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Sanchez-Rangel E, Deajon-Jackson J, Hwang JJ. Pathophysiology and management of hypoglycemia in diabetes. Ann N Y Acad Sci 2022; 1518:25-46. [PMID: 36202764 DOI: 10.1111/nyas.14904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
In the century since the discovery of insulin, diabetes has changed from an early death sentence to a manageable chronic disease. This change in longevity and duration of diabetes coupled with significant advances in therapeutic options for patients has fundamentally changed the landscape of diabetes management, particularly in patients with type 1 diabetes mellitus. However, hypoglycemia remains a major barrier to achieving optimal glycemic control. Current understanding of the mechanisms of hypoglycemia has expanded to include not only counter-regulatory hormonal responses but also direct changes in brain glucose, fuel sensing, and utilization, as well as changes in neural networks that modulate behavior, mood, and cognition. Different strategies to prevent and treat hypoglycemia have been developed, including educational strategies, new insulin formulations, delivery devices, novel technologies, and pharmacologic targets. This review article will discuss current literature contributing to our understanding of the myriad of factors that lead to the development of clinically meaningful hypoglycemia and review established and novel therapies for the prevention and treatment of hypoglycemia.
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Affiliation(s)
- Elizabeth Sanchez-Rangel
- Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Jelani Deajon-Jackson
- Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Janice Jin Hwang
- Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, USA.,Division of Endocrinology, Department of Internal Medicine, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, USA
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Heerspink HJL, Sattar N, Pavo I, Haupt A, Duffin KL, Yang Z, Wiese RJ, Tuttle KR, Cherney DZI. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol 2022; 10:774-785. [PMID: 36152639 DOI: 10.1016/s2213-8587(22)00243-1] [Citation(s) in RCA: 129] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 08/10/2022] [Accepted: 08/13/2022] [Indexed: 12/21/2022]
Abstract
BACKGROUND In the SURPASS-4 trial, the dual GIP and GLP-1 receptor agonist tirzepatide reduced HbA1c concentrations, bodyweight, and blood pressure more than titrated daily insulin glargine in people with type 2 diabetes inadequately controlled on oral diabetes treatments and with high cardiovascular risk. We aimed to compare the effects of tirzepatide and insulin glargine on kidney parameters and outcomes in people with type 2 diabetes. METHODS We did a post-hoc analysis of data from SURPASS-4, a randomised, open-label, parallel-group, phase 3 study at 187 sites (including private practice, research institutes, and hospitals) in 14 countries. Eligible participants were adults (age ≥18 years), with type 2 diabetes treated with any combination of metformin, sulfonylurea, or SGLT2 inhibitor, and with baseline HbA1c of 7·5-10·5% (58-91 mmol/mol), BMI of 25 kg/m2 or greater, and established cardiovascular disease or a high risk of cardiovascular events. Randomisation via an interactive web-response system was 1:1:1:3 to a once-weekly subcutaneous injection of tirzepatide (5 mg, 10 mg, or 15 mg) or a once-daily subcutaneous injection of titrated insulin glargine (100 U/mL). The study included up to 104 weeks of treatment, with a median treatment duration of 85 weeks. We compared the rates of estimated glomerular filtration rate (eGFR) decline and the urine albumin-creatinine ratio (UACR) between the combined tirzepatide groups and the insulin glargine group in the modified intention-to-treat population. The kidney composite outcome was time to first occurrence of eGFR decline of at least 40% from baseline, end-stage kidney disease, death owing to kidney failure, or new-onset macroalbuminuria. This study is registered with ClinicalTrials.gov, NCT03730662. FINDINGS Between Nov 20, 2018, and Dec 30, 2019, we screened 3045 people, of whom 1043 (34%) were ineligible, and 2002 (66%) were randomly assigned to a study drug (997 to tirzepatide and 1005 to insulin glargine). 1995 (>99%) of 2002 received at least one dose of tirzepatide (n=995) or insulin glargine (n=1000). At baseline, participants had a mean eGFR of 81·3 (SD 21·11) mL/min per 1·73 m2 and a median UACR of 15·0 mg/g (IQR 5·0-55·8). The mean rate of eGFR decline was -1·4 (SE 0·2) mL/min per 1·73 m2 per year in the combined tirzepatide groups and -3·6 (0·2) mL/min per 1·73 m2 per year in the insulin group (between-group difference 2·2 [95% CI 1·6 to 2·8]). Compared with insulin glargine, the reduction in the annual rate of eGFR decline induced by tirzepatide was more pronounced in participants with eGFR less than 60 mL/min per 1·73 m2 than in those with eGFR 60 mL/min per 1·73 m2 or higher (between-group difference 3·7 [95% CI 2·4 to 5·1]). UACR increased from baseline to follow-up with insulin glargine (36·9% [95% CI 26·0 to 48·7]) but not with tirzepatide (-6·8% [-14·1 to 1·1]; between-group difference -31·9% [-37·7 to -25·7]). Participants who received tirzepatide showed a significantly lower occurrence of the composite kidney endpoint compared with those who received insulin glargine (hazard ratio 0·58 [95% CI 0·43 to 0·80]). INTERPRETATION Our analysis suggests that in people with type 2 diabetes and high cardiovascular risk, tirzepatide slowed the rate of eGFR decline and reduced UACR in clinically meaningful ways compared with insulin glargine. FUNDING Eli Lilly and Company.
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Affiliation(s)
- Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; The George Institute for Global Health, Sydney, NSW, Australia.
| | - Naveed Sattar
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Imre Pavo
- Eli Lilly and Company, Indianapolis, IN, USA
| | - Axel Haupt
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | | | | | | | - David Z I Cherney
- Division of Nephrology, Department of Medicine, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
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Gerstein HC, Ramasundarahettige C, Avezum A, Basile J, Conget I, Cushman WC, Dagenais GR, Franek E, Lakshmanan M, Lanas F, Leiter LA, Pogosova N, Probstfield J, Raubenheimer PJ, Riddle M, Shaw J, Sheu WHH, Temelkova-Kurktschiev T, Turfanda I, Xavier D. A novel kidney disease index reflecting both the albumin-to-creatinine ratio and estimated glomerular filtration rate, predicted cardiovascular and kidney outcomes in type 2 diabetes. Cardiovasc Diabetol 2022; 21:158. [PMID: 35996147 PMCID: PMC9396793 DOI: 10.1186/s12933-022-01594-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 06/14/2022] [Indexed: 12/03/2022] Open
Abstract
Background The estimated glomerular filtration rate (eGFR) and the albumin-to-creatinine ratio (ACR) are risk factors for diabetes-related outcomes. A composite that captures information from both may provide a simpler way of assessing risk. Methods 9115 of 9901 Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) participants with both an ACR and eGFR at baseline were included in this post hoc epidemiologic analysis. The hazard of higher baseline levels of 1/eGFR and natural log transformed ACR (calculated as ln [ACR × 100] to eliminate negative values) and their interaction for incident major adverse cardiovascular events (MACE), kidney outcomes, and deaths was estimated. The hazard of the geometric mean of these two baseline measures (the kidney disease index or KDI) was also assessed. Results A non-linear relationship was observed between 1/eGFR and all three outcomes, and between ln [ACR × 100] and the kidney outcome. There was also a negative interaction between these two risk factors with respect to MACE and death. Conversely, a linear relationship was noted between the KDI and all three outcomes. People in the highest KDI fifth experienced the highest incidence of MACE, death, and the kidney outcome (4.43, 4.56, and 5.55/100 person-years respectively). C statistics for the KDI were similar to those for eGFR and albuminuria. Conclusions The KDI combines the baseline eGFR and ACR into a novel composite risk factor that has a simple linear relationship with incident serious outcomes in people with diabetes and additional CV risk factors. Trial Registration clinicaltrials.gov NCT01394952. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-022-01594-6.
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Affiliation(s)
- Hertzel C Gerstein
- Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Canada. .,Department of Medicine, McMaster University, HSC 3V38, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
| | | | - Alvero Avezum
- International Research Center, Hospital Alemao Oswaldo Cruz, Sao Paulo, Brazil
| | - Jan Basile
- Medical University of South Carolina, Charleston, SC, USA
| | - Ignacio Conget
- Endocrinology and Nutrition Department, University of Barcelona, Barcelona, Spain
| | - William C Cushman
- Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Gilles R Dagenais
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec, Canada
| | - Edward Franek
- Mossakowski Clinical Research Center, Polish Academy of Sciences, Warsaw, Poland
| | | | | | - Lawrence A Leiter
- St. Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Canada
| | - Nana Pogosova
- National Medical Research Center of Cardiology, Moscow, Russia
| | | | | | - Matthew Riddle
- Department of Medicine, Oregon Health & Science University Portland, Oregon, USA
| | - Jonathan Shaw
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Wayne H-H Sheu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,School of Medicine, National Defense Medical Center, Taipei, Taiwan
| | | | - Ibrahim Turfanda
- Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
| | - Denis Xavier
- St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India
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Pan D, Xu L, Guo M. The role of protein kinase C in diabetic microvascular complications. Front Endocrinol (Lausanne) 2022; 13:973058. [PMID: 36060954 PMCID: PMC9433088 DOI: 10.3389/fendo.2022.973058] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 07/25/2022] [Indexed: 11/17/2022] Open
Abstract
Protein kinase C (PKC) is a family of serine/threonine protein kinases, the activation of which plays an important role in the development of diabetic microvascular complications. The activation of PKC under high-glucose conditions stimulates redox reactions and leads to an accumulation of redox stress. As a result, various types of cells in the microvasculature are influenced, leading to changes in blood flow, microvascular permeability, extracellular matrix accumulation, basement thickening and angiogenesis. Structural and functional disorders further exacerbate diabetic microvascular complications. Here, we review the roles of PKC in the development of diabetic microvascular complications, presenting evidence from experiments and clinical trials.
