Glucose control and vascular complications in veterans with type 2 diabetes
Open accessAbstract
BACKGROUND: The effects of intensive glucose control on cardiovascular events in patients with long-standing type 2 diabetes mellitus remain uncertain. METHODS: We randomly assigned 1791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. Other cardiovascular risk factors were treated uniformly. The mean number of years since the diagnosis of diabetes was 11.5, and 40% of the patients had already had a cardiovascular event. The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level, as compared with the standard-therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene. RESULTS: The median follow-up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. The primary outcome occurred in 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group (hazard ratio in the intensive-therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P=0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P=0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard-therapy group and 24.1% in the intensive-therapy group. CONCLUSIONS: Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications with the exception of progression of albuminuria (P = 0.01) [added]. (ClinicalTrials.gov number, NCT00032487.)
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Glucose and BP optimization are proven for primary prevention and slowing of nonproliferative retinopathy.
“Optimization of glucose and BP are the proven strategies for primary prevention of diabetic retinopathy and for slowing the progression of preexisting nonproliferative retinopathy.78,185,186,193,522,523”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [78]
The Microvascular Results (page not available in our copy) report no significant difference in new-onset retinopathy or progression to proliferative retinopathy between intensive and standard glucose-control groups; the trend in retinopathy severity was also nonsignificant. This trial therefore does not establish the claimed prevention or slowing of retinopathy through glucose optimization. It did not test blood-pressure optimization as a retinopathy intervention. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe Look AHEAD randomized clinical trial reported that a long-term behavioral weight loss intervention compared with diabetes self-management education and support resulted in no difference between groups for the primary cardiovascular outcome over a median of 9.6 years of follow-up.
“The Action for Health in Diabetes (Look AHEAD) randomized clinical trial (including 5145 overweight persons with type 2 diabetes) reported that a long-term behavioral weight loss intervention including a goal of at least 175 minutes per week of moderate-intensity physical activity, compared with diabetes self-management education and support, resulted in no difference between groups for the”
From Diagnosis and Treatment of Type 2 Diabetes in Adults (2025) · cites this paper as [35]
Split into 2 atoms — 0 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredGlycaemic control alone does not fully explain the reduction in cardiovascular mortality associated with GLP-1RAs.
“Whilst indirect effects such as improved glycaemic control are likely to be important, glycaemic control alone does not fully explain the reduction in cardiovascular mortality associated with GLP-1RAs. 75”
From <scp>Glucagon‐like peptide‐1 receptor agonists</scp> improve biomarkers of inflammation and oxidative stress: A systematic review and meta‐analysis of randomised controlled trials (2021) · cites this paper as [75]
The Discussion says intensive glucose control did not reduce cardiovascular events in patients with previously diagnosed type 2 diabetes, supporting the general point that glucose control alone may not account for cardiovascular benefit. The paper does not assess GLP-1RAs or explain any reduction in cardiovascular mortality associated with them. Page numbers are not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe risks of intensive glycemic control may be avoided by using agents not associated with hypoglycemia, especially in people with frequent severe hypoglycemia, hypoglycemia unawareness, long diabetes duration, advanced atherosclerosis, advanced age, or terminal illness.
“The potential risks of intensive glycemic control may be obviated by incorporating agents that are not associated with hypoglycemia, especially in persons with frequent severe hypoglycemia, hypoglycemia unawareness, or a very long duration of DM, and particularly in the presence of established and advanced atherosclerosis, advanced age, and terminal illness.69,70,76–81”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [78]
The Results report more hypoglycemic episodes and serious adverse events with intensive therapy, and the Discussion suggests that avoiding severe hypoglycemia may matter when intensifying control earlier in diabetes. The paper does not establish that agents without hypoglycemia risk would avert those harms, or make that recommendation for the listed groups, including people with hypoglycemia unawareness, advanced atherosclerosis, advanced age, or terminal illness. The indexed passages provide no page numbers. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIntensive glucose control (A1C <7% in T2D, <7.5% in T1D) lowers risk of incident albuminuria and DKD onset.
