: Diabetes, obesity and metabolism. - : WILEY. - 1462-8902 .- 1463-1326. ; 25:11, s. 3400-3409
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To test, for the first time in latent autoimmune diabetes in adults (LADA), the effects of autoantigen-specific immunotherapy by intralymphatic administration of aluminium-formulated recombinant human glutamic acid decarboxylase 65 (GAD-alum); specifically, to test if this treatment is safe, to test whether it induces a strong immunological response akin to a similar protocol in type 1 diabetes and to look for associations with preserved beta-cell function. Materials and Methods: Three GAD-alum injections, 4 mu g each, were administered 1 month apart into an inguinal lymph node in 14 people with newly diagnosed LADA (age 30-62 years) presenting with high levels of antibodies against glutamic acid decarboxylase (GADA). Adverse effects, immunological variables and beta-cell function were monitored, with detailed measurements at 5 and 12 months from baseline. Results: Clinical adverse effects were minor and transient and measured laboratory variables were unaffected. All participants completed the study. Treatment raised levels of GADA, elicited strong effects on reactivity of peripheral blood mononuclear cells to GAD and raised cytokine/chemokine levels. Beta-cell function appeared stable preferentially in the seven participants carrying human leukocyte antigen (HLA) haplotypes DR3DQ2, as assessed by C-peptide glucagon tests (P < 0.05 vs. seven non-carriers). Conclusion: Intralymphatic treatment with GAD-alum in LADA is without clinical or other safety concerns over a 12-month period. As in a similar protocol used in type 1 diabetes, treatment exerts a strong immunological impact and is compatible with protection of beta-cell function preferentially in HLA-DR3DQ2 LADA patients. These findings pave the way for a randomized controlled trial in this important subgroup of LADA patients.
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| 21. |
- Hellgren, Margareta, 1955, et al.
(författare)
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The burden of poor glycaemic control in people with newly diagnosed type 2 diabetes in Sweden: A health economic modelling analysis based on nationwide data
- 2021
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Ingår i: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 23:7, s. 1604-1613
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Tidskriftsartikel (refereegranskat)abstract
- Aim To evaluate the economic and clinical burden associated with poor glycaemic control in Sweden, in people with type 2 diabetes (T2D) initiating first-line glucose-lowering therapy. Materials and Methods Population data were obtained from Swedish national registers. Immediate glycaemic control was compared with delays in achieving control of 1 and 3 years, with outcomes projected over 3, 10 and 50 years in the validated IQVIA CORE Diabetes Model. Glycaemic control was defined as glycated haemoglobin (HbA1c) targets of 52, 48 and 42 mmol/mol, as recommended in Swedish guidelines, according to age and disease duration. Costs (expressed in 2019 Swedish krona [SEK]) were accounted from a Swedish societal perspective. Results Immediate glycaemic control was associated with population-level cost savings of up to SEK 279 million and SEK 673 million versus delays of 1 and 3 years, respectively, as well as small population-level life expectancy benefits of up to 1305 and 2590 life years gained. Reduced levels of burden were a result of lower incidence and delayed time to onset of diabetes-related complications. Conclusions Even in people with T2D initiating first-line glucose-lowering therapy, the economic burden of poor glycaemic control in Sweden is substantial, but could be reduced by early and effective treatment to achieve glycaemic targets.
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| 22. |
- Hellman, Jarl, et al.
(författare)
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Associations of bolus insulin injection frequency and smart pen engagement with glycaemic control in people living with type 1 diabetes
- 2024
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 26:1, s. 301-310
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Tidskriftsartikel (refereegranskat)abstract
- AimTo evaluate whether both bolus insulin injection frequency and smart pen engagement were associated with changes in glycaemic control, using real-world data from adults with type 1 diabetes (T1D).Materials and MethodsAdults using a smart pen (NovoPen 6) to administer bolus insulin (fast-acting insulin aspart or insulin aspart) alongside continuous glucose monitoring were eligible for inclusion. Smart pen engagement was characterized by number of days with pen data uploads over the previous 14 days. Glycaemic control was evaluated by analysing glucose metrics.ResultsOverall, data from 1194 individuals were analysed. The number of daily bolus injections was significantly associated with time in range (TIR; 3.9-10.0 mmol/L [70-180 mg/dL]; P < 0.0001). Individuals administering, on average, three daily bolus insulin injections had an estimated 11% chance of achieving >70% TIR. The probability of achieving >70% TIR increased with the mean number of daily bolus injections. However, the percentage of TIR was lower on days when individuals administered higher-than-average numbers of injections. The observed mean number of daily bolus injections administered across the study population was lower than the optimal number required to reach glycaemic targets (4.8 injections vs. 6-8 injections). Smart pen engagement was significantly associated with improved TIR.ConclusionsGlycaemic control was associated with daily bolus insulin injection frequency and smart pen engagement. A treatment regimen combining an optimal bolus injection strategy, and effective smart pen engagement, may improve glycaemic control among adults with T1D.