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Affiliation(s)
- Deng Pan
- Xiyuan hospital of China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
- Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Lin Xu
- Gynecological Department of Traditional Chinese Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Ming Guo
- Xiyuan hospital of China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Centre for Chinese Medicine Cardiology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China
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White NH, Pan Q, Knowler WC, Schroeder EB, Dabelea D, Chew EY, Blodi B, Goldberg RB, Pi-Sunyer X, Darwin C, Schlögl M, Nathan DM. The Effect of Interventions to Prevent Type 2 Diabetes on the Development of Diabetic Retinopathy: The DPP/DPPOS Experience. Diabetes Care 2022; 45:1640-1646. [PMID: 40315174 PMCID: PMC9375445 DOI: 10.2337/dc21-2417] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 04/09/2022] [Indexed: 03/14/2023]
Abstract
OBJECTIVE To determine whether interventions that slow or prevent the development of type 2 diabetes in those at risk reduce the subsequent prevalence of diabetic retinopathy. RESEARCH DESIGN AND METHODS The Diabetes Prevention Program (DPP) randomized subjects at risk for developing type 2 diabetes because of overweight/obesity and dysglycemia to metformin (MET), intensive lifestyle intervention (ILS), or placebo (PLB) to assess the prevention of diabetes. During the DPP and DPP Outcome Study (DPPOS), we performed fundus photography over time on study participants, regardless of their diabetes status. Fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study grading system, with diabetic retinopathy defined as typical lesions of diabetic retinopathy (microaneurysms, exudates, or hemorrhage, or worse) in either eye. RESULTS Despite reduced progression to diabetes in the ILS and MET groups compared with PLB, there was no difference in the prevalence of diabetic retinopathy between treatment groups after 1, 5, 11, or 16 years of follow-up. No treatment group differences in retinopathy were found within prespecified subgroups (baseline age, sex, race/ethnicity, baseline BMI). In addition, there was no difference in the prevalence of diabetic retinopathy between those exposed to metformin and those not exposed to metformin, regardless of treatment group assignment. CONCLUSION Interventions that delay or prevent the onset of type 2 diabetes in overweight/obese subjects with dysglycemia who are at risk for diabetes do not reduce the development of diabetic retinopathy for up to 20 years.
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Affiliation(s)
- Neil H. White
- Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO
| | - Qing Pan
- The Biostatistics Center, Milken Institute School of Public Health, George Washington University, Rockville, MD
| | - William C. Knowler
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ
| | | | - Dana Dabelea
- Colorado School of Public Health, Anschutz Medical Campus, Aurora, CO
| | - Emily Y. Chew
- Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD
| | - Barbara Blodi
- Fundus Photograph Reading Center, Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Ronald B. Goldberg
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | | | - Christine Darwin
- Department of Medicine/Endocrinology Diabetes, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA
| | - Mathias Schlögl
- University Clinic for Acute Geriatric Care, City Hospital Ward Zurich, Zurich, Switzerland
| | - David M. Nathan
- Diabetes Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA
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Alvarez Campano CG, Macleod MJ, Aucott L, Thies F. Marine-derived n-3 fatty acids therapy for stroke. Cochrane Database Syst Rev 2022; 6:CD012815. [PMID: 35766825 PMCID: PMC9241930 DOI: 10.1002/14651858.cd012815.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Currently, with stroke burden increasing, there is a need to explore therapeutic options that ameliorate the acute insult. There is substantial evidence of a neuroprotective effect of marine-derived n-3 polyunsaturated fatty acids (PUFAs) in animal models of stroke, leading to a better functional outcome. OBJECTIVES To assess the effects of administration of marine-derived n-3 PUFAs on functional outcomes and dependence in people with stroke. SEARCH METHODS We searched the Cochrane Stroke Trials Register (last searched 31 May 2021), the Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 5), MEDLINE Ovid (from 1948 to 31 May 2021), Embase Ovid (from 1980 to 31 May 2021), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; from 1982 to 31 May 2021), Science Citation Index Expanded ‒ Web of Science (SCI-EXPANDED), Conference Proceedings Citation Index-Science - Web of Science (CPCI-S), and BIOSIS Citation Index. We also searched ongoing trial registers, reference lists, relevant systematic reviews, and used the Science Citation Index Reference Search. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing marine-derived n-3 PUFAs to placebo or open control (no placebo) in people with a history of stroke or transient ischaemic attack (TIA), or both. DATA COLLECTION AND ANALYSIS At least two review authors independently selected trials for inclusion, extracted data, assessed risk of bias, and used the GRADE approach to assess the certainty of the body of evidence. We contacted study authors for clarification and additional information on stroke/TIA participants. We conducted random-effects meta-analysis or narrative synthesis, as appropriate. The primary outcome was efficacy (functional outcome) assessed using a validated scale, for example, the Glasgow Outcome Scale Extended (GOSE) dichotomised into poor or good clinical outcome, the Barthel Index (higher score is better; scale from 0 to 100), or the Rivermead Mobility Index (higher score is better; scale from 0 to 15). Our secondary outcomes were vascular-related death, recurrent events, incidence of other type of stroke, adverse events, quality of life, and mood. MAIN RESULTS We included 30 RCTs; nine of them provided outcome data (3339 participants). Only one study included participants in the acute phase of stroke (haemorrhagic). Doses of marine-derived n-3 PUFAs ranged from 400 mg/day to 3300 mg/day. Risk of bias was generally low or unclear in most trials, with a higher risk of bias in smaller studies. We assessed results separately for short (up to three months) and longer (more than three months) follow-up studies. Short follow-up (up to three months) Functional outcome was reported in only one pilot study as poor clinical outcome assessed with the GOSE (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.36 to 1.68, P = 0.52; 40 participants; very low-certainty evidence). Mood (assessed with the GHQ-30, lower score better) was reported by only one study and favoured control (mean difference (MD) 1.41, 95% CI 0.07 to 2.75, P = 0.04; 102 participants; low-certainty evidence). We found no evidence of an effect of the intervention for the remainder of the secondary outcomes: vascular-related death (two studies, not pooled due to differences in population, RR 0.33, 95% CI 0.01 to 8.00, P = 0.50, and RR 0.33, 95% CI 0.01 to 7.72, P = 0.49; 142 participants; low-certainty evidence); recurrent events (RR 0.41, 95% CI 0.02 to 8.84, P = 0.57; 18 participants; very low-certainty evidence); incidence of other type of stroke (two studies, not pooled due to different type of index stroke, RR 6.11, 95% CI 0.33 to 111.71, P = 0.22, and RR 0.63, 95% CI 0.25 to 1.58, P = 0.32; 58 participants; very low-certainty evidence); and quality of life (physical component, MD -2.31, 95% CI -4.81 to 0.19, P = 0.07, and mental component, MD -2.16, 95% CI -5.91 to 1.59, P = 0.26; 1 study; 102 participants; low-certainty evidence). Adverse events were reported by two studies (57 participants; very low-certainty evidence), one trial reporting extracranial haemorrhage (RR 0.25, 95% CI 0.04 to 1.73, P = 0.16) and the other one reporting bleeding complications (RR 0.32, 95% CI 0.01 to 7.35, P = 0.47). Longer follow-up (more than three months) One small trial assessed functional outcome with both the Barthel Index for activities of daily living (MD 7.09, 95% CI -5.16 to 19.34, P = 0.26), and the Rivermead Mobility Index for mobility (MD 1.30, 95% CI -1.31 to 3.91, P = 0.33) (52 participants; very low-certainty evidence). We carried out meta-analysis for vascular-related death (RR 1.02, 95% CI 0.78 to 1.35, P = 0.86; 5 studies; 2237 participants; low-certainty evidence) and fatal recurrent events (RR 0.69, 95% CI 0.31 to 1.55, P = 0.37; 3 studies; 1819 participants; low-certainty evidence). We found no evidence of an effect of the intervention for mood (MD 1.00, 95% CI -2.07 to 4.07, P = 0.61; 1 study; 14 participants; low-certainty evidence). Incidence of other type of stroke and quality of life were not reported. Adverse events (all combined) were reported by only one study (RR 0.94, 95% CI 0.56 to 1.58, P = 0.82; 1455 participants; low-certainty evidence). AUTHORS' CONCLUSIONS We are very uncertain of the effect of marine-derived n-3 PUFAs therapy on functional outcomes and dependence after stroke as there is insufficient high-certainty evidence. More well-designed RCTs are needed, specifically in acute stroke, to determine the efficacy and safety of the intervention. Studies assessing functional outcome might consider starting the intervention as early as possible after the event, as well as using standardised, clinically relevant measures for functional outcomes, such as the modified Rankin Scale. Optimal doses remain to be determined; delivery forms (type of lipid carriers) and mode of administration (ingestion or injection) also need further consideration.