“Intensive glucose control (A1C levels <7% in T2D and <7.5% in T1D) in several clinical trials was found to reduce the risk of incident albuminuria (A2) and DKD onset.70,78,90,406–410”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [78]
Table 3 (Discussion; page not provided) reports fewer transitions from normal albumin excretion to micro- or macroalbuminuria with intensive treatment in veterans with type 2 diabetes (10.0% versus 14.7%, P=0.03), and the intensive group's median A1C was 6.9%. The study did not include people with type 1 diabetes, and it found no significant reduction in severe nephropathy; it therefore does not establish the claim about T1D or DKD onset broadly. (LLM, conf=0.89)
Experimental — accuracy not yet measured
A relationship between mortality and randomization to intensive glucose control was not observed in ADVANCE or VADT.
“A relationship between mortality and randomization to intensive glucose control was not observed in ADVANCE or VADT, although VADT was underpowered to explore this relationship.”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [3]
The Results report no significant difference in all-cause mortality between the intensive- and standard-therapy groups in VADT (hazard ratio 1.07; P = 0.62). The Discussion says ADVANCE found no change in cardiovascular-event rates, but does not specifically report its mortality result. It also says VADT may have been underpowered, without tying that limitation specifically to mortality. (LLM, conf=0.84)
Experimental — accuracy not yet measuredVADT was underpowered to explore the relationship between mortality and randomization to intensive glucose control.
“A relationship between mortality and randomization to intensive glucose control was not observed in ADVANCE or VADT, although VADT was underpowered to explore this relationship.”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [3]
The Results (page not available in our copy) report no significant difference in mortality between the intensive- and standard-control groups. The Discussion says the study may have been underpowered, but does not establish that it was underpowered specifically to assess mortality; the Statistical Analysis describes power for the composite cardiovascular outcome. (LLM, conf=0.84)
Experimental — accuracy not yet measuredBetween ACCORD, ADVANCE, and VADT, a total of 24,000 patients with high cardiovascular risk were randomly assigned to either intensive glycemic control or standard therapy.
“Between them, a total of 24,000 patients with high cardiovascular risk were randomly assigned to either intensive glycemic control or standard therapy (3–5).”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [3]
The Abstract reports that VADT randomly assigned 1,791 veterans to intensive or standard glucose control, and the Discussion identifies ACCORD and ADVANCE as the other two studies. The paper does not give a combined enrollment of 24,000 or establish that all participants across the three trials had high cardiovascular risk. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe frequency of severe hypoglycemia in the intensive therapy groups of the ACCORD, ADVANCE and VADT trials was 2 to 3 times higher than in standard therapy groups.
“the frequency of severe hypoglycemia in these trials was 2 to 3 times higher in the intensive therapy groups”
From Targets for Glycemic Control (2018) · cites this paper as [25]
The Discussion says hypoglycemia rates were higher with intensive therapy in ACCORD, ADVANCE, and VADT, but gives no two- to threefold comparison for ACCORD or ADVANCE. Table 2 reports threefold rates for VADT episodes involving impaired consciousness or complete loss of consciousness (9 versus 3 and 3 versus 1 per 100 patient-years). Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe ADVANCE and VADT trials found modest reduction in nephropathy with intensive glycemic management; ACCORD was stopped after a median of 3.5 years due to higher mortality in the intervention arm.
“The ADVANCE and VADT trials found modest reduction in nephropathy with intensive glycemic management; ACCORD was stopped after a median of 3.5 years due to higher mortality in the intervention arm (51-55).”
From 6. Glycemic Goals, Hypoglycemia, and Hyperglycemic Crises: Standards of Care in Diabetes-2026. (2026) · cites this paper as [51]
The Discussion reports reduced progression of albuminuria in both ADVANCE and VADT, and says ACCORD was stopped after 3.5 years because mortality was higher with intensive therapy. The nephropathy claim is broader than the findings: the paper reports no reduction in severe or major nephropathy. It also does not identify 3.5 years as ACCORD’s median follow-up. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA target HbA1c ≤6.0% probably increased all-cause mortality.
“Two studies comparing a target HbA1c of # 6.0% to higher HbA1c targets (standard glycemic control) found that the lower HbA1c target probably increased all-cause mortality (Supplementary Table S13 240,242,255 )”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [242]
The Results (page unavailable) report slightly more all-cause deaths with intensive therapy, but the difference was not statistically significant (102 versus 95; hazard ratio 1.07, 95% CI 0.81–1.42). The Treatment Protocol specifies a target 1.5 percentage points below standard therapy, not an HbA1c target of ≤6.0%; the intensive group's median was 6.9%. Thus this trial does not establish that the stated target probably increased all-cause mortality. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAn HbA1c target of ≤6.5% probably decreased the incidence of moderately increased albuminuria and kidney failure.