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| 23. |
- Jendle, Johan, 1963-, et al.
(författare)
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Use of insulin pumps and closed-loop systems among people living with diabetes : A narrative review of clinical and cost-effectiveness to enable access to technology and meet the needs of payers
- 2023
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Ingår i: Diabetes, obesity and metabolism. - : Wiley-Blackwell Publishing Inc.. - 1462-8902 .- 1463-1326. ; 25:Sup. 2, s. 21-32
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Forskningsöversikt (refereegranskat)abstract
- The use of continuous subcutaneous insulin infusion delivery via insulin pumps is today considered standard of care for type 1 diabetes (T1D). Closed-loop systems combining continuous glucose monitoring (CGM) with automated algorithm-driven insulin delivery have been shown to be safe and efficacious in randomized controlled studies and in real-life studies in both pediatric and adult individuals with T1D. Implementation of hybrid closed-loop (HCL) systems have shown incremental effectiveness with further reduction of hypoglycemia and hyperglycemia. Although less extensively studied in type 2 diabetes (T2D), insulin pumps have demonstrated their effectiveness on glucose control together with the reduction in insulin needs and a neutral effect on weight. Recent studies have also shown promising results with the use of HCL in T2D. Cost-effectiveness studies both in T1D and T2D have shown that pump is cost effective in several countries, leading to improvements in quality adjusted life years. Insulin pumps are currently reimbursed for T1D in many European countries, but only in a few for individuals with T2D. HCL systems are to be evaluated in future trials performed in T2D to compare their incremental efficacy and cost effectiveness in comparison with available intensification tools which include multiple daily insulin injections, metformin, SGLT-2 inhibitors and GLP-1 receptor agonists. There is a need for updated guidelines for the use of CSII and HCL in individuals living with T2D based on the emerging evidence, identifying, and recommending for the people who'd benefit the most, which would eventually form a basis for the reimbursement and health policies.
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| 24. |
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| 25. |
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| 26. |
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| 27. |
- Koomen, J. V., et al.
(författare)
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Exposure and response analysis of aleglitazar on cardiovascular risk markers and safety outcomes: An analysis of the AleCardio trial
- 2020
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 22:1, s. 30-38
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Tidskriftsartikel (refereegranskat)abstract
- Aims The AleCardio trial aimed to characterize the efficacy and safety of peroxisome proliferator-activated receptor-alpha gamma agonist aleglitazar in patients with type 2 diabetes mellitus and acute coronary syndrome. The trial terminated early because of futility and safety signals. We evaluated whether the safety signals could be attributed to increased exposure to aleglitazar. Materials and Methods The AleCardio trial enrolled 7226 patients to receive aleglitazar 150 mu g or matching placebo on top of standard care. A population pharmacokinetic analysis was conducted in a pharmacokinetic substudy to identify covariates that explained interindividual variability in exposure. Subsequently, the effect of these covariates on surrogate and clinical outcomes was assessed in the full patient population. Results Concomitant administration of clopidogrel was identified as a covariate that influenced the apparent clearance of aleglitazar. Patients using clopidogrel had a mean predicted area under the plasma-concentration-time curve (AUC(0-24)) of 174.7 ng h/mL (SD: +/- 112.9 ng h/mL) versus 142.2 ng h/mL (SD: +/- 92.6 ng h/mL) in patients without clopidogrel. The effect of aleglitazar compared with placebo on HbA1c, haemoglobin, serum creatinine and adiponectin was modified by concomitant clopidogrel use (P for interaction 0.007, 0.002, <0.001 and < 0.001, respectively). Conclusions Concomitant use of clopidogrel was identified as a covariate that explained interindividual variability in exposure to aleglitazar. Patients using clopidogrel showed an additional lowering of HbA1c, at the expense of an additional decrease in haemoglobin, and an increase in serum creatinine and adiponectin. Clopidogrel is a moderate inhibitor of CYP2C8. Because aleglitazar is metabolized by CYP2C8, a pharmacokinetic interaction could explain differences in exposure and response to aleglitazar.
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| 28. |
- Lafferty, Ryan A., et al.