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Affiliation(s)
| | | | - Lorna Aucott
- Health Services Research Unit, University of Aberdeen, Aberdeen, UK
| | - Frank Thies
- The Rowett Institute, University of Aberdeen, Aberdeen, UK
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Kommentar zu Diabetes-Subtypen unterscheiden sich in Bezug auf Komplikationen. DIABETOL STOFFWECHS 2022. [DOI: 10.1055/a-1723-3751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Pigeyre M, Hess S, Gomez MF, Asplund O, Groop L, Paré G, Gerstein H. Validation of the classification for type 2 diabetes into five subgroups: a report from the ORIGIN trial. Diabetologia 2022; 65:206-215. [PMID: 34676424 DOI: 10.1007/s00125-021-05567-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 07/14/2021] [Indexed: 02/01/2023]
Abstract
AIMS/HYPOTHESIS Data analyses from Swedish individuals with newly diagnosed diabetes have suggested that diabetes could be classified into five subtypes that differ with respect to the progression of dysglycaemia and the incidence of diabetes consequences. We assessed this classification in a multiethnic cohort of participants with established and newly diagnosed diabetes, randomly allocated to insulin glargine vs standard care. METHODS In total, 7017 participants from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were assigned to the five predefined diabetes subtypes (namely, severe auto-immune diabetes, severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes, mild age-related diabetes) based on the age at diabetes diagnosis, BMI, HbA1c, fasting C-peptide levels and the presence of glutamate decarboxylase antibodies at baseline. Differences between diabetes subtypes in cardiovascular and renal outcomes were investigated using Cox regression models for a median follow-up of 6.2 years. We also compared the effect of glargine vs standard care on hyperglycaemia, defined by having a mean post-randomisation HbA1c ≥6.5%, between subtypes. RESULTS The five diabetes subtypes were replicated in the ORIGIN trial and exhibited similar baseline characteristics in Europeans and Latin Americans, compared with the initially described clusters in the Swedish cohort. We confirmed differences in renal outcomes, with a higher incidence of events in the severe insulin-resistant diabetes subtype compared with the mild age-related diabetes subtype (i.e., chronic kidney disease stage 3A: HR 1.49 [95% CI 1.31, 1.71]; stage 3B: HR 2.25 [1.82, 2.78]; macroalbuminuria: HR 1.56 [1.22, 1.99]). No differences were observed in the incidence of retinopathy and cardiovascular diseases after adjusting for multiple hypothesis testing. Diabetes subtypes also differed in glycaemic response to glargine, with a particular benefit of receiving glargine (vs standard care) in the severe insulin-deficient diabetes subtype compared with the mild age-related diabetes subtype, with a decreased occurrence of hyperglycaemia by 13% (OR 1.36 [1.30, 1.41] on glargine; OR 1.49 [1.43, 1.57] on standard care; p for interaction subtype × intervention = 0.001). CONCLUSIONS/INTERPRETATION Cluster analysis enabled the characterisation of five subtypes of diabetes in a multiethnic cohort. Both the incidence of renal outcomes and the response to insulin varied between diabetes subtypes. These findings reinforce the clinical utility of applying precision medicine to predict comorbidities and treatment responses in individuals with diabetes. TRIAL REGISTRATION ORIGIN trial, ClinicalTrials.gov NCT00069784.
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Affiliation(s)
- Marie Pigeyre
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, ON, Canada.
- Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, ON, Canada.
- Department of Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada.
| | - Sibylle Hess
- R&D, Translational Medicine & Early Development, Biomarkers & Clinical Bioanalyses (BCB), Sanofi Aventis Deutschland GmbH, Frankfurt, Germany
| | - Maria F Gomez
- Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Olof Asplund
- Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
- Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
| | - Leif Groop
- Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
- Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
| | - Guillaume Paré
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, ON, Canada
- Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, ON, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada
- Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, ON, Canada
| | - Hertzel Gerstein
- Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, ON, Canada
- Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada
- Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, ON, Canada
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Mannon EC, Sartain CL, Wilkes TC, Sun J, Polichnowski AJ, O'Connor PM. RENAL MASS REDUCTION INCREASES THE RESPONSE TO EXOGENOUS INSULIN INDEPENDENT OF ACID-BASE STATUS OR PLASMA INSULIN LEVELS IN RATS. Am J Physiol Renal Physiol 2021; 321:F494-F504. [PMID: 34396787 DOI: 10.1152/ajprenal.00679.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Impairments in insulin sensitivity can occur in patients with chronic kidney disease (CKD). Correction of metabolic acidosis has been associated with improved insulin sensitivity in CKD, suggesting metabolic acidosis may directly promote insulin resistance. Despite this, the effect of acid or alkali loading on insulin sensitivity in a rodent model of CKD (remnant kidney) has not been directly investigated. Such studies could better define the relationship between blood pH and insulin sensitivity. We hypothesized that in remnant kidney rats, acid or alkali loading would promote loss of pH homeostasis and consequently decrease insulin sensitivity. To test this hypothesis, we determined the impact of alkali (2 weeks) or acid (5-7 days) loading on plasma electrolytes, acid-base balance, and insulin sensitivity in either sham control, 2/3 or 5/6 nephrectomy rats. Rats with 5/6 nephrectomy had the greatest response to insulin followed by animals with 2/3 nephrectomy and sham control rats. We found that treatment with a 0.1M sodium bicarbonate solution in drinking water had no effect on insulin sensitivity. Acid loading with 0.1M ammonium chloride resulted in significant reductions in pH and plasma bicarbonate. However, acidosis did not significantly impair insulin sensitivity. Similar effects were observed in Zucker obese rats with 5/6 nephrectomy. The effect of renal mass reduction on insulin sensitivity could not be explained by reduced insulin clearance or increased plasma insulin levels. We found that renal mass reduction alone increases sensitivity to exogenous insulin in rats, and that this is not acutely reversed by development of acidosis.
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Affiliation(s)
- Elinor C Mannon
- Department of Physiology, Augusta University, Augusta, Georgia, United States
| | - Christina L Sartain
- Department of Physiology, Augusta University, Augusta, Georgia, United States
| | - Trevin C Wilkes
- Medical College of Georgia at Augusta University, Augusta, Georgia, United States
| | - Jingping Sun
- Department of Physiology, Augusta University, Augusta, Georgia, United States
| | - Aaron J Polichnowski
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States
| | - Paul M O'Connor
- Department of Physiology, Augusta University, Augusta, Georgia, United States
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10
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Mosslemi M, Wong ND. Importance of applying treatment data to ascertain type 1 diabetes cases in health registries. BMJ Open Diabetes Res Care 2021; 9:9/1/e002280. [PMID: 33863717 PMCID: PMC8055103 DOI: 10.1136/bmjdrc-2021-002280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 04/02/2021] [Indexed: 11/08/2022] Open
Affiliation(s)
- Mitra Mosslemi
- Heart Disease Prevention Program, Division of Cardiology, University of California Irvine, Irvine, California, USA
| | - Nathan D Wong
- Heart Disease Prevention Program, Division of Cardiology, University of California Irvine, Irvine, California, USA
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11
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Lian H, Wu H, Ning J, Lin D, Huang C, Li F, Liang Y, Qi Y, Ren M, Yan L, You L, Xu M. The Risk Threshold for Hemoglobin A1c Associated With Albuminuria: A Population-Based Study in China. Front Endocrinol (Lausanne) 2021; 12:673976. [PMID: 34135862 PMCID: PMC8202121 DOI: 10.3389/fendo.2021.673976] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/28/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Diabetic kidney disease (DKD) is a kind of common microvascular complication of diabetes. This study aims to explore the possible links between blood sugar level and albuminuria, providing the exact cut point of the "risk threshold" for blood glucose with DKD. METHODS The relationship between blood glucose and albuminuria was modeled using linear and logistic regression in the REACTION study cohorts (N= 8932). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression model. Two-slope linear regression was used to simulate associations between blood glucose and ACR. RESULTS We found that the increase in ACR was accompanied by increased HbA1c, with a turning point at 5.5%. The positive correlation remained highly significant (P<0.001) when adjusted for age, sex, marital status, education, smoking status, drinking status, BMI, waistline, SBP and DBP. In subgroup analyses including gender, obesity, hypertension, and smoking habits, the relationship was significant and stable. CONCLUSIONS We determined a risk threshold for HbA1c associated with albuminuria in a Chinese population over the age of 40. HbA1c ≥ 5.5% was positively and independently associated with ACR. These results suggest the necessity of early blood glucose control and renal function screening for DKD in at-risk populations.