“Six studies compared a target HbA1c of # 6.5% to higher HbA1c targets (standard glycemic control) and found that an HbA1c target of # 6.5% probably decreased the incidence of moderately increased albuminuria, and kidney failure (Supplementary Table S12 239,240,242 -244,252 )”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [242]
The Microvascular Results report less overall worsening of albumin excretion with intensive therapy (P = 0.01). However, new microalbuminuria—the measure relevant to moderately increased albuminuria—was not significantly reduced, severe renal changes were unaffected, and the Discussion reports an achieved HbA1c of 6.9%, not ≤6.5%. (LLM, conf=0.89)
Experimental — accuracy not yet measuredPoor control, defined as a hemoglobin A1c level >9.0%, contributes to complications, including nephropathy, retinopathy, and neuropathy.
“Poor control, defined as a hemoglobin A1c (HbA1c) level >9.0%, contributes to complications, including nephropathy [1-6], retinopathy [4,7], and neuropathy [4,8].”
From An Assessment of How Clinicians and Staff Members Use a Diabetes Artificial Intelligence Prediction Tool: Mixed Methods Study (2023) · cites this paper as [3]
The Discussion says glucose control may reduce microvascular complications, and the Microvascular Results report less worsening of albumin excretion with intensive treatment. But the paper does not define poor control as HbA1c >9.0% or establish that this threshold contributes to nephropathy, retinopathy, and neuropathy; it reports no significant treatment-group differences in those three outcomes. Page numbers were not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe ACCORD study and the Veterans Affairs Diabetes Trial showed that intensive treatment protocols aimed to achieve an A1C <6.0% with complex drug plans significantly increased the risk for hypoglycemia requiring assistance compared with standard treatment.
“This recommendation is supported by results from multiple randomized controlled trials, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and the Veterans Affairs Diabetes Trial (VADT), which showed that intensive treatment protocols aimed to achieve an A1C <6.0% with complex drug plans significantly increased the risk for hypoglycemia requiring assistance compared with”
From 13. Older Adults: <i>Standards of Care in Diabetes—2024</i> (2024) · cites this paper as [36]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIntensive treatment protocols aimed to achieve an A1C <6.0% with complex drug plans significantly increased the risk for hypoglycemia requiring assistance compared with standard treatment in the ACCORD and VADT studies.
“This recommendation is supported by results from multiple randomized controlled trials, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and the Veterans Affairs Diabetes Trial (VADT), which showed that intensive treatment protocols aimed to achieve an A1C <6.0% with complex drug plans significantly increased the risk for hypoglycemia requiring assistance compared with”
From 13. Older Adults: Standards of Care in Diabetes—2025 (2025) · cites this paper as [38]
The Treatment Protocol describes intensive drug dosing and adding insulin if A1C remained at or above 6%, but gives VADT’s overall goal as a 1.5-percentage-point difference from standard treatment, not an A1C target below 6%. Table 2 and the Results report significantly more hypoglycemic episodes with intensive treatment in VADT (P<0.001), and the Discussion reports higher hypoglycemia rates in ACCORD. Our copy does not establish that the increased episodes in both studies specifically required assistance. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIntensive treatment protocols aimed to achieve an A1C <6.0% with complex drug plans significantly increased the risk for hypoglycemia requiring assistance compared with standard treatment.
“This recommendation is also supported by results from multiple randomized controlled trials (RCTs), such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and the Veterans Affairs Diabetes Trial (VADT), which showed that intensive treatment protocols aimed to achieve an A1C <6.0% with complex drug plans significantly increased the risk for hypoglycemia requiring assistance”
From 13. Older Adults: Standards of Care in Diabetes—2026 (2026) · cites this paper as [43]
The Treatment Protocol describes a multidrug regimen and adding insulin if intensive-therapy patients had not reached an A1C below 6%, but states the trial’s goal as a 1.5-percentage-point difference between groups, not an A1C target below 6%. Table 2 reports significantly more hypoglycemic episodes in the intensive group, including episodes with impaired or lost consciousness (P<0.001), but does not identify episodes requiring assistance as a separate outcome. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn each of ACCORD, ADVANCE, and VADT, subjects randomly assigned to the intensive arm experienced more episodes of hypoglycemia than did those randomly assigned to the standard treatment arm.