(författare)
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Peptide YY (1–36) peptides from phylogenetically ancient fish targeting mammalian neuropeptide Y1 receptors demonstrate potent effects on pancreatic β-cell function, growth and survival
- 2020
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 22:3, s. 404-416
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To investigate the antidiabetic efficacy of enzymatically stable Peptide YY (PYY) peptides from phylogenetically ancient fish. Materials and methods: N-terminally stabilized, PYY (1–36) sequences from Amia calva (bowfin), Oncorhynchus mykiss (trout), Petromyzon marinus (sea lamprey) and Scaphirhynchus albus (sturgeon), were synthesized, and both biological actions and antidiabetic therapeutic efficacy were assessed. Results: All fish PYY (1–36) peptides were resistant to dipeptidyl peptidase-4 (DPP-4) degradation and inhibited glucose- and alanine-induced (P < 0.05 to P < 0.001) insulin secretion. In addition, PYY (1–36) peptides imparted significant (P < 0.05 to P < 0.001) β-cell proliferative and anti-apoptotic benefits. Proliferative effects were almost entirely absent in β cells with CRISPR-Cas9-induced knockout of Npyr1. In contrast to human PYY (1–36), the piscine-derived peptides lacked appetite-suppressive actions. Twice-daily administration of sea lamprey PYY (1–36), the superior bioactive peptide, for 21 days significantly (P < 0.05 to P < 0.001) decreased fluid intake, non-fasting glucose and glucagon in streptozotocin (STZ)-induced diabetic mice. In addition, glucose tolerance, insulin sensitivity, pancreatic insulin and glucagon content were significantly improved. Metabolic benefits were linked to positive changes in pancreatic islet morphology as a result of augmented (P < 0.001) proliferation and decreased apoptosis of β cells. Sturgeon PYY (1–36) exerted similar but less impressive effects in STZ mice. Conclusion: These observations reveal, for the first time, that PYY (1–36) peptide sequences from phylogenetically ancient fish replicate the pancreatic β-cell benefits of human PYY (1–36) and have clear potential for the treatment of type 2 diabetes.
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| 29. |
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| 30. |
- Leohr, Jennifer, et al.
(författare)
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Postprandial triglyceride reduction following acute treatment of a selective 5-hydroxytryptamine-2c agonist and characterization using a semi-physiological model
- 2021
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 23:4, s. 1001-1010
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To investigate the tolerability, pharmacokinetics (PK), and postprandial triglyceride (TG) response of single, escalating oral doses of a selective 5-hydroxytryptamine-2c (5-HT2c) agonist in subjects with overweight/obesity and apply mechanistic population pharmacokinetic-pharmacodynamic modeling to identify a plausible drug mechanism of action.METHODS: This phase 1, single-center, double‑blind, randomized, placebo-controlled, 4 period, 2-alternating cohort, evaluated single escalating oral doses ranging 5-130 mg of LY2140112 (LY) in subjects with overweight/obesity (BMI: 27-39 kg/m2). Postprandial TG response (total TG, chylomicrons, and VLDL-V6) following a high fat meal were assessed for 11-hours post-meal for each dose level. The PK profile was assessed for 96 hours post-dose. Drug exposure and TG concentrations in chylomicrons and VLDL-V6 were used to characterize the drug mechanism of action using nonlinear mixed-effect modeling.RESULT: Seventeen subjects entered the study and 16 subjects received at least one dose of LY. LY2140112 was generally well tolerated up to 75mg. The PK of LY were described by a two-compartment model with first-order elimination. The 100 mg and 130 mg dose levels of LY significantly reduced the postprandial TG of VLDL-V6 by ~50%, while total TG and chylomicrons were not significantly different from placebo. The application of a published lipokinetic model successfully described the postprandial TG response in this study and indicated that LY reduced the conversion of TGs from chylomicron to VLDL-V6.CONCLUSIONS: LY significantly reduced in the postprandial TG of VLDL-V6 following a single dose, when food consumption was controlled. The data indicates that a selective 5-HT2c agonist alters lipid metabolism, beyond the reported reduction in satiety. The application of a lipokinetic model enabled identification of a plausible drug mechanism of action of LY.
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| 31. |
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| 32. |
- Mathieu, C., et al.
(författare)
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Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 52-week results from a randomized controlled trial
- 2020
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 22:9, s. 1516-1526
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Tidskriftsartikel (refereegranskat)abstract
- Aim To investigate the long-term efficacy and safety of dapagliflozin as an adjunct to adjustable insulin in adults with type 1 diabetes (T1D) and inadequate glycaemic control. Materials and Methods Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT-2) was a placebo-controlled, double-blind, multicentre, phase III study of adults with T1D (HbA1c 7.5%-10.5%) randomized (1:1:1) to receive dapagliflozin 5, 10 mg, or placebo. The efficacy and safety of dapagliflozin over 52 weeks were exploratory endpoints in this extension to DEPICT-2. Results Of 813 participants randomized, 88.2% completed the study. From baseline to 52 weeks, dapagliflozin 5 and 10 mg were associated with reduction in HbA1c (difference [95% CI] vs. placebo: -0.20% [-0.34, -0.06] and -0.25% [-0.38, -0.11], respectively) and adjusted mean percentage change in body weight (difference [95% CI] vs. placebo: -4.42% [-5.19, -3.64] and -4.86% [-5.63, -4.08], respectively). Serious adverse events were reported in the dapagliflozin 5, 10 mg, and placebo groups (32 [11.8%], 19 [7.0%] and 16 [5.9%], respectively). The proportion of hypoglycaemic events was similar across groups; severe hypoglycaemia was uncommon. More participants with events adjudicated as definite diabetic ketoacidosis (DKA) were in the dapagliflozin 5 and 10 mg groups versus placebo (11 [4.1%], 10 [3.7%] and 1 [0.4%], respectively); the majority of events were mild or moderate in severity and all were resolved with treatment. Conclusions Dapagliflozin led to long-term reductions in HbA1c and body weight in adults with T1D, but increased DKA risk compared with placebo.