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Affiliation(s)
- Hong Lian
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hongshi Wu
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jie Ning
- Department of Metabolic Endocrinology, Shenzhen Longhua, District Central Hospital, Shenzhen, China
| | - Diaozhu Lin
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chulin Huang
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Feng Li
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ying Liang
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yiqin Qi
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Meng Ren
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li Yan
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lili You
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mingtong Xu
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Mingtong Xu,
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12
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Hanefeld M, Fleischmann H, Siegmund T, Seufert J. Rationale for Timely Insulin Therapy in Type 2 Diabetes Within the Framework of Individualised Treatment: 2020 Update. Diabetes Ther 2020; 11:1645-1666. [PMID: 32564335 PMCID: PMC7376805 DOI: 10.1007/s13300-020-00855-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes is characterised by chronic hyperglycaemia and variable degrees of insulin deficiency and resistance. Hyperglycaemia and elevated fatty acids exert harmful effects on β-cell function, regeneration and apoptosis (gluco-lipotoxicity). Furthermore, chronic hyperglycaemia triggers a vicious cycle of insulin resistance, low-grade inflammation and a cascade of pro-atherogenic processes. Thus, timely near to normal glucose control is of utmost importance in the management of type 2 diabetes and prevention of micro- and macroangiopathy. The majority of patients are multimorbid and obese, with critical comorbidities such as cardiovascular disease, heart failure and chronic kidney disease. Recently published guidelines therefore recommend patient-centred risk/benefit-balanced use of oral glucose-lowering drugs or a glucagon-like peptide 1 (GLP-1) receptor agonist, or switching to insulin with glycated haemoglobin (HbA1c) out of target. This article covers the indications of early insulin treatment to prevent diabetes-related complications, particularly in subgroups with severe insulin deficit, and to achieve recovery of residual β-cell function. Furthermore, the individualised, risk/benefit-balanced, timely initiation of insulin as second and third option is analysed. Timely insulin initiation may prevent diabetes progression, reduce diabetes-related complications and has less serious adverse effects. Basal insulin is the preferred option in most clinical situations with consequences of undertreatment of chronic hyperglycaemia.
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Affiliation(s)
- Markolf Hanefeld
- Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl Gustav Carus, Dresden, Germany.
| | - Holger Fleischmann
- Diabetes and Cardiovascular, Sanofi-Aventis Deutschland GmbH, Berlin, Germany
| | - Thorsten Siegmund
- Diabetes-, Hormon- und Stoffwechselzentrum, Isar Klinikum München GmbH, München, Germany
| | - Jochen Seufert
- Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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13
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Nathan DM, Bennett PH, Crandall JP, Edelstein SL, Goldberg RB, Kahn SE, Knowler WC, Mather KJ, Mudaliar S, Orchard TJ, Temprosa M, White NH. Does diabetes prevention translate into reduced long-term vascular complications of diabetes? Diabetologia 2019; 62:1319-1328. [PMID: 31270584 PMCID: PMC6818092 DOI: 10.1007/s00125-019-4928-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 05/14/2019] [Indexed: 12/22/2022]
Abstract
The global epidemic of type 2 diabetes has prompted numerous studies and public health efforts to reduce its development. A variety of interventions, including lifestyle modifications and pharmacological agents directed at ameliorating the major risk factors for type 2 diabetes, are of proven efficacy in reducing the development of type 2 diabetes in people with impaired glucose tolerance. While prevention of the hyperglycaemia characteristic of diabetes is arguably an important, clinically relevant outcome, a more compelling outcome with greater clinical significance is the prevention or reduction of the relatively diabetes-specific microvascular and less-specific cardiovascular disease (CVD) complications associated with diabetes. These complications cause the majority of morbidity and excess mortality associated with diabetes. Any reduction in diabetes should, logically, also reduce the occurrence of its long-term complications; however, most diabetes prevention trials have not been of sufficient duration to allow such an evaluation. The limited long-term data, largely from the Da Qing Diabetes Prevention Study (DQDPS) and the Diabetes Prevention Program (DPP) and their respective follow-up studies (DQDPOS and DPPOS), suggest a reduction in microvascular complications and amelioration of CVD risk factors. Only the DQDPOS and Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) studies have shown a reduction in CVD events and only DQDPOS has demonstrated a decrease in CVD and overall mortality. While these limited data are promising, whether diabetes prevention directly reduces complication-related morbidity and mortality remains unclear. Longer follow-up of prevention studies is needed to supplement the limited current clinical trial data, to help differentiate the effects of diabetes prevention itself from the means used to reduce diabetes development and to understand the balance among benefits, risks and costs of prevention.
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Affiliation(s)
- David M Nathan
- Massachusetts General Hospital Diabetes Center and Harvard Medical School, Boston, MA, USA.
| | - Peter H Bennett
- National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
| | | | - Sharon L Edelstein
- DPP/DPPOS Coordinating Center, Biostatistics Center, The George Washington University, 6110 Executive Blvd, Rockville, MD, USA
| | | | - Steven E Kahn
- VA Puget Sound Health Center and University of Washington School of Medicine, Seattle, WA, USA
| | - William C Knowler
- National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
| | - Kieren J Mather
- Indiana University School of Medicine, Indianapolis, IN, USA
| | | | - Trevor J Orchard
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA
| | - Marinella Temprosa
- DPP/DPPOS Coordinating Center, Biostatistics Center, The George Washington University, 6110 Executive Blvd, Rockville, MD, USA
| | - Neil H White
- Washington University School of Medicine, St Louis, MO, USA
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14
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Abstract
BACKGROUND Currently, with stroke burden increasing, there is a need to explore therapeutic options that ameliorate the acute insult. There is substantial evidence of a neuroprotective effect of marine-derived n-3 polyunsaturated fatty acids (PUFAs) in experimental stroke, leading to a better functional outcome. OBJECTIVES To assess the effects of administration of marine-derived n-3 PUFAs on functional outcomes and dependence in people with stroke.Our secondary outcomes were vascular-related death, recurrent events, incidence of other type of stroke, adverse events, quality of life, and mood. SEARCH METHODS We searched the Cochrane Stroke Group trials register (6 August 2018), the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, January 2019), MEDLINE Ovid (from 1948 to 6 August 2018), Embase Ovid (from 1980 to 6 August 2018), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; from 1982 to 6 August 2018), Science Citation Index Expanded ‒ Web of Science (SCI-EXPANDED), Conference Proceedings Citation Index-Science - Web of Science (CPCI-S), and BIOSIS Citation Index. We also searched ongoing trial registers, reference lists, relevant systematic reviews, and used the Science Citation Index Reference Search. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing marine-derived n-3 PUFAs to placebo or open control (no placebo) in people with a history of stroke or transient ischaemic attack (TIA), or both. DATA COLLECTION AND ANALYSIS At least two review authors independently selected trials for inclusion, extracted data, assessed risk of bias, and used the GRADE approach to assess the quality of the body of evidence. We contacted study authors for clarification and additional information on stroke/TIA participants. We conducted random-effects meta-analysis or narrative synthesis, as appropriate. The primary outcome was efficacy (functional outcome) assessed using a validated scale e.g. Glasgow Outcome Scale Extended (GOSE) dichotomised into poor or good clinical outcome, Barthel Index (higher score is better; scale from 0 to 100) or Rivermead Mobility Index (higher score is better; scale from 0 to 15). MAIN RESULTS We included 29 RCTs; nine of them provided outcome data (3339 participants). Only one study included participants in the acute phase of stroke (haemorrhagic). Doses of marine-derived n-3 PUFAs ranged from 400 mg/day to 3300 mg/day. Risk of bias was generally low or unclear in most trials, with a higher risk of bias in smaller studies. We assessed results separately for short (up to three months) and longer (more than three months) follow-up studies.Short follow-up (up to three months)Functional outcome was reported in only one pilot study as poor clinical outcome assessed with GOSE (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.36 to 1.68; 40 participants; very low quality evidence). Mood (assessed with GHQ-30, lower score better), was reported by only one study and favoured control (mean difference (MD) 1.41, 95% CI 0.07 to 2.75; 102 participants; low-quality evidence).We found no evidence of an effect of the intervention for the remainder of the secondary outcomes: vascular-related death (two studies, not pooled due to differences in population, RR 0.33, 95% CI 0.01 to 8.00, and RR 0.33, 95% CI 0.01 to 7.72; 142 participants; low-quality evidence); recurrent events (RR 0.41, 95% CI 0.02 to 8.84; 18 participants; very low quality evidence); incidence of other type of stroke (two studies, not pooled due to different type of index stroke, RR 6.11, 95% CI 0.33 to 111.71, and RR 0.63, 95% CI 0.25 to 1.58; 58 participants; very low quality evidence); and quality of life (physical component mean difference (MD) -2.31, 95% CI -4.81 to 0.19, and mental component MD -2.16, 95% CI -5.91 to 1.59; one study; 102 participants; low-quality evidence).Adverse events were reported by two studies (57 participants; very low quality evidence), one trial reporting extracranial haemorrhage (RR 0.25, 95% CI 0.04 to 1.73) and the other one reporting bleeding complications (RR 0.32, 95% CI 0.01 to 7.35).Longer follow-up (more than three months)One small trial assessed functional outcome with both Barthel Index (MD 7.09, 95% CI -5.16 to 19.34) for activities of daily living, and Rivermead Mobility Index (MD 1.30, 95% CI -1.31 to 3.91) for mobility (52 participants; very low quality evidence). We carried out meta-analysis for vascular-related death (RR 1.02, 95% CI 0.78 to 1.35; five studies; 2237 participants; low-quality evidence) and fatal recurrent events (RR 0.69, 95% CI 0.31 to 1.55; three studies; 1819 participants; low-quality evidence).We found no evidence of an effect of the intervention for mood (MD 1.00, 95% CI -2.07 to 4.07; one study; 14 participants; low-quality evidence). Incidence of other type of stroke and quality of life were not reported.Adverse events (all combined) were reported by only one study (RR 0.94, 95% CI 0.56 to 1.58; 1455 participants; low-quality evidence). AUTHORS' CONCLUSIONS We are very uncertain of the effect of marine-derived n-3 PUFAs therapy on functional outcomes and dependence after stroke as there is insufficient high-quality evidence. More well-designed RCTs are needed, specifically in acute stroke, to determine the efficacy and safety of the intervention.Studies assessing functionality might consider starting the intervention as early as possible after the event, as well as using standardised clinically-relevant measures for functional outcomes, such as the modified Rankin Scale. Optimal doses remain to be determined; delivery forms (type of lipid carriers) and mode of administration (ingestion or injection) also need further consideration.