“In each, subjects who were randomly assigned to the intensive arm experienced more episodes of hypoglycemia than did those who were randomly assigned to the standard treatment arm.”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [3]
In the VADT, during a median follow-up of 5.6 years, there was a nonsignificant reduction in the primary outcome, but progression to albuminuria was significantly reduced in the intensive-treatment participants (9.1% vs. 13.8%).
“During a median follow up of 5.6 years, there was a nonsignificant reduction in the primary outcome (first occurrence of a major CV event), but the progression to albuminuria was significantly reduced in the intensive-treatment participants, with 9.1% of participants having significantly reduced progression compared to 13.8% in the standard therapy group.”
From Targets for Glycemic Control (2018) · cites this paper as [25]
The DCCT in individuals with type 1 diabetes and the UKPDS, ACCORD, ADVANCE, and VADT studies in type 2 diabetes all sought to address whether intensive glycemic management reduced cardiovascular disease events.
“The DCCT in individuals with type 1 diabetes and the UKPDS, ACCORD, ADVANCE, and VADT studies in type 2 diabetes all sought to address whether intensive glycemic management reduced cardiovascular disease (CVD) events (43,51,52,54).”
From 6. Glycemic Goals, Hypoglycemia, and Hyperglycemic Crises: Standards of Care in Diabetes-2026. (2026) · cites this paper as [51]
Vision prognosis has improved greatly over 40 years due to better metabolic and BP control.
“The prognosis for retaining vision has improved dramatically over the past 40 years owing to improved metabolic and BP control.78,432,488–490”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [78]
The Microvascular Results section reports eye outcomes over the trial, not changes in vision prognosis over 40 years. The Discussion addresses glucose control and hypertension but does not attribute a historical improvement in vision retention to better control of either; searches for vision prognosis, historical trends, and blood-pressure-related visual outcomes found no such passage. Page numbers were unavailable in our copy. (LLM, conf=0.77)
Experimental — accuracy not yet measuredIntensive glucose control in T1D markedly lowers DPN incidence, with a 78% relative risk reduction.
“Enhanced glucose control in people with T1D dramatically reduces the incidence of DPN (78% relative risk reduction),78,542,547,549”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [78]
The Discussion mentions people with type 1 diabetes only in relation to cardiovascular events, not neuropathy. The Microvascular Results report no significant change in neuropathy among veterans with type 2 diabetes. A search for the claimed 78% reduction found no passage addressing DPN incidence in type 1 diabetes. (LLM, conf=0.75)
Experimental — accuracy not yet measuredAll three trials clearly demonstrated that an episode of severe hypoglycemia was associated with an increased risk of subsequent mortality.
“All three trials clearly demonstrated that an episode of severe hypoglycemia was associated with an increased risk of subsequent mortality.”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [3]
The Results (page unavailable) report more hypoglycemic episodes with intensive therapy but no significant difference in mortality between treatment groups. The Discussion (page unavailable) mentions increased mortality in ACCORD’s intensive-therapy group, not mortality following severe hypoglycemia. Searches for severe hypoglycemia, subsequent death, and mortality found no analysis of that association in any of the three trials. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn VADT, a recent severe hypoglycemic event was the strongest independent predictor of death at 90 days.
“In VADT, a recent severe hypoglycemic event was the strongest independent predictor of death at 90 days (3).”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [3]
The Results section reports hypoglycemic episodes and deaths separately, but does not link a recent severe episode to subsequent death. Searches for “90 days,” “predictor of death,” and “severe hypoglycemic event” found no analysis identifying the strongest independent predictor of death within 90 days. Page numbers were not available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredHigher mortality was reported in participants with 1 or more episodes of severe hypoglycemia in the ACCORD, ADVANCE and VADT trials, irrespective of treatment arms.
“a higher mortality was reported in participants with 1 or more episodes of severe hypoglycemia in the ACCORD (30), ADVANCE (31) and VADT trials (25), irrespective of the different treatment arms in which individual participants were allocated.”