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| 33. |
- Mauricio, Dídac, et al.
(författare)
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How many people with type 2 diabetes fulfil the eligibility criteria for randomized, controlled trials of insulin glargine 300 U/mL in a real-world setting?
- 2021
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Ingår i: Diabetes, obesity & metabolism. - : Wiley. - 1463-1326 .- 1462-8902. ; 23:3, s. 838-843
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Tidskriftsartikel (refereegranskat)abstract
- Randomized controlled trial (RCT) populations often do not reflect those typically seen in clinical practice. This retrospective, observational cohort study analysed the real-world data of people with type 2 diabetes (T2DM) prescribed basal insulin analogues from electronic medical records (EMRs) in the Explorys database, which includes data from 39 integrated healthcare systems in the United States, to determine how representative selected RCTs investigating insulin glargine 300U/mL (Gla-300) are of T2DM populations in a real-world setting. Applying eligibility criteria derived from the EDITION 1, 2 and 3 (Gla-300 vs. insulin glargine 100U/mL [Gla-100]) and BRIGHT (Gla-300 vs. insulin degludec) RCTs, we observed that only 17% (33345/191 218) of people captured in the real-world database would have been eligible for such trials. Those who were ineligible tended to be older, had more comorbidities and a higher baseline hypoglycaemia rate than the eligible group. Using another large US EMR database (Optum Humedica) as corroboration, we found that 15% (36285/235 697) would have been eligible to participate in the EDITION/BRIGHT RCTs. Furthermore, only 7% (1734/24 547) would have been eligible for the CONCLUDE (insulin degludec vs. Gla-300) RCT. Our findings remind us of the value of real-world data studies, complementing the results of RCTs, and providing additional insights into groups who would typically be excluded from RCTs.
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| 34. |
- Mulder, Skander, et al.
(författare)
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A metabolomics-based molecular pathway analysis of how the sodium-glucose co-transporter-2 inhibitor dapagliflozin may slow kidney function decline in patients with diabetes
- 2020
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Ingår i: Diabetes, obesity and metabolism. - : WILEY. - 1462-8902 .- 1463-1326. ; 22:7, s. 1157-1166
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Tidskriftsartikel (refereegranskat)abstract
- Aim To investigate which metabolic pathways are targeted by the sodium-glucose co-transporter-2 inhibitor dapagliflozin to explore the molecular processes involved in its renal protective effects. Methods An unbiased mass spectrometry plasma metabolomics assay was performed on baseline and follow-up (week 12) samples from the EFFECT II trial in patients with type 2 diabetes with non-alcoholic fatty liver disease receiving dapagliflozin 10 mg/day (n = 19) or placebo (n = 6). Transcriptomic signatures from tubular compartments were identified from kidney biopsies collected from patients with diabetic kidney disease (DKD) (n = 17) and healthy controls (n = 30) from the European Renal cDNA Biobank. Serum metabolites that significantly changed after 12 weeks of dapagliflozin were mapped to a metabolite-protein interaction network. These proteins were then linked with intra-renal transcripts that were associated with DKD or estimated glomerular filtration rate (eGFR). The impacted metabolites and their protein-coding transcripts were analysed for enriched pathways. Results Of all measured (n = 812) metabolites, 108 changed (P < 0.05) during dapagliflozin treatment and 74 could be linked to 367 unique proteins/genes. Intra-renal mRNA expression analysis of the genes encoding the metabolite-associated proteins using kidney biopsies resulted in 105 genes that were significantly associated with eGFR in patients with DKD, and 135 genes that were differentially expressed between patients with DKD and controls. The combination of metabolites and transcripts identified four enriched pathways that were affected by dapagliflozin and associated with eGFR: glycine degradation (mitochondrial function), TCA cycle II (energy metabolism), L-carnitine biosynthesis (energy metabolism) and superpathway of citrulline metabolism (nitric oxide synthase and endothelial function). Conclusion The observed molecular pathways targeted by dapagliflozin and associated with DKD suggest that modifying molecular processes related to energy metabolism, mitochondrial function and endothelial function may contribute to its renal protective effect.
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| 35. |
- Neeland, Ian J., et al.
(författare)
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Changes in lean body mass with glucagon-like peptide-1-based therapies and mitigation strategies
- 2024
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Ingår i: Diabetes, obesity and metabolism. - : WILEY. - 1462-8902 .- 1463-1326.
