Early Treatment with Basal Insulin Glargine in People with Type 2 Diabetes: Lessons from ORIGIN and Other Cardiovascular Trials

Dysglycemia results from a deficit in first-phase insulin secretion compounded by increased insulin insensitivity, exposing beta 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 beta-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

Antihyperglykaemiás kezelés hatékonyságát megítélő randomizált, kontrollált klinikai tanulmányok obszervációs jellegű utánkövetései. I. A vizsgálatok fontosabb eredményei = Randomized, controlled clinical trials with observational follow-up investigations for evaluating efficacy of antihyperglycaemic treatment. I. Main results of the studies

Absztrakt: Az antihyperglykaemiás (antidiabetikus) kezelés és a diabetes idült szövődményeinek alakulása régóta a diabetológiai kutatások előterében áll. A glykaemiás kontroll és a szövődmények kialakulásának összefüggése terén alapvető ismeretekhez jutottunk az 1-es típusú diabetesben szenvedők körében végzett DCCT (Diabetes Control and Complications Trial), illetve a 2-es típusú cukorbetegek körében folytatott UKPDS (United Kingdom Prospective Diabetes Study) alapadatainak és utánkövetésének publikációjakor. A két, úgynevezett „mérföldkő”-tanulmányon túlmenően a szakirodalomban több olyan randomizált, kontrollált, nagy klinikai vizsgálat lelhető fel, amelynek obszervációs jellegű utánkövetését szintén megvalósították. Ezek a megfigyelések – többek között – megalapozták a metabolikus memória, illetve a metabolikus örökség fogalmát. A közlemény az áttekintett vizsgálatok fontosabb eredményeit összegzi. Orv Hetil. 2018; 159(15): 575–582. | Abstract: The effect of antihyperglycaemic (antidiabetic) treatment on the late diabetic complications is one of the most important research areas in clinical diabetology. The relationship between glycaemic control and late micro- and macrovascular complications was highlighted by the results of the DCCT (Diabetes Control and Complications Trial) with type 1 and by the UKPDS (United Kingdom Prospective Diabetes Study) with type 2 diabetic patients. In these studies, observational follow-up investigations were also performed after the close-out of the randomized phase of the trial. In addition to these landmark studies, other randomized, controlled efficacy trials were also performed with observational follow-up investigations resulting in the development of the concept of metabolic memory or metabolic legacy. In this article, the main results of the studies are summarized. Orv Hetil. 2018; 159(15): 575–582

Cardiovascular Outcomes Trials in Type 2 Diabetes: Where Do We Go From Here? Reflections From a Diabetes Care Editors’ Expert Forum

In December 2008, the U.S. Food and Drug Administration issued guidance to the pharmaceutical industry setting new expectations for the development of antidiabetes drugs for type 2 diabetes. This guidance expanded the scope and cost of research necessary for approval of such drugs by mandating long-term cardiovascular outcomes trials (CVOTs) for safety. Since 2008, 9 CVOTs have been reported, 13 are under way, and 4 have been terminated. Reassuringly, each of the completed trials demonstrated the noninferiority of their respective drugs to placebo for their primary cardiovascular (CV) composite end point. Notably, four additionally provided evidence of CV benefit in the form of significant decreases in the primary CV composite end point, two suggested reductions in CV death, and three suggested reductions in all-cause mortality. Although these trials have yielded much valuable information, whether that information justifies the investment of time and resources is controversial. In June 2016, a Diabetes Care Editors' Expert Forum convened to review the processes and challenges of CVOTs, discuss the benefits and limitations of their current designs, and weigh the merits of modifications that might improve the efficiency and clinical value of future trials. Discussion and analysis continued with the CVOT trial results released in June 2017 at the American Diabetes Association's Scientific Sessions and in September 2017 at the European Association for the Study of Diabetes scientific meeting. This article summarizes the discussion and findings to date

Wpływ badań oceniających bezpieczeństwo sercowo-naczyniowe na wybór preparatu insuliny w leczeniu cukrzycy typu 2: opinia ekspertów