From Targets for Glycemic Control (2018) · cites this paper as [25]
The VADT Results report deaths and hypoglycemic episodes separately, and the Discussion compares VADT with ACCORD and ADVANCE. Neither section reports whether participants who experienced severe hypoglycemia had higher mortality, within either treatment arm. Searches for hypoglycemia-related deaths and mortality by treatment assignment found no such analysis in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe Look AHEAD weight loss intervention was associated with sustained weight loss, lower HbA1C, delayed progression of kidney disease, and improvements in quality of life, depression, sleep apnea, urinary incontinence, and health care utilization and costs.
“However, the weight loss intervention was associated with sustained weight loss, lower HbA1C, delayed progression of kidney disease, and improvements in quality of life, depression, sleep apnea, urinary incontinence, and health care utilization and costs.35”
From Diagnosis and Treatment of Type 2 Diabetes in Adults (2025) · cites this paper as [35]
The Results and Discussion describe intensive glucose control in veterans, not the Look AHEAD weight-loss intervention. Although they report lower HbA1c and less progression of albuminuria with intensive glucose control, those findings cannot verify outcomes attributed to Look AHEAD. Searches for Look AHEAD, sustained weight loss, and the listed quality-of-life and cost outcomes found no relevant passage in our copy; page numbers were unavailable. (LLM, conf=0.76)
Experimental — accuracy not yet measuredRecent trials in type 2 diabetes that targeted HbA1c below 6.5% with multiple drugs showed inconsistent benefits and no macrovascular advantage over strategies leaving HbA1c 0.8-1.1% higher.
“recent studies that used multiple medications to treat type 2 diabetes and aimed for HbA 1c concentrations ,6.5% (48 mmol/mol) have not demonstrated consistent benefits and failed to observe any benefit with regard to macrovascular disease, compared with interventions that achieved HbA 1c values 0.8% to 1.1% higher (50)(51)(52).”
From Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus (2011) · cites this paper as [52]
Three major clinical trials of intensive glycemic control, targeting HbA1c <6%-6.5%, demonstrated no reduction in major cardiovascular events compared with less intensive glycemic control in patients with type 2 diabetes.
“3 major clinical trials of intensive glycemic control (lowering HbA1c levels to <6%–6.5%) demonstrated no reduction in major cardiovascular events compared with less intensive glycemic control in patients with T2DM”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [183]
Intensive glycemic control generally reduces the risk of microvascular end points, even if it does not reduce major cardiovascular events.
“intensive glycemic control generally reduces the risk of microvascular end points, even if it does not reduce major cardiovascular events”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [183]
Evidence for microvascular benefit with intensive glycemic control is more robust in UKPDS compared with ACCORD, ADVANCE, and VADT.
“the evidence for microvascular benefit with intensive glycemic control is more robust in the UKPDS study187 compared with the 3 more recent trials (ACCORD, ADVANCE, and VADT).182–184”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [182]
Subsequent clinical trials of intensive versus standard glycemic control among patients with long-standing type 2 diabetes and multiple cardiovascular risk factors did not show similar benefits.
“Subsequent clinical trials of intensive versus standard glycemic control among patients with long-standing T2DM and with multiple risk factors for cardiovascular disease did not show similar benefits.”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [182]
Subsequent clinical trials of intensive versus standard glycemic control among patients with long-standing type 2 diabetes and multiple cardiovascular risk factors did not show similar benefits.
“Subsequent clinical trials of intensive versus standard glycemic control among patients with long-standing T2DM and with multiple risk factors for cardiovascular disease did not show similar benefits.”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [183]
The other two trials demonstrated no benefit for major cardiovascular events, with no heterogeneity of effect based on the presence or absence of established macrovascular disease.
“The other 2 trials demonstrated no benefit with respect to the primary outcome, major cardiovascular events, with no heterogeneity of effect based on the presence or absence of established macrovascular disease.”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [182]
Intensive glycemic control generally reduces the risk of microvascular end points, even if it does not reduce major cardiovascular events.
“intensive glycemic control generally reduces the risk of microvascular end points, even if it does not reduce major cardiovascular events”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [182]
These trials included substantial proportions of patients with established macrovascular disease (ACCORD, 35.2%; ADVANCE, 32.3%; VADT, 40.3%) and generally targeted HbA1c levels <6.5%.