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Tidskriftsartikel (refereegranskat)abstract
- Weight loss induced by glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic polypeptide receptor agonists is coming closer to the magnitudes achieved with surgery. However, with greater weight loss there is concern about potential side effects on muscle quantity (mass), health and function. There is heterogeneity in the reported effects of GLP-1-based therapies on lean mass changes in clinical trials: in some studies, reductions in lean mass range between 40% and 60% as a proportion of total weight lost, while other studies show lean mass reductions of approximately 15% or less of total weight lost. There are several potential reasons underlying this heterogeneity, including population, drug-specific/molecular, and comorbidity effects. Furthermore, changes in lean mass may not always reflect changes in muscle mass as the former measure includes not only muscle but also organs, bone, fluids, and water in fat tissue. Based on contemporary evidence with the addition of magnetic resonance imaging-based studies, skeletal muscle changes with GLP-1RA treatments appear to be adaptive: reductions in muscle volume seem to be commensurate with what is expected given ageing, disease status, and weight loss achieved, and the improvement in insulin sensitivity and muscle fat infiltration likely contributes to an adaptive process with improved muscle quality, lowering the probability for loss in strength and function. Nevertheless, factors such as older age and severity of disease may influence the selection of appropriate candidates for these therapies due to risk of sarcopenia. To further improve muscle health during weight loss, several pharmacological treatments to maintain or improve muscle mass designed in combination with GLP-1-based therapies are under development. Future research on GLP-1-based and other therapies designed for weight loss should focus on more accurate and meaningful assessments of muscle mass, composition, as well as function, mobility or strength, to better define their impact on muscle health for the substantial number of patients who will likely be taking these medications well into the future.
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| 36. |
- Nilsson, Kristoffer, et al.
(författare)
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Model-based predictions on health benefits and budget impact of implementing empagliflozin in people with type 2 diabetes and established cardiovascular disease
- 2023
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Ingår i: Diabetes, obesity and metabolism. - : Wiley-Blackwell Publishing Inc.. - 1462-8902 .- 1463-1326. ; 25:3, s. 748-757
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To perform a model-based analysis of the short- and long-term health benefits and costs of further increased implementation of empagliflozin for people with type 2 diabetes and established cardiovascular disease (eCVD) in Sweden.MATERIALS AND METHODS: The validated Institute for Health Economics Diabetes Cohort Model (IHE-DCM) was used to estimate health benefits and 3-years' budget impact, and lifetime costs per quality-adjusted life year (QALY) gained of increased implementation of adding empagliflozin to standard of care (SoC) for people with type 2 diabetes and eCVD in a Swedish setting. Scenarios with 100%/75%/50% implementation were explored. Analyses were based on 30 model cohorts with type 2 diabetes and eCVD (n=131,412 at baseline) from national health data registers. Sensitivity analyses explored the robustness of results.RESULTS: Over 3 years, SoC with empagliflozin (100% implementation) vs. SoC before empagliflozin resulted in 7,700 total life years gained and reductions in cumulative incidence of cardiovascular deaths by 30% and heart failures by 28%. Annual costs increased by 6% from higher treatment costs and increased survival. Half of these benefits and costs are not yet reached with current implementation below 50%. SoC with empagliflozin yielded 0.37 QALYs per person, with an incremental cost-effectiveness ratio of €16,000 EUR per QALY vs. SoC before empagliflozin.CONCLUSIONS: Model simulations using real-world data and trial treatment effects indicated that a broader implementation of empagliflozin, in line with current guidelines for treatment of people with type 2 diabetes and eCVD, would lead to further benefits even in a short-term perspective.
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| 37. |
- Norhammar, Anna, et al.
(författare)
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Cost of healthcare utilization associated with incident cardiovascular and renal disease in individuals with type 2 diabetes : A multinational, observational study across 12 countries
- 2022
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 24:7, s. 1277-1287
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Tidskriftsartikel (refereegranskat)abstract
- AimTo examine how the development of cardiovascular and renal disease (CVRD) translates to hospital healthcare costs in individuals with type 2 diabetes (T2D) initially free from CVRD.MethodsData were obtained from the digital healthcare systems of 12 nations using a prespecified protocol. A fixed country-specific index date of 1 January was chosen to secure sufficient cohort disease history and maximal follow-up, varying between each nation from 2006 to 2017. At index, all individuals were free from any diagnoses of CVRD (including heart failure [HF], chronic kidney disease [CKD], coronary ischaemic disease, stroke, myocardial infarction [MI], or peripheral artery disease [PAD]). Outcomes during follow-up were hospital visits for CKD, HF, MI, stroke, and PAD. Hospital healthcare costs obtained from six countries, representing 68% of the total study population, were cumulatively summarized for CVRD events occurring during follow-up.ResultsIn total, 1.2 million CVRD-free individuals with T2D were identified and followed for 4.5 years (mean), that is, 4.9 million patient-years. The proportion of individuals indexed before 2010 was 18% (n = 207 137); 2010-2015, 31% (361 175); and after 2015, 52% (609 095). Overall, 184 420 (15.7%) developed CVRD, of which cardiorenal disease was most frequently the first disease to develop (59.7%), consisting of 23.0% HF and 36.7% CKD, and more common than stroke (16.9%), MI (13.7%), and PAD (9.7%). The total cumulative cost for CVRD was US$1 billion, of which 59.0% was attributed to cardiorenal disease, 3-, 5-, and 6-fold times greater than the costs for stroke, MI, and PAD, respectively.ConclusionAcross all nations, HF or CKD was the most frequent CVRD manifestation to develop in a low-risk population with T2D, accounting for the highest proportion of hospital healthcare costs. These novel findings highlight the importance of cardiorenal awareness when planning healthcare.