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15
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Xu Y, Gomes T, Mamdani MM, Juurlink DN, Cadarette SM, Tadrous M. Analysis of Trends in Insulin Utilization and Spending Across Canada From 2010 to 2015. Can J Diabetes 2019; 43:179-185.e1. [DOI: 10.1016/j.jcjd.2018.08.190] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/20/2018] [Accepted: 08/09/2018] [Indexed: 01/01/2023]
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16
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Birkeland KI, Grill V, Wium C, McQueen MJ, Lopez-Jaramillo P, Lee SF, Gerstein HC. The association of basal insulin treatment versus standard care with outcomes in anti-GAD positive and negative subjects: A post-hoc analysis of the ORIGIN trial. Diabetes Obes Metab 2019; 21:429-433. [PMID: 30203580 DOI: 10.1111/dom.13528] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 08/25/2018] [Accepted: 09/05/2018] [Indexed: 11/29/2022]
Abstract
We compared cardiovascular and other outcomes in patients with dysglycaemia with or without anti-glutamic acid dehydrogenase (GAD) antibodies participating in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. Of the 12 537 participants, 8162 had anti-GAD measured at baseline and 267 were anti-GAD positive. The effects of insulin glargine versus standard care and of n-3 fatty acids supplements versus placebo were compared by testing the interaction of the treatment effects and anti-GAD status. The effect of glargine on development of new diabetes was assessed in participants without previous diabetes at baseline. The overall incidence of outcomes did not differ between anti-GAD positive and anti-GAD negative subjects. The incidence of the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke did not differ between anti-GAD positive participants randomized to insulin glargine or to standard care, with a hazard ratio (HR) (95% confidence interval [CI]) of 0.80 (0.44-1.44) or in anti-GAD negative participants with a HR of 1.07 (0.96-1.20) (P for interaction = 0.20).
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Affiliation(s)
- Kåre I Birkeland
- Department of Transplantation Medicine, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Valdemar Grill
- Department of Endocrinology, St. Olav's Hospital, Trondheim, Norway
- Institute of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Cecilie Wium
- Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
| | - Matthew J McQueen
- Department of Pathology and Molecular Medicine, Population Health Research Institute, McMaster University Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Patricio Lopez-Jaramillo
- Research Institute, FOSCAL, Bucaramanga, Colombia and Universidad Tecnológica Equinoccial, Facultad de Ciencias de la Salud Eugenio Espejo, Quito, Ecuador
| | - Shun Fu Lee
- Department of Statistics, Population Health Research institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Hertzel C Gerstein
- Department of Medicine, Population Health Research institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
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17
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Santos Cavaiola T, Kiriakov Y, Reid T. Primary Care Management of Patients With Type 2 Diabetes: Overcoming Inertia and Advancing Therapy With the Use of Injectables. Clin Ther 2019; 41:352-367. [PMID: 30655008 DOI: 10.1016/j.clinthera.2018.11.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 11/07/2018] [Accepted: 11/26/2018] [Indexed: 12/31/2022]
Abstract
Type 2 diabetes (T2D) is a progressive disease caused by insulin resistance and associated progressive β-cell functional decline, as well as multiple other related metabolic and pathophysiologic changes. Left unchecked, T2D increases the risk of long-term microvascular and cardiovascular complications and is associated with excess morbidity and mortality. Despite multiple effective options for reducing hyperglycemia, patients are not optimally managed, largely due to delays in appropriate and timely advancement of therapy. Glucagon-like peptide-1 receptor agonists and basal insulin are recommended by treatment guidelines as effective options for advancing therapy to achieve glycemic control. However, injected therapies often face resistance from patients and clinicians. Glucagon-like peptide-1 receptor agonists are associated with weight loss, low risk of hypoglycemia, and potential beneficial cardiovascular effects. The class is recommended for patients across the spectrum of disease severity and represents an attractive option to add to basal insulin therapy when additional control is needed. Newer second-generation basal insulin analogues offer advantages over first-generation basal insulins in terms of lower hypoglycemia rates and greater flexibility in dosing. Incorporating injectable therapy into patient care in a timely manner has the potential to improve outcomes and must not be overlooked. Primary care clinicians play a significant role in managing patients with T2D, and they must be able to address and overcome patient resistance and their own barriers to advancing therapy if optimal treatment outcomes are to be achieved. The purpose of this expert opinion article was to provide a commentary on the key principle of advancing therapy with injectables to control hyperglycemia.
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Affiliation(s)
| | - Yan Kiriakov
- Abington-Jefferson Urgent Care, Willow Grove, PA, United States
| | - Timothy Reid
- Mercy Diabetes Center, Janesville, WI, United States
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18
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Scheen AJ. Effects of glucose-lowering agents on surrogate endpoints and hard clinical renal outcomes in patients with type 2 diabetes. DIABETES & METABOLISM 2018; 45:110-121. [PMID: 30477733 DOI: 10.1016/j.diabet.2018.10.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 09/17/2018] [Accepted: 10/08/2018] [Indexed: 12/12/2022]
Abstract
Diabetic kidney disease (DKD) represents an enormous burden in patients with type 2 diabetes mellitus (T2DM). Preclinical studies using most glucose-lowering agents have suggested renal-protective effects, but the proposed mechanisms of renoprotection have yet to be defined, and the promising results from experimental studies remain to be translated into human clinical findings to improve the prognosis of patients at risk of DKD. Also, it is important to distinguish effects on surrogate endpoints, such as decreases in albuminuria and estimated glomerular filtration rate (eGFR), and hard clinical endpoints, such as progression to end-stage renal disease (ESRD) and death from renal causes. Data regarding insulin therapy are surprisingly scarce, and it is nearly impossible to separate the effects of better glucose control from those of insulin per se, whereas favourable preclinical data with metformin, thiazolidinediones and dipeptidyl peptidase (DPP)-4 inhibitors are plentiful, and positive effects have been observed in clinical studies, at least for surrogate endpoints. The most favourable renal results have been reported with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter type-2 inhibitors (SGLT2is). Significant reductions in both albuminuria and eGFR decline have been reported with these classes of glucose-lowering medications compared with placebo and other glucose-lowering agents. Moreover, in large prospective cardiovascular outcome trials using composite renal outcomes as secondary endpoints, both GLP-1RAs and SGLT2is added to standard care reduced renal outcomes combining persistent macro-albuminuria, doubling of serum creatinine, progression to ESRD and kidney-related death; however, to date, only SGLT2is have been clearly shown to reduce such hard clinical outcomes. Yet, as the renoprotective effects of SGLT2is and GLP-1RAs appear to be independent of glucose-lowering activity, the underlying mechanisms are still a matter of debate. For this reason, further studies with renal outcomes as primary endpoints are now awaited in T2DM patients at high risk of DKD, including trials evaluating the potential add-on benefits of combined GLP-1RA-SGLT2i therapies.
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Affiliation(s)
- A J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium; Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU de Liège, Liège, Belgium.
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19
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Giugliano D, Maiorino MI, Bellastella G, Esposito K. Type 2 diabetes and cardiovascular prevention: the dogmas disputed. Endocrine 2018; 60:224-228. [PMID: 28895030 DOI: 10.1007/s12020-017-1418-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 08/31/2017] [Indexed: 11/25/2022]
Abstract
In randomized controlled trials (RCTs), more intensive glucose control in patients with type 2 diabetes leads to a modest (9%) reduction in major cardiovascular events (MACE), associated with a 20% reduction of kidney events and 13% reduction of eye events. The FDA issued guidance in 2008 led to the conduct of numerous cardiovascular outcomes (CVOT) trials to assess cardiovascular safety of new antihyperglycemic therapies in patients with type 2 diabetes. The results of these trials show that insulin glargine, three different dipeptidyl peptidase-4 (DPP-4) inhibitors (saxagliptin, alogliptin, and sitagliptin) and lixisenatide (a glucagon like peptide-1 receptor agonist) produce no significant difference in CVOT when compared with usual care or placebo. Other trials with newer diabetes drugs, including empagliflozin and canagliflozin (two sodium-glucose co-transporter-2 inhibitors), liraglutide and semaglutide (two GLP-1 receptor agonists) succeeded in demonstrating CV benefit in people with type 2 diabetes. In the last two decades, the equation "diabetes equals myocardial infarction" have contributed to the development of preventive therapy for risk factors in diabetes. In both primary and secondary prevention, the diabetic patients with high rates of statin and aspirin treatment have improved CV outcome, as compared with non-users. The drugs used to reduce glucose levels in patients with type 2 diabetes seem important for the ultimate cardiovascular outcome: the combination of intensive glycemic control, when safely attainable, with newer diabetes drugs (empagliflozin, canagliflozin, liraglutide, and semaglutide) may decrease the incidence of MACE, nephropathy and retinopathy. Moreover, depending on the drug used, CV mortality and heart failure may also be reduced.