“These trials included a substantial proportion of patients with established macrovascular disease (ACCORD, 35.2%; ADVANCE [Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation], 32.3%; and VADT [Veterans Affairs Diabetes Trial], 40.3%) and generally targeted HbA1c levels <6.5%.”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [182]
These trials included substantial proportions of patients with established macrovascular disease (ACCORD, 35.2%; ADVANCE, 32.3%; VADT, 40.3%) and generally targeted HbA1c levels <6.5%.
“These trials included a substantial proportion of patients with established macrovascular disease (ACCORD, 35.2%; ADVANCE [Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation], 32.3%; and VADT [Veterans Affairs Diabetes Trial], 40.3%) and generally targeted HbA1c levels <6.5%.”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [183]
Intensive glycemic control in all major clinical trials increased the risk of severe hypoglycemia 2- to 3-fold.
“Intensive glycemic control in all major clinical trials was shown to increase the risk of severe hypoglycemia 2- to 3-fold.”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [183]
The other two trials demonstrated no benefit for major cardiovascular events, with no heterogeneity of effect based on the presence or absence of established macrovascular disease.
“The other 2 trials demonstrated no benefit with respect to the primary outcome, major cardiovascular events, with no heterogeneity of effect based on the presence or absence of established macrovascular disease.”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [183]
Evidence for microvascular benefit with intensive glycemic control is more robust in UKPDS compared with ACCORD, ADVANCE, and VADT.
“the evidence for microvascular benefit with intensive glycemic control is more robust in the UKPDS study187 compared with the 3 more recent trials (ACCORD, ADVANCE, and VADT).182–184”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [183]
Although sulfonylureas have been associated with increased cardiovascular mortality in retrospective observational studies, most large controlled clinical trials have generally proved sulfonylureas, particularly second-generation agents, to be safe and cardiovascular neutral.
“although sulfonylureas have been associated with increased cardiovascular mortality in retrospective observational studies, most large controlled clinical trials have generally proved sulfonylureas (particularly second-generation agents) to be safe and cardiovascular neutral”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [183]
Intensive glycemic control in all major clinical trials increased the risk of severe hypoglycemia 2- to 3-fold.
“Intensive glycemic control in all major clinical trials was shown to increase the risk of severe hypoglycemia 2- to 3-fold.”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [182]
Three major clinical trials of intensive glycemic control, targeting HbA1c <6%-6.5%, demonstrated no reduction in major cardiovascular events compared with less intensive glycemic control in patients with type 2 diabetes.
“3 major clinical trials of intensive glycemic control (lowering HbA1c levels to <6%–6.5%) demonstrated no reduction in major cardiovascular events compared with less intensive glycemic control in patients with T2DM”
From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [182]
The VADT found no significant difference between intensive and standard groups for any individual composite of the primary outcome or for all-cause mortality.
“There was no significant difference between groups for any of the individual composites of the primary outcome or for all-cause mortality.”
From European Guidelines on cardiovascular disease prevention in clinical practice (version 2012) (2012) · cites this paper as [438]
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 [145]
Numerous anti-diabetes medications lower plasma glucose levels without significantly impacting CVD development or MACE risks.
“numerous anti-diabetes medications lower plasma glucose levels without significantly impacting CVD development or MACE risks”
From A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors (2020) · cites this paper as Duckworth et al., 2009
The degree of blood-glucose control within T2DM is a poor indicator of incident CVD risks.
“Interestingly, the degree of blood-glucose control within T2DM is a poor indicator of incident CVD risks”
From A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors (2020) · cites this paper as Duckworth et al., 2009
A relationship between mortality and randomization to intensive glucose control was not observed in ADVANCE or VADT, although VADT was underpowered to explore this relationship.
“A relationship between mortality and randomization to intensive glucose control was not observed in ADVANCE or VADT, although VADT was underpowered to explore this relationship.”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [3]
In ACCORD, ADVANCE, and VADT, subjects randomly assigned to the intensive arm experienced more episodes of hypoglycemia than did those randomly assigned to the standard treatment arm.
“In each, subjects who were randomly assigned to the intensive arm experienced more episodes of hypoglycemia than did those who were randomly assigned to the standard treatment arm.”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [3]
There is growing evidence that patients with type 2 diabetes might be particularly vulnerable to adverse events associated with hypoglycemia.
“There is growing evidence that patients with type 2 diabetes might be particularly vulnerable to adverse events associated with hypoglycemia.”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [3]
In VADT, a recent severe hypoglycemic event was the strongest independent predictor of death at 90 days.