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Olafsdottir, Arndis, 1978, et al.
(författare)
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The majority of people with type 1 diabetes and multiple daily insulin injections benefit from using continuous glucose monitoring: An analysis based on the GOLD randomized trial (GOLD-5)
- 2021
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 23:2, s. 619-630
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Tidskriftsartikel (refereegranskat)abstract
- Aim To identify responders to continuous glucose monitoring (CGM) in relation to reductions in HbA1c and percentage of time spent in hypoglycaemia after initiation of CGM for individuals with type 1 diabetes treated with multiple daily insulin injections. Materials and Methods We analysed data from 142 participants in the GOLD randomized clinical trial. We evaluated how many lowered their HbA1c by more than 0.4% (>4.7 mmol/mol) or decreased the time spent in hypoglycaemia over 24 hours by more than 20 or 30 minutes, and which baseline variables were associated with those improvements. Results Lower reduction of HbA1c was associated with greater reduction of hypoglycaemia (r = -0.52; P < .0001). During CGM, 47% of participants lowered their HbA1c values by more than 0.4% (>4.7 mmol/mol) than with self-measurement of blood glucose, and 47% decreased the time spent in hypoglycaemia by more than 20 minutes over 24 hours. Overall, 78% either reduced their HbA1c by more than 0.4% (>4.7 mmol/mol) or the time spent in hypoglycaemia by more than 20 minutes over 24 hours, but only 14% improved both. Higher HbA1c, a lower percentage of time at less than 3.0 or 3.9 mmol/L, a lower coefficient of variation (CV) and a higher percentage of time above 13.9 mmol/L (P = .016) were associated with greater HbA1c reduction during CGM. The variables associated with a greater reduction of time in hypoglycaemia were female sex, greater time with glucose levels at less than 3.0 mmol/L, higher CV, and higher hypoglycaemia confidence as evaluated by a hypoglycaemic confidence questionnaire. Conclusion The majority of people with type 1 diabetes managed by multiple daily insulin injections benefit from CGM; some experienced reduced HbA1c while others reduced the time spent in hypoglycaemia. These factors need to be considered by healthcare professionals and decision-makers for reimbursement and diabetes guidelines.
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| 42. |
- Oldgren, Jonas, 1964-, et al.
(författare)
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Effects of 6 weeks of treatment with dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on myocardial function and metabolism in patients with type 2 diabetes : A randomized, placebo-controlled, exploratory study
- 2021
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 23:7, s. 1505-1517
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Tidskriftsartikel (refereegranskat)abstract
- Aim To explore the early effects of dapagliflozin on myocardial function and metabolism in patients with type 2 diabetes without heart failure. Materials and Methods Patients with type 2 diabetes on metformin treatment were randomized to double-blind, 6-week placebo or dapagliflozin 10 mg daily treatment. Investigations included cardiac function and structure with myocardial resonance imaging; cardiac oxygen consumption, perfusion and efficiency with [C-11]-acetate positron emission tomography (PET); and cardiac and hepatic fatty acid uptake with [F-18]-6-thia-heptadecanoic acid PET, analysed by ANCOVA as least square means with 95% confidence intervals. Results Evaluable patients (placebo: n = 24, dapagliflozin: n = 25; 53% males) had a mean age of 64.4 years, a body mass index of 30.2 kg/m(2) and an HbA1c of 6.7%. Body weight and HbA1c were significantly decreased by dapagliflozin versus placebo. Dapagliflozin had no effect on myocardial efficiency, but external left ventricular (LV) work (-0.095 [-0.145, -0.043] J/g/min) and LV oxygen consumption were significantly reduced (-0.30 [-0.49, -0.12] J/g/min) by dapagliflozin, although the changes were not statistically significant versus changes in the placebo group. Change in left atrial maximal volume with dapagliflozin versus placebo was -3.19 (-6.32, -0.07) mL/m(2) (p = .056). Peak global radial strain decreased with dapagliflozin versus placebo (-3.92% [-7.57%, -0.28%]; p = .035), while peak global longitudinal and circumferential strains were unchanged. Hepatic fatty acid uptake was increased by dapagliflozin versus placebo (0.024 [0.004, 0.044] mu mol/g/min; p = .018), while cardiac uptake was unchanged. Conclusions This exploratory study indicates reduced heart work but limited effects on myocardial function, efficiency and cardiac fatty acid uptake, while hepatic fatty acid uptake increased, after 6 weeks of treatment with dapagliflozin.
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| 43. |
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| 44. |
- Pemberton, J. S., et al.