Wstęp: Niniejszą opinię ekspertów opracowano w celu omówienia epidemiologii i patofizjologii chorób układu sercowo-naczyniowego (CVD) u chorych na cukrzycę typu 2 (T2DM), wyjaśnienia różnych zagadnień statystycznych i niuansów w interpretacji wyników badań oceniających bezpieczeństwo sercowo-naczyniowe (CVOT) ze szczególnym zaakcentowaniem badań typu CVOT dotyczących insulinoterapii i ich wpływu badań na wybór preparatów insuliny w codziennej praktyce klinicznej. Metody: Grupa ekspertów krytycznie przeanalizowała opublikowane dane z badań obserwacyjnych, badań klinicznych z randomizacją, metaanaliz i badań CVOT dotyczących bezpieczeństwa stosowania preparatów insuliny w odniesieniu do układu sercowo-naczyniowego i uzgodniła serię opinii popartych dostępnymi dowodami naukowymi i oceną kliniczną ekspertów. Wyniki: Wielu chorych na T2DM charakteryzuje się wysokim ryzykiem CVD i zgonu sercowo-naczyniowego, które częściowo wynika z czynników ryzyka związanychz insulinoopornością i hiperglikemią. W ciągu ostatniej dekady badania CVOT stały się integralną częścią procesu rejestracji leków przeciwcukrzycowych przez Amerykańską Agencję ds. Żywności i Leków (FDA). Większość obecnie stosowanych preparatów insulinowych, poza kilkoma opracowanymi w ostatnich latach insulinami, dopuszczono do obrotu długo przed wprowadzeniem tego wymogu rejestracyjnego, a zatem nie poddano ich rygorystycznym badaniom CVOT. Istnieje wiele danych obserwacyjnych dotyczących sercowo-naczyniowego bezpieczeństwa stosowania preparatów insuliny. Dane te są często niejednoznaczne, a czasami — sprzeczne. W tym kontekście należy zauważyć, że badania CVOT dwóch analogów insuliny bazowej — insuliny glargine ocenianej w badaniu Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia Trial (ORIGIN) i insuliny degludec ocenianej w badaniu Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes Trial (DEVOTE) — wykazały długoterminowe bezpieczeństwo sercowo-naczyniowe ich stosowania. Badanie DEVOTE dostarczyło dodatkowych danych o bezpieczeństwie, wskazujących, że stosowanie insuliny degludec wiązało się z mniejszą liczbą epizodów ciężkiej hipoglikemii niż stosowanie insuliny glargine. Wnioski: W niniejszej pracy dokonano krytycznej analizy dwóch badań CVOT oceniających analogi insuliny bazowej w połączeniu z ogólnym przeglądem meto-dologicznych i interpretacyjnych aspektów badań typu CVOT. Omówiono długoterminowe bezpieczeństwo sercowo-naczyniowe stosowania analogów insuliny bazowej. Za główną lukę badawczą w tej dziedzinie uznano brak badań CVOT z mieszankami insulin ludzkich i analogów insulinowych

Noninvasive tests of vascular function and structure: Why and how to perform them

Background Early atherosclerosis involves the endothelium of many arteries. Information about peripheral arterial anatomy and function derived from vascular imaging studies such as brachial artery reactivity (BAR) and carotid intima media thickness (IMT) may be pertinent to the coronary circulation. The prevention and early treatment of atherosclerosis is gaining more attention, and these tests might be used as indications or perhaps guides to the effectiveness of therapy, but their application in clinical practice has been limited. This review seeks to define the anatomy and pathophysiology underlying these investigations, their methodology, the significance of their Findings, and the issues that must be resolved before their application. Methods The literature on BAR and IMT is extensively reviewed, especially in relation to clinical use. Results Abnormal flow-mediated dilation is present in atherosclerotic vessels, is associated with cardiovascular risk factors, and may be a marker of preclinical disease. Treatment of known atherosclerotic risk Factors has been shown to improve flow-mediated dilation, and some data suggest that vascular responsiveness is related to outcome. Carotid IMT is associated with cardiovascular risk factors, and increased levels can predict myocardial infarction and stroke. Aggressive risk factor management can decrease IMT. Conclusions BAR and IMT ate functional and structural markers of the atherosclerotic process. The clinical use of BAR has been limited by varying reproducibility and the influence by exogenous factors, but IMT exhibits less variability. A desirable next step in the development of BAR and IMT as useful clinical tools would be to show an association of improvement in response to treatment with improvement in prognosis

Cardiovascular and other outcomes postintervention with insulin glargine and omega-3 fatty acids (ORIGINALE)

© 2016 by the American Diabetes Association. 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 allocatedto 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 \u3e6 years of treatment followed by \u3e2.5 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

Cardiovascular and other outcomes postintervention with insulin glargine and omega-3 fatty acids (ORIGINALE)

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

Cardiovascular and other outcomes postintervention with insulin glargine and omega-3 fatty acids (ORIGINALE)

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

Cardiovascular and other outcomes postintervention with insulin glargine and omega-3 fatty acids (ORIGINALE)

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