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Affiliation(s)
- Dario Giugliano
- Section of Endocrinology and Diabetes, Department of Medical, Surgical, Neurological, Metabolic Sciences and Aging, L. Vanvitelli University, Naples, Italy.
| | - Maria Ida Maiorino
- Section of Endocrinology and Diabetes, Department of Medical, Surgical, Neurological, Metabolic Sciences and Aging, L. Vanvitelli University, Naples, Italy
| | - Giuseppe Bellastella
- Section of Endocrinology and Diabetes, Department of Medical, Surgical, Neurological, Metabolic Sciences and Aging, L. Vanvitelli University, Naples, Italy
| | - Katherine Esposito
- Section of Endocrinology and Diabetes, Department of Medical, Surgical, Neurological, Metabolic Sciences and Aging, L. Vanvitelli University, Naples, Italy
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MacIsaac RJ, Jerums G, Ekinci EI. Glycemic Control as Primary Prevention for Diabetic Kidney Disease. Adv Chronic Kidney Dis 2018; 25:141-148. [PMID: 29580578 DOI: 10.1053/j.ackd.2017.11.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 11/27/2017] [Accepted: 11/28/2017] [Indexed: 12/23/2022]
Abstract
Improving strategies to prevent the development and progression of CKD is a highly desirable outcome for all involved in the care of patients with diabetes. This is because CKD is a major factor contributing to morbidly and mortality in patients with diabetes. Furthermore, diabetes is the leading cause of ESRD in most developed countries. Although tight glucose control is now an established modality for preventing the development and progression of albuminuria, evidence is now accumulating to suggest that it can also ameliorate glomerular filtration rate loss and possibly progression to ESRD. These benefits of intensive glucose control appear to be most pronounced when applied to patients with the early stages of CKD. Recently, medications that belong to the sodium glucose cotransporter-type 2 inhibitor and the glucagon-like peptide-1 receptor analogue classes have been shown to reduce progression of CKD in patients with type 2 diabetes and relatively well-preserved kidney function. Here, we review the evidence from observational and interventional clinical studies that link good glucose control with the primary prevention of diabetic kidney disease with a focus on preventing early glomerular filtration rate loss.
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Abstract
With the rising incidence and prevalence rates of type 2 diabetes globally, it is imperative that diabetes prevention strategies are implemented to stem the flow of new cases. Successful interventions include both lifestyle modification and pharmaceutical agents, and large, multicentre, randomised, controlled studies in different populations have identified the benefits of both. However, translating positive trial outcomes to the real world is particularly challenging, as lifestyle interventions require regular reinforcement from healthcare professionals to be maintained. Pharmaceutical therapies may therefore play an adjunctive role in combination with lifestyle to prevent diabetes. Population-based strategies are also necessary to reduce sedentary behaviour and obesity. Well-established glucose-lowering therapies such as metformin, sulphonylureas, thiazolidinediones and insulin and newer agents such as incretin therapies and sodium glucose co-transporter 2 inhibitors have all been investigated in randomised controlled trials for diabetes prevention with varying success. Non-glucose-lowering therapies such as orlistat and renin angiotensin system blockers can prevent diabetes, whereas statins are associated with slightly increased risk. Diabetes prevention strategies should carefully consider the use of these agents according to individual patient circumstances and phenotypic profile.
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Skolnik N, Dupree RS, Johnson EL. iGlarLixi, a titratable once-daily fixed-ratio combination of basal insulin and lixisenatide for intensifying type 2 diabetes management for patients inadequately controlled on basal insulin with or without oral agents. Curr Med Res Opin 2017; 33:2187-2194. [PMID: 28741967 DOI: 10.1080/03007995.2017.1359518] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Achieving and maintaining glycemic control is important for people with type 2 diabetes (T2D), to reduce disease-related complications and mortality; however, about half of US patients fail to meet glycemic targets. iGlarLixi, a titratable fixed-ratio combination of insulin glargine 100 U/mL (iGlar) and lixisenatide for once-daily administration, was recently approved by the US Food and Drug Administration for use in adults with T2D inadequately controlled on basal insulin (<60 U daily) or lixisenatide. iGlar and lixisenatide have complementary mechanisms of action, primarily targeting fasting plasma glucose and postprandial plasma glucose, respectively. In the US, iGlarLixi is available in a 3:1 ratio of iGlar and lixisenatide, respectively, across the dosage range of 15-60 U of iGlar and 5-20 µg of lixisenatide. METHODS This study identified phase 3 trials which assessed the efficacy and safety of iGlarLixi. Relevant trials were LixiLan-O, which compared iGlarLixi with iGlar or lixisenatide alone in insulin-naïve patients, and LixiLan-L, which compared iGlarLixi with iGlar alone in insulin-experienced patients. RESULTS Patients on iGlarLixi experienced greater A1C reduction and were more likely to achieve A1C <7.0% than its comparators. iGlarLixi mitigated the weight gain associated with iGlar without increasing hypoglycemia risk, and resulted in a lower frequency of gastrointestinal adverse events compared with lixisenatide. CONCLUSIONS iGlarLixi provides a new approach to therapy intensification in patients with T2D. iGlarLixi showed greater A1C efficacy compared with either iGlar or lixisenatide, mitigating iGlar-associated weight gain, without increasing hypoglycemia risk, and reducing the gastrointestinal side-effects seen with lixisenatide.
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Affiliation(s)
- Neil Skolnik
- a Abington Family Medicine , Jenkintown , PA , USA
- b Abington Jefferson Health , Jenkintown , PA , USA
| | | | - Eric L Johnson
- c University of North Dakota School of Medicine and Health Sciences , Grand Forks , ND , USA
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Papademetriou V, Nylen ES, Doumas M, Probstfield J, Mann JFE, Gilbert RE, Gerstein HC. Chronic Kidney Disease, Basal Insulin Glargine, and Health Outcomes in People with Dysglycemia: The ORIGIN Study. Am J Med 2017; 130:1465.e27-1465.e39. [PMID: 28842165 DOI: 10.1016/j.amjmed.2017.05.047] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Revised: 05/26/2017] [Accepted: 05/29/2017] [Indexed: 01/16/2023]
Abstract
BACKGROUND Early stages of chronic kidney disease are associated with an increased cardiovascular risk in patients with established type 2 diabetes and macrovascular disease. The role of early stages of chronic kidney disease on macrovascular outcomes in prediabetes and early type 2 diabetes mellitus is not known. In the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, the introduction of insulin had no effect on cardiovascular outcomes compared with standard therapy. In this post hoc analysis of ORIGIN, we compared cardiovascular outcomes in subjects without to those with mild (Stages 1-2) or moderate chronic kidney disease (Stage 3). METHODS Τwo co-primary composite cardiovascular outcomes were assessed. The first was the composite end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes; and the second was a composite of any of these events plus a revascularization procedure, or hospitalization for heart failure. Several secondary outcomes were prespecified, including microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers. RESULTS Complete renal function data were available in 12,174 of 12,537 ORIGIN participants. A total of 8114 (67%) had no chronic kidney disease, while 4060 (33%) had chronic kidney disease stage 1-3. When compared with nonchronic kidney disease participants, the risk of developing the composite primary outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) in those with mild to moderate chronic kidney disease was 87% higher; hazard ratio (HR) 1.87; 95% confidence interval (CI), 1.71-2.04 (P < .0001). The presence of chronic kidney disease 1-3 was also associated with a greater than twofold higher risk for both all-cause mortality (HR 2.17; 95% CI, 1.98-2.38; P < .0001) and cardiovascular mortality (HR 2.39; 95% CI, 2.13-2.69; P < .0001). Moreover, patients with mild to moderate chronic kidney disease had significantly higher risk for nonfatal myocardial infarction (50%), nonfatal stroke (68%), any stroke (84%), the above composite primary end point plus revascularization or heart failure requiring hospitalization (59%), or a major coronary artery disease event (56%). Furthermore, in patients with chronic kidney disease and early diabetes mellitus type 2, the primary end point occurred 83% more frequently as compared with nonchronic kidney disease participants (HR 1.83; 95% CI, 1.67-2.01; P < .001) and in patients with prediabetes and chronic kidney disease 67% more frequently (HR 1.67; 95% CI,1.25-2.24; P < .001). CONCLUSIONS In high-risk patients with dysglycemia (prediabetes and early diabetes), mild and moderate chronic kidney disease significantly increased cardiovascular events.