(författare)
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CGM accuracy: Contrasting CE marking with the governmental controls of the USA (FDA) and Australia (TGA): A narrative review
- 2023
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 25:4, s. 916-939
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Tidskriftsartikel (refereegranskat)abstract
- The National Institute for Clinical Excellence updated guidance for continuous glucose monitoring (CGM) in 2022, recommending that CGM be available to all people living with type 1 diabetes. Manufacturers can trade in the UK with Conformite Europeenne (CE) marking without an initial national assessment. The regulatory process for CGM CE marking, in contrast to the Food and Drug Administration (FDA) and Australian Therapeutic Goods Administration (TGA) process, is described. Manufacturers operating in the UK provided clinical accuracy studies submitted for CE marking. Critical appraisal of the studies shows several CGM devices have CE marking for wide-ranging indications beyond available data, unlike FDA and TGA approval. The FDA and TGA use tighter controls, requiring comprehensive product-specific clinical data evaluation. In 2018, the FDA published the integrated CGM (iCGM) criteria permitting interoperability. Applying the iCGM criteria to clinical data provided by manufacturers trading in the UK identified several study protocols that minimized glucose variability, thereby improving CGM accuracy on all metrics. These results do not translate into real-life performance. Furthermore, for many CGM devices available in the UK, accuracy reported in the hypoglycaemic range is below iCGM standards, or measurement is absent. We offer a framework to evaluate CGM accuracy studies critically. The review concludes that FDA- and TGA-approved indications match the available clinical data, whereas CE marking indications can have discrepancies. The UK can bolster regulation with UK Conformity Assessed marking from January 2025. However, balanced regulation is needed to ensure innovation and timely technological access are not hindered.
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| 45. |
- Persson, Sofie, et al.
(författare)
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Burden of established cardiovascular disease in people with type 2 diabetes and matched controls : Hospital-based care, days absent from work, costs, and mortality
- 2023
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 53:3, s. 726-734
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To assess hospital-based care, work absence, associated costs, and mortality in type 2 diabetes with and without established cardiovascular disease (eCVD) compared to matched controls.METHODS: In a population-based cohort study, we analysed individual-level data from national health, social insurance, and socio-economic registers for people with type 2 diabetes diagnosis<70 years and controls (5:1) in Sweden. Regression analysis attributed costs and days absent to eCVD. Mortality was analysed using Cox proportional hazard regression stratified for birthyear and adjusted for sex and education.RESULTS: Thirty percent (n=136 135 of 454 983) of people with type 2 diabetes had ≥1 person-year with eCVD (women 24%; men 34%). The mean annual costs of hospital-based care for diabetes complications were EUR 2 629 (95% confidence interval [CI] 2 601 to 2 657) of which EUR 2 337 (95% CI 2 309 to 2 365) were attributed to eCVD (89%). The highest-costing person-years (10th percentile) were observed in a broad subgroup, 42% of people with type 2 diabetes and eCVD. People with type 2 diabetes had on average 146 days absent (95% CI 145-147) per year of which 68 days (47%; 95% CI 67-70) were attributed to eCVD. Mortality was increased in type 2 diabetes: eCVD hazard rate [HR] 4.63 (95% CI 4.58-4.68), no eCVD HR 1.86 (95% CI 1.84-1.88).CONCLUSIONS: The sizable burden of eCVD, on the individual with type 2 diabetes and the society, calls for efficient management for reducing the risks for those living with eCVD and postponing its onset. This article is protected by copyright. All rights reserved.
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| 46. |
- Persson, Sofie, et al.
(författare)
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Days absent from work as a result of complications associated with type 2 diabetes : Evidence from 20 years of linked national registry data in Sweden
- 2020
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 22:9, s. 1586-1597
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To analyse days absent from work related to individual microvascular, macrovascular and other complications of type 2 diabetes (T2D) and to identify key drivers of absence. Materials and methods: National health and socio-economic individual-level data were analysed for the years 1997 to 2016 for people with T2D, and age-, sex- and residential region-matched controls (5:1) using linkage to Swedish national administrative registers, based on personal identity numbers. Regression analyses accounting for individual-level clustering and education were estimated to obtain days absent by individual complications. Alternative analyses, for example, workforce indicator and age subgroups, were explored for robustness and comparison purposes. Results: A total of 413 000 people with T2D aged <66 years, comprising 4.9 million person-years, was included. The crude proportion with any absence was higher among those with T2D compared to controls (47% vs. 26%) in the index year, and the median (IQR) number of days was higher (223 [77;359] vs. 196 [59;352]) if any absence. Regression analyses showed that complications per se were a key driver of days absent: stroke (+102 days); end-stage renal disease (+70 days); severe vision loss (+56 days); and angina pectoris, heart failure, and osteoarthritis (+53 days each). The alternative analyses showed similar levels of days absent and age subgroups differed in expected directions. Conclusions: This study provides evidence of the persisting impact on productivity from complications that supports continued efforts to reduce risk factors in T2D. Future studies on burden of disease and economic evaluations of new therapies and disease management may use this new set of complication-specific estimates to improve understanding of the value of reducing complications.
