Basal insulin and cardiovascular and other outcomes in dysglycemia
Open accessAbstract
BACKGROUND: The provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events, but such a possibility has not been formally tested. METHODS: We randomly assigned 12,537 people (mean age, 63.5 years) with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes to receive insulin glargine (with a target fasting blood glucose level of ≤95 mg per deciliter [5.3 mmol per liter]) or standard care and to receive n-3 fatty acids or placebo with the use of a 2-by-2 factorial design. The results of the comparison between insulin glargine and standard care are reported here. The coprimary outcomes were nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and these events plus revascularization or hospitalization for heart failure. Microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers were also compared between groups. RESULTS: The median follow-up was 6.2 years (interquartile range, 5.8 to 6.7). Rates of incident cardiovascular outcomes were similar in the insulin-glargine and standard-care groups: 2.94 and 2.85 per 100 person-years, respectively, for the first coprimary outcome (hazard ratio, 1.02; 95% confidence interval [CI], 0.94 to 1.11; P=0.63) and 5.52 and 5.28 per 100 person-years, respectively, for the second coprimary outcome (hazard ratio, 1.04; 95% CI, 0.97 to 1.11; P=0.27). New diabetes was diagnosed approximately 3 months after therapy was stopped among 30% versus 35% of 1456 participants without baseline diabetes (odds ratio, 0.80; 95% CI, 0.64 to 1.00; P=0.05). Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years. Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the standard-care group. There was no significant difference in cancers (hazard ratio, 1.00; 95% CI, 0.88 to 1.13; P=0.97). CONCLUSIONS: When used to target normal fasting plasma glucose levels for more than 6 years, insulin glargine had a neutral effect on cardiovascular outcomes and cancers. Although it reduced new-onset diabetes, insulin glargine also increased hypoglycemia and modestly increased weight. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).
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Both insulin glargine U100 and insulin degludec have demonstrated cardiovascular safety in dedicated cardiovascular outcome trials.
“Both insulin glargine U100 and insulin degludec have demonstrated cardiovascular safety in dedicated CVOTs (207,208).”
From Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2022) · cites this paper as [208]
The Discussion reports that the ORIGIN trial found no increase in cardiovascular outcomes with basal insulin glargine compared with standard care over more than six years. This supports the glargine portion of the sentence, but our copy does not specify the U100 formulation. It does not study degludec, for which the sentence provides a separate citation. (LLM, conf=0.82)
Experimental — accuracy not yet measuredOther trials in high-risk type 2 diabetes patients showed similar glycemic control effects but without significant benefits for cardiovascular events or death.
“There are a number of other trials regarding cardiovascular outcomes in high-risk cohorts of patients with type 2 diabetes in which similar magnitude effects on glycemic control have been shown but without significant benefits with respect to rates of cardiovascular events or death.”
From Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes (2016) · cites this paper as [16]
Insulin glargine is associated with a 1.6 kg weight gain over 6 years in the ORIGIN trial.
“ORIGIN reported a 1.6 kg gain over 6 years with insulin glargine [46].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [46]
Modest survival benefits with metformin have been reported for breast, ovarian, endometrial, prostate, lung, kidney, liver, and earlier stage pancreatic cancers.
“Modest survival benefits also have been reported for breast, ovarian, endometrial, prostate, lung, kidney, liver, and earlier stage pancreatic cancers.1791–1800”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [1800]
The Discussion mentions metformin only in relation to possible cardiovascular protection and its use in the trial groups. Other Outcomes reports no significant difference in cancer deaths between the insulin-glargine and standard-care groups, but does not assess survival benefits from metformin for the listed cancers. Searches for metformin and site-specific cancer survival found no supporting passage in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredDipeptidyl peptidase-4 inhibitors, sulfonylureas, and insulin were excluded due to lack of current evidence of efficacy in cardiovascular outcome trials.
“The following drug classes were excluded due to lack of current evidence of efficacy in cardiovascular outcome trials: dipeptidyl peptidase-4 inhibitors,19 sulfonylureas,20 and insulin.21,22”
From Cardioprotective Glucose-Lowering Agents and Dementia Risk: A Systematic Review and Meta-Analysis (2025) · cites this paper as [21]
Dedicated randomized controlled cardiovascular outcome trials evaluating the safety and efficacy of metformin have not been conducted.