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Affiliation(s)
- Vasilios Papademetriou
- Veterans Administration Medical Center, Washington, DC; Georgetown University Medical Center, Washington, DC.
| | - Eric S Nylen
- Veterans Administration Medical Center, Washington, DC; George Washington University Medical Centers, Washington, DC
| | - Michael Doumas
- George Washington University Medical Centers, Washington, DC; Aristotle University of Thessaloniki, Greece
| | | | | | | | - Hertzel C Gerstein
- Department of Medicine and Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada
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Hasslacher C, Lorenzo Bermejo J. Treatment with insulin analogs and prevalence of cardiovascular complications in patients with type 1 diabetes. Ther Adv Endocrinol Metab 2017; 8:149-157. [PMID: 29114384 PMCID: PMC5656110 DOI: 10.1177/2042018817732732] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 08/24/2017] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND A lower incidence of cardiovascular events has been reported in type 2 diabetes patients treated with insulin analogs (IAs). Corresponding data on people affected by type 1 diabetes are not available yet. METHODOLOGY We investigated demographic and clinical data from 509 type 1 diabetics, who were treated in an outpatient clinic from 2006 to 2012. Multiple logistic regression was used to investigate the relationship between the type of insulin treatment and the prevalence of cardiovascular (CV) complications, that is, presence of coronary heart, cerebrovascular and peripheral arterial diseases, adjusting for potential confounders. RESULTS Results from multiple logistic regression revealed that patients with impaired renal function [estimated glomerular filtration rate (eGFR) < 90 ml/min] show lower CV complication rates when treated with IAs (25%) compared with patients treated with human insulin (HI; 28%) and HI/IA (38%, p = 0.06). CV complication rates in the complete patient collective amounted to 17% (IA), 21% (HI) and 21% (HI/IA, p = 0.08). Examination of CV complications according to the type of IA revealed the lowest complication rates in type 1 diabetics treated with insulin lispro (5.9%) and glargine (16%). However, complication rate differences among insulin treatments did not reach statistical significance. CONCLUSION The present cross-sectional study shows a borderline significantly lower CV morbidity in people with type 1 diabetes and impaired renal function when treated with IA compared with HI treatment after adjustment for multiple potential confounders [odds ratio (OR) = 0.78, which translates into a 22% lower complication rate]. Validation of these preliminary findings in confirmatory, prospective studies may have important clinical implications.
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MacIsaac RJ, Jerums G, Ekinci EI. Effects of glycaemic management on diabetic kidney disease. World J Diabetes 2017; 8:172-186. [PMID: 28572879 PMCID: PMC5437616 DOI: 10.4239/wjd.v8.i5.172] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 11/07/2016] [Accepted: 03/17/2017] [Indexed: 02/05/2023] Open
Abstract
Hyperglycaemia contributes to the onset and progression of diabetic kidney disease (DKD). Observational studies have not consistently demonstrated a glucose threshold, in terms of HbA1c levels, for the onset of DKD. Tight glucose control has clearly been shown to reduce the incidence of micro- or macroalbuminuria. However, evidence is now also emerging to suggest that intensive glucose control can slow glomerular filtration rate loss and possibly progression to end stage kidney disease. Achieving tight glucose control needs to be balanced against the increasing appreciation that glucose targets for the prevention of diabetes related complications need be individualised for each patient. Recently, empagliflozin which is an oral glucose lowering agent of the sodium glucose cotransporter-2 inhibitor class has been shown to have renal protective effects. However, the magnitude of empagliflozin’s reno-protective properties are over and above that expected from its glucose lowering effects and most likely largely result from mechanisms involving alterations in intra-renal haemodynamics. Liraglutide and semaglutide, both injectable glucose lowering agents which are analogues of human glucagon like peptide-1 have also been shown to reduce progression to macroalbuminuria through mechanisms that remain to be fully elucidated. Here we review the evidence from observational and interventional studies that link good glucose control with improved renal outcomes. We also briefly review the potential reno-protective effects of newer glucose lowering agents.
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Abstract
Insulin resistance is a systemic disorder that affects many organs and insulin-regulated pathways. The disorder is characterized by a reduced action of insulin despite increased insulin concentrations (hyperinsulinaemia). The effects of insulin on the kidney and vasculature differ in part from the effects on classical insulin target organs. Insulin causes vasodilation by enhancing endothelial nitric oxide production through activation of the phosphatidylinositol 3-kinase pathway. In insulin-resistant states, this pathway is impaired and the mitogen-activated protein kinase pathway stimulates vasoconstriction. The action of insulin on perivascular fat tissue and the subsequent effects on the vascular wall are not fully understood, but the hepatokine fetuin-A, which is released by fatty liver, might promote the proinflammatory effects of perivascular fat. The strong association of salt-sensitive arterial hypertension with insulin resistance indicates an involvement of the kidney in the insulin resistance syndrome. The insulin receptor is expressed on renal tubular cells and podocytes and insulin signalling has important roles in podocyte viability and tubular function. Renal sodium transport is preserved in insulin resistance and contributes to the salt-sensitivity of blood pressure in hyperinsulinaemia. Therapeutically, renal and vascular insulin resistance can be improved by an integrated holistic approach aimed at restoring overall insulin sensitivity and improving insulin signalling.
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Stefan N, Fritsche A, Schick F, Häring HU. Phenotypes of prediabetes and stratification of cardiometabolic risk. Lancet Diabetes Endocrinol 2016; 4:789-798. [PMID: 27185609 DOI: 10.1016/s2213-8587(16)00082-6] [Citation(s) in RCA: 155] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 02/17/2016] [Accepted: 02/26/2016] [Indexed: 02/07/2023]
Abstract
Prediabetes is associated with increased risks of type 2 diabetes, cardiovascular disease, dementia, and cancer, and its prevalence is increasing worldwide. Lifestyle and pharmacological interventions in people with prediabetes can prevent the development of diabetes and possibly cardiovascular disease. However, prediabetes is a highly heterogeneous metabolic state, both with respect to its pathogenesis and prediction of disease. Improved understanding of these features and precise phenotyping of prediabetes could help to improve stratification of disease risk. In this Personal View, we focus on the extreme metabolic phenotypes of metabolically healthy obesity and metabolically unhealthy normal weight, insulin secretion failure, insulin resistance, visceral obesity, and non-alcoholic fatty liver disease. We present new analyses aimed at improving characterisation of phenotypes in lean, overweight, and obese people with prediabetes. We discuss evidence from lifestyle intervention studies to explore whether these phenotypes can also be used for individualised prediction and prevention of cardiometabolic diseases.
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Affiliation(s)
- Norbert Stefan
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany; German Centre for Diabetes Research (DZD), Tübingen, Germany.
| | - Andreas Fritsche
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany; German Centre for Diabetes Research (DZD), Tübingen, Germany
| | - Fritz Schick
- Section of Experimental Radiology, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany; German Centre for Diabetes Research (DZD), Tübingen, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany; German Centre for Diabetes Research (DZD), Tübingen, Germany
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Hanefeld M, Monnier L, Schnell O, Owens D. Early Treatment with Basal Insulin Glargine in People with Type 2 Diabetes: Lessons from ORIGIN and Other Cardiovascular Trials. Diabetes Ther 2016; 7:187-201. [PMID: 26861811 PMCID: PMC4900970 DOI: 10.1007/s13300-016-0153-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Indexed: 01/09/2023] Open
Abstract
UNLABELLED Dysglycemia results from a deficit in first-phase insulin secretion compounded by increased insulin insensitivity, exposing β cells to chronic hyperglycemia and excessive glycemic variability. Initiation of intensive insulin therapy at diagnosis of type 2 diabetes mellitus (T2DM) to achieve normoglycemia has been shown to reverse glucotoxicity, resulting in recovery of residual β-cell function. The United Kingdom Prospective Diabetes Study (UKPDS) 10-year post-trial follow-up reported reductions in cardiovascular outcomes and all-cause mortality in persons with T2DM who initially received intensive glucose control compared with standard therapy. In the cardiovascular outcome trial, outcome reduction with an initial glargine intervention (ORIGIN), a neutral effect on cardiovascular disease was observed in the population comprising prediabetes and T2DM. Worsening of glycemic control was prevented over the 6.7 year treatment period, with few serious hypoglycemic episodes and only moderate weight gain, with a lesser need for dual or triple oral treatment versus standard care. Several other studies have also highlighted the benefits of early insulin initiation as first-line or add-on therapy to metformin. The decision to introduce basal insulin to metformin must, however be individualized based on a risk-benefit analysis. The landmark ORIGIN trial provides many lessons relating to the concept and application of early insulin therapy for the prevention and safe and effective induction and maintenance of glycemic control in type 2 diabetes. FUNDING Sanofi.
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Affiliation(s)
| | - Louis Monnier
- Institute of Clinical Research, University Montpellier 1, Montpellier, France
| | | | - David Owens
- Institute of Life Sciences, Swansea University, Swansea, UK.