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| 47. |
- Phillip, M., et al.
(författare)
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Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: pooled 52-week outcomes from the DEPICT-1 and-2 studies
- 2021
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 23:2, s. 549-560
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Tidskriftsartikel (refereegranskat)abstract
- Aim To evaluate the efficacy and safety of adjunct dapagliflozin therapy in patients with type 1 diabetes (T1D). Materials and Methods DEPICT-1 and -2 were randomized, double-blind, parallel-group, 24-week studies, with 28-week extension periods. Adults with T1D and HbA1c 7.5%-10.5% were randomized (1:1:1) to receive dapagliflozin 5 mg, 10 mg or placebo. The short- and long-term efficacy and safety of dapagliflozin were examined in an exploratory pooled analysis of both studies. Results Efficacy analyses included 530, 529 and 532 and safety analysis included 548, 566 and 532 patients in the dapagliflozin 5 mg, 10 mg and placebo groups, respectively. Baseline characteristics were similar between treatment groups. At week 24, reductions were seen with dapagliflozin 5 and 10 mg compared with placebo in HbA1c (-0.40%, -0.43% vs. 0.00%) and body weight (-2.45, -2.91 vs. 0.11 kg). HbA1c and body weight reductions versus placebo were also seen after 52 weeks of treatment. There was no imbalance in occurrence of severe hypoglycaemic events between groups. The proportion of patients experiencing definite diabetic ketoacidosis (DKA) was higher with dapagliflozin 5 mg (4.0%) and 10 mg (3.5%) compared with placebo (1.1%) over 52 weeks; most events were of mild or moderate severity, and all resolved with treatment. Conclusions Over 52 weeks, dapagliflozin provided glycaemic and weight benefits, with no increased frequency of severe hypoglycaemia compared with placebo. More DKA events were reported with dapagliflozin than placebo, highlighting the importance of appropriate patient selection, education and risk-mitigation strategies.
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| 48. |
- Raghavan, Sridharan, et al.
(författare)
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Interaction of diabetes genetic risk and successful lifestyle modification in the Diabetes Prevention Programme
- 2021
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 23:4, s. 1030-1040
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To test whether diabetes genetic risk modifies the association of successful lifestyle changes with incident diabetes. Materials and methods: We studied 823 individuals randomized to the intensive lifestyle intervention (ILS) arm of the Diabetes Prevention Programme who were diabetes-free 1 year after enrolment. We tested additive and multiplicative interactions of a 67-variant diabetes genetic risk score (GRS) with achievement of three ILS goals at 1 year (≥7% weight loss, ≥150 min/wk of moderate leisure-time physical activity, and/or a goal for self-reported total fat intake) on the primary outcome of incident diabetes over 3 years of follow-up. Results: A lower GRS and achieving each or all three ILS goals were each associated with lower incidence of diabetes (all P < 0.05). Additive interactions were significant between the GRS and achievement of the weight loss goal (P < 0.001), physical activity goal (P = 0.02), and all three ILS goals (P < 0.001) for diabetes risk. Achievement of all three ILS goals was associated with 1.8 (95% CI 0.3, 3.4), 3.1 (95% CI 1.5, 4.7), and 3.9 (95% CI 1.6, 6.2) fewer diabetes cases/100-person-years in the first, second and third GRS tertiles (P < 0.001 for trend). Multiplicative interactions between the GRS and ILS goal achievement were significant for the diet goal (P < 0.001), but not for weight loss (P = 0.18) or physical activity (P = 0.62) goals. Conclusions: Genetic risk may identify high-risk subgroups for whom successful lifestyle modification is associated with greater absolute reduction in the risk of incident diabetes.
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| 49. |
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| 50. |
- Roeske-Nielsen, A., et al.
(författare)
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Sulfatide inhibits fibroblast growth, activation and oxidative stress induced by ectopic insulin
- 2023
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Ingår i: Diabetes Obesity & Metabolism. - 1462-8902.
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To study the effect of sulfatide on gene expression and proliferation of human primary fibroblasts induced by insulin, insulin-like growth factor-1 and human growth hormone. Materials and Methods: Human primary fibroblasts were exposed to 1, 3 and 30 mu M of sulfatide or its precursor galactosylceramide (GalCer). Proliferation was determined by 3H-thymidine incorporation and gene expression via microarray analysis. Results: Sulfatide and GalCer reduced the growth rate of fibroblasts by 32%-82% when exposed to 0.5 nM insulin. After challenge with 120 mu M of H2O2, sulfatide reduced membrane leakage. Fibroblast gene expression was altered by sulfatide in gene pathways associated with cell cycle/growth, transforming growth factor-beta function, and encoding of proteins involved in intracellular signalling. NFKBIA, a key control element in NF-kappa B regulation, was decreased 2-fold by sulfatide. Conclusions: Sulfatide strongly inhibits fibroblast growth. We therefore suggest the addition of sulfatide to injectable commercial insulin formulations, which would reduce adverse fibroblast growth and improve well-being in patients with diabetes.
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