“In VADT, a recent severe hypoglycemic event was the strongest independent predictor of death at 90 days (3).”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [3]
All three trials clearly demonstrated that an episode of severe hypoglycemia was associated with an increased risk of subsequent mortality.
“All three trials clearly demonstrated that an episode of severe hypoglycemia was associated with an increased risk of subsequent mortality.”
From Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society (2013) · cites this paper as [3]
In ADVANCE pre-specified subgroup analysis of age < or ≥ 65 years, there was no difference between age groups for the primary outcome.
“In pre-specified subgroup analysis of age < or ≥ 65 years, there was no difference between age groups for the primary outcome29.”
From Diabetes in Older Adults: A Consensus Report (2012) · cites this paper as [29]
The ADVANCE trial did not demonstrate excessive deaths attributable to intensive glucose control during a median follow-up of 5 years.
“The ADVANCE trial did not demonstrate excessive deaths attributable to intensive glucose control during a median follow-up of 5 years.”
From Diabetes in Older Adults: A Consensus Report (2012) · cites this paper as [29]
ADVANCE had no statistically significant cardiovascular benefits, but there was a significant reduction in the incidence of nephropathy.
“While there were no statistically significant cardiovascular benefits, there was a significant reduction in the incidence of nephropathy.”
From Diabetes in Older Adults: A Consensus Report (2012) · cites this paper as [29]
Three large randomized controlled trials found that frequent, inadvertent hypoglycemia secondary to intensive (HbA1C <7%) versus standard (HbA1C <9%) glycemic control in patients with longstanding T2D largely negated the cardiovascular benefits of intensive glycemic management.
“Three large randomized controlled trials found that frequent, inadvertent hypoglycemia, secondary to intensive (HbA1C <7%) versus standard (HbA1C <9%) glycemic control in patients with longstanding T2D largely negated the cardiovascular benefits of intensive glycemic management ( Patel et al., 2005 ; ADVANCE Collaborative Group et al., 2008 ; Duckworth et al., 2009 ).”
From Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes (2024) · cites this paper as Duckworth et al., 2009
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- Authors
- Duckworth, W., Abraira, C., Moritz, T., Reda, D., Emanuele, N., Reaven, P. D., Zieve, F. J., Marks, J., Davis, S. N., Hayward, R., Warren, S. R., Goldman, S., McCarren, M., Vitek, M. E., Henderson, W. G., & Huang, G. D.
- Affiliations
- Phoenix VA Health Care System (US)
- Miami VA Healthcare System (US)
- Edward Hines, Jr. VA Hospital (US)
- Hunter Holmes McGuire VA Medical Center (US)
- VA Tennessee Valley Healthcare System (US)
- VA Ann Arbor Healthcare System (US)
- Southern Arizona VA Health Care System (US)
- VA Office of Research and Development (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2009-01-08
- Volume
- 360
- Issue
- 2
- Pages
- 129-139
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2158666727
- Semantic Scholar
- 0905c5577c0e796e2b98a9fb49fc40f726a3702a
- Cited by
- 4,762
- References
- 27
- Citations by year
- 2026: 75 · 2025: 90 · 2024: 150 · 2023: 164 · 2022: 168 · 2021: 244 · 2020: 268 · 2019: 265 · 2018: 279 · 2017: 325 · 2016: 320 · 2015: 317 · 2014: 381 · 2013: 349 · 2012: 364
- FWCI
- 239.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- U.S. Department of Veterans Affairs
- Eli Lilly and Company
- Pfizer
- Amylin Pharmaceuticals
- GlaxoSmithKline
- Sanofi
- Office of Research and Development
- MannKind Corporation
- Novo Nordisk
- National Eye Institute
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079637)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- type 2 diabetes, tight glycemic control, glycemic control, veterans, cardiovascular events, HbA1c, microvascular complications, albuminuria, hypoglycemia, cardiovascular mortality, long-standing diabetes
- MeSH terms
- Rosiglitazone, Blood Glucose, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Diabetic Neuropathies, Drug Therapy, Combination, Female, Follow-Up Studies, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Insulin, Male, Metformin, Middle Aged, Sulfonylurea Compounds, United States, Veterans, Thiazolidinediones, Kaplan-Meier Estimate
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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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