“It is associated with a lower risk of death and HF hospitalization compared with insulin and sulphonylureas in observational studies, though dedicated randomized, controlled, CVOTs evaluating safety and efficacy of metformin have not been conducted.[555][556][557]”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [555]
Metformin is associated with a lower risk of death and heart failure hospitalization compared with insulin and sulphonylureas in observational studies.
“It is associated with a lower risk of death and HF hospitalization compared with insulin and sulphonylureas in observational studies, though dedicated randomized, controlled, CVOTs evaluating safety and efficacy of metformin have not been conducted.[555][556][557]”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [555]
Studies testing lifestyle and drug interventions to delay diabetes onset have generally shown benefit, with lifestyle outperforming all medications except thiazolidinediones.
“These trials have more or less uniformly demonstrated a benefit, with lifestyle more efficacious than all medications with the exception of the thiazolidinediones140–152.”
From Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future (2014) · cites this paper as [146]
In the ORIGIN trial, insulin was not associated with higher rates of HF hospitalization than placebo.
“In the only RCT of insulin vs. placebo [ORIGIN, 12 537 people with CV risk factors plus impaired fasting glucose, impaired glucose tolerance, or T2DM (i.e.not in patients with HF)], insulin was not associated with higher rates of HF hospitalization than placebo.187”
From Type 2 diabetes mellitus and heart failure: A position statement from the Heart Failure Association of the European Society of Cardiology (2018) · cites this paper as [187]
Lowering glucose without addressing the vascular effects of insulin resistance may be insufficient to reduce risk of cardiovascular events.
“Lowering glucose without addressing the vascular effects of insulin resistance may be insufficient to reduce risk of cardiovascular events.”
From The Vasculature in Prediabetes (2018) · cites this paper as [27]
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RetractedPost-transplant diabetes mellitus in patients with solid organ transplants
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Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists
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β-cell dysfunction: Its critical role in prevention and management of type 2 diabetes
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3. Prevention or Delay of Diabetes and Associated Comorbidities: Standards of Care in Diabetes—2023
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Retracted
- Authors
- The ORIGIN Trial Investigators
- Affiliations
- Population Health Research Institute (CA)
- Corresponding author
- The ORIGIN Trial Investigators
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-07-26
- Volume
- 367
- Issue
- 4
- Pages
- 319-328
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W1975663485
- Semantic Scholar
- 695c6a8e398d66ae418b143a3491ad91d28443bb
- Cited by
- 1,636
- References
- 29
- Citations by year
- 2026: 34 · 2025: 41 · 2024: 76 · 2023: 86 · 2022: 82 · 2021: 108 · 2020: 101 · 2019: 139 · 2018: 155 · 2017: 152 · 2016: 155 · 2015: 132 · 2014: 168 · 2013: 147 · 2012: 53
- FWCI
- 128.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Monash University Research Portal (Monash University) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- HAL (submittedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- IRIS (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- University of Oxford
- AFA Försäkring
- Hjärt-Lungfonden
- Novo Nordisk
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- basal insulin, insulin glargine, impaired fasting glucose, impaired glucose tolerance, type 2 diabetes, cardiovascular outcomes, myocardial infarction, stroke, heart failure, omega-3 fatty acids, hypoglycemia, weight gain, cancer risk, microvascular outcomes, cardiovascular risk factors, revascularization, hospitalization, new-onset diabetes
- MeSH terms
- Insulin Glargine, Aged, Blood Glucose, Cardiovascular Diseases, Cholesterol, Diabetes Mellitus, Type 2, Double-Blind Method, Drug Therapy, Combination, Fasting, Female, Follow-Up Studies, Hospitalization, Humans, Hypoglycemia, Hypoglycemic Agents, Male, Middle Aged, Triglycerides, Fatty Acids, Omega-3, Incidence, Proportional Hazards Models, Glucose Intolerance, Insulin, Long-Acting, Intention to Treat Analysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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