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29
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Galligan A, Greenaway TM. Novel approaches to the treatment of hyperglycaemia in type 2 diabetes mellitus. Intern Med J 2016; 46:540-9. [DOI: 10.1111/imj.13070] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 12/01/2015] [Accepted: 12/03/2015] [Indexed: 12/15/2022]
Affiliation(s)
- A. Galligan
- Department of Endocrinology; The Royal Hobart Hospital; Hobart Tasmania Australia
| | - T. M. Greenaway
- Department of Endocrinology; The Royal Hobart Hospital; Hobart Tasmania Australia
- The School of Medicine, Faculty of Health Science; University of Tasmania; Hobart Tasmania Australia
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30
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Cardiovascular and Other Outcomes Postintervention With Insulin Glargine and Omega-3 Fatty Acids (ORIGINALE). Diabetes Care 2016; 39:709-716. [PMID: 26681720 DOI: 10.2337/dc15-1676] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 11/09/2015] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial reported neutral effects of insulin glargine on cardiovascular outcomes and cancers and reduced incident diabetes in high-cardiovascular risk adults with dysglycemia after 6.2 years of active treatment. Omega-3 fatty acids had neutral effects on cardiovascular outcomes. The ORIGIN and Legacy Effects (ORIGINALE) study measured posttrial effects of these interventions during an additional 2.7 years. RESEARCH DESIGN AND METHODS Surviving ORIGIN participants attended up to two additional visits. The hazard of clinical outcomes during the entire follow-up period from randomization was calculated. RESULTS Of 12,537 participants randomized, posttrial data were analyzed for 4,718 originally allocated to insulin glargine (2,351) versus standard care (2,367), and 4,771 originally allocated to omega-3 fatty acid supplements (2,368) versus placebo (2,403). Posttrial, small differences in median HbA1c persisted (glargine 6.6% [49 mmol/mol], standard care 6.7% [50 mmol/mol], P = 0.025). From randomization to the end of posttrial follow-up, no differences were found between the glargine and standard care groups in myocardial infarction, stroke, or cardiovascular death (1,185 vs. 1,165 events; hazard ratio 1.01 [95% CI 0.94-1.10]; P = 0.72); myocardial infarction, stroke, cardiovascular death, revascularization, or hospitalization for heart failure (1,958 vs. 1,910 events; 1.03 [0.97-1.10]; P = 0.38); or any cancer (524 vs. 529 events; 0.99 [0.88-1.12]; P = 0.91) or between omega-3 and placebo groups in cardiovascular death (688 vs. 700; 0.98 [0.88-1.09]; P = 0.68) or other outcomes. CONCLUSIONS During >6 years of treatment followed by >2.5 years of observation, insulin glargine had neutral effects on health outcomes and salutary effects on metabolic control, whereas omega-3 fatty acid supplementation had no effect.
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31
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Mast R, Danielle Jansen AP, Walraven I, Rauh SP, van der Heijden AAWA, Heine RJ, Elders PJM, Dekker JM, Nijpels G, Hugtenburg JG. Time to insulin initiation and long-term effects of initiating insulin in people with type 2 diabetes mellitus: the Hoorn Diabetes Care System Cohort Study. Eur J Endocrinol 2016; 174:563-71. [PMID: 26837781 DOI: 10.1530/eje-15-1149] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 02/02/2016] [Indexed: 11/08/2022]
Abstract
OBJECTIVE The aim of this study was to assess the time to insulin initiation in type 2 diabetes mellitus (T2DM) patients treated with oral glucose-lowering agents and to determine the baseline characteristics associated with time to insulin initiation. This was evaluated in T2DM patients with HbA1c levels consistently ≥7.0% during total follow up and in those with fluctuating HbA1c levels around 7.0%. DESIGN AND METHODS Prospective, observational study was performed, comprising 2418 persons with T2DM aged ≥40 years who entered the Diabetes Care System between 1998 and 2012 with a minimum follow up of at least 3 years, following the first HbA1c level ≥7.0%. Cox regression analyses were performed to assess the determinants of time to insulin initiation. Data related to long-term effects of insulin initiation were studied at baseline and at the end of follow up using descriptive summary statistics. RESULTS Two-thirds of the patients initiated insulin during follow up. The time to insulin varied from 1.2 years (range 0.3-3.1) in patients with HbA1c levels consistently ≥7.0% to 5.4 years (range 3.0-7.5) in patients with fluctuating HbA1c levels around 7.0%. Longer diabetes duration (hazard ratio (HR) 1.04 95% CI 1.03-1.05) and lower age (HR 1.00 95% CI 0.99-1.00) at baseline were associated with a shorter time to initiation. More insulin initiators had retinopathy compared with patients that remained on oral glucose-lowering agents during follow up. CONCLUSION The time to insulin initiation was short, and most of the patients with HbA1c levels consistently ≥7.0% were initiating insulin. Longer diabetes duration and younger age shortened the time to insulin.
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Affiliation(s)
- Ruth Mast
- EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA
| | - A P Danielle Jansen
- EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA
| | - Iris Walraven
- EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA
| | - Simone P Rauh
- EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA
| | - Amber A W A van der Heijden
- EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA
| | - Robert J Heine
- EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA
| | - Petra J M Elders
- EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA
| | - Jacqueline M Dekker
- EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA
| | - Giel Nijpels
- EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA
| | - Jacqueline G Hugtenburg
- EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA EMGO Institute for Health and Care ResearchDepartments of Clinical Pharmacology and PharmacyGeneral Practice and Elderly Care MedicineEpidemiology and BiostatisticsOphthalmologyVU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The NetherlandsEli Lilly and Company893 S Delaware St, Indianapolis, Indiana, USA
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Abstract
This article discusses the recently published EMPA-REG OUTCOME trial, which assessed cardiovascular outcomes with empagliflozin therapy in persons with type 2 diabetes mellitus and coexisting cardiovascular disease. The article describes the background and challenges of modern cardiovascular outcome trials, points out the strengths of the EMPA-REG OUTCOME study, and places the results in perspective. It highlights the significant impact that these results will have on cardiovascular preventive pharmacotherapy, and on future drug development in diabetes. At the same time, it reminds readers of the limitations of the results, and lists the questions raised by, or left unanswered by, the trial.
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Affiliation(s)
- Sanjay Kalra
- Department of Endocrinology, Bharti Hospital, Karnal, India.
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Regele F, Jelencsics K, Shiffman D, Paré G, McQueen MJ, Mann JF, Oberbauer R. Genome-wide studies to identify risk factors for kidney disease with a focus on patients with diabetes. Nephrol Dial Transplant 2015. [DOI: 10.1093/ndt/gfv087] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Affiliation(s)
- Richard E Gilbert
- Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
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35
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Joseph JJ, Donner TW. Long-term insulin glargine therapy in type 2 diabetes mellitus: a focus on cardiovascular outcomes. Vasc Health Risk Manag 2015; 11:107-16. [PMID: 25657589 PMCID: PMC4315664 DOI: 10.2147/vhrm.s50286] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Cardiovascular disease is the leading cause of mortality in type 2 diabetes mellitus. Hyperinsulinemia is associated with increased cardiovascular risk, but the effects of exogenous insulin on cardiovascular disease progression have been less well studied. Insulin has been shown to have both cardioprotective and atherosclerosis-promoting effects in laboratory animal studies. Long-term clinical trials using insulin to attain improved diabetes control in younger type 1 and type 2 diabetes patients have shown improved cardiovascular outcomes. Shorter trials of intensive diabetes control with high insulin use in higher risk patients with type 2 diabetes have shown either no cardiovascular benefit or increased all cause and cardiovascular mortality. Glargine insulin is a basal insulin analog widely used to treat patients with type 1 and type 2 diabetes. This review focuses on the effects of glargine on cardiovascular outcomes. Glargine lowers triglycerides, leads to a modest weight gain, causes less hypoglycemia when compared with intermediate-acting insulin, and has a neutral effect on blood pressure. The Outcome Reduction With Initial Glargine Intervention (ORIGIN trial), a 6.2 year dedicated cardiovascular outcomes trial of glargine demonstrated no increased cardiovascular risk.
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Affiliation(s)
- Joshua J Joseph
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Thomas W Donner
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Gilbert R. SGLT-2 inhibition in patients with kidney disease. DIABETES & METABOLISM 2014; 40:S23-7. [DOI: 10.1016/s1262-3636(14)72692-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Phillips LS, Ratner RE, Buse JB, Kahn SE. We can change the natural history of type 2 diabetes. Diabetes Care 2014; 37:2668-76. [PMID: 25249668 PMCID: PMC4170125 DOI: 10.2337/dc14-0817] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 06/01/2014] [Indexed: 02/03/2023]
Abstract
As diabetes develops, we currently waste the first ∼10 years of the natural history. If we found prediabetes and early diabetes when they first presented and treated them more effectively, we could prevent or delay the progression of hyperglycemia and the development of complications. Evidence for this comes from trials where lifestyle change and/or glucose-lowering medications decreased progression from prediabetes to diabetes. After withdrawal of these interventions, there was no "catch-up"-cumulative development of diabetes in the previously treated groups remained less than in control subjects. Moreover, achieving normal glucose levels even transiently during the trials was associated with a substantial reduction in subsequent development of diabetes. These findings indicate that we can change the natural history through routine screening to find prediabetes and early diabetes, combined with management aimed to keep glucose levels as close to normal as possible, without hypoglycemia. We should also test the hypothesis with a randomized controlled trial.
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Affiliation(s)
- Lawrence S Phillips
- Atlanta VA Medical Center, Decatur, GA Division of Endocrinology and Metabolism, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | | | - John B Buse
- Division of Endocrinology and Metabolism, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
| | - Steven E Kahn
- VA Puget Sound Health Care System, Seattle, WA Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA
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