User login
ORLANDO – , according to final results from the VADT follow-up study (VADT-F).
Participants in the randomized, controlled VADT, which compared the effects of intensive versus standard glucose control in more than 1,700 patients with type 2 diabetes mellitus (T2DM), did not experience a significant improvement in the primary cardiovascular disease (CVD) outcome – a composite of myocardial infarction, stroke, cardiovascular death, new congestive heart failure, cardiovascular surgery or inoperable coronary artery disease, and ischemic amputation – after a median of 5.6 years of active treatment (hazard ratio, 0.88; P = .14). Nor did they experience significant improvement in secondary cardiovascular outcomes, including cardiovascular death and death from any cause (HRs, 1.32 and 1.07, respectively), or in a renal composite outcome (HR, 0.85), according to the findings published in 2009 (N Engl J Med. 2009 Jan 8;360[2]:129-39).
This was despite a rapid and statistically significant separation of hemoglobin A1c (HbA1c) levels between the treatment groups, Peter Reaven, MD, noted during a presentation of the final follow-up data at the annual scientific sessions of the American Diabetes Association.
Approximately 6 months after the start of the VADT, median HbA1c levels decreased from more than 9% in both groups to 6.9% and 8.4% in intensive and standard treatment groups, respectively (a median separation of 1.5%), said Dr. Reaven, director of the diabetes research program at the Phoenix VA Health Care System and a professor of clinical medicine at the University of Arizona in Phoenix.
“This was maintained throughout the study period,” he said. “All other risk factors during this period of time were equal between the two treatment groups.”
10-year outcomes
However, 10-year interim data from VADT-F, published in the New England Journal of Medicine (2015 Jun 4;372[23]:2197-206), showed a delayed benefit in these outcomes among those in the intensive control group: The incidence of the primary CVD composite outcome was reduced by 17% (HR, 0.83; P = .04) in favor of the intensive therapy at that time, Dr. Reaven said.
The incidence of the renal composite outcome, which included estimated glomerular filtration rate less than 54 mL/min per 1.73m2, sustained macroalbuminuria, and end-stage renal disease, was reduced by 32% (HR, 0.68; P = .008), said Nicholas Emanuele, MD, who presented the VADT-F renal and microvascular outcomes at the ADA meeting.
At that 10-year follow-up, HbA1c levels in the intensive and standard treatment groups had nearly equalized (although they remained slightly better in the intensive treatment group), and eventually, the levels stabilized at about 8.2% in both groups through the end of the 15-year follow-up, the investigators said.
“So it was still lower by nearly 1.2 hemoglobin percent units, compared to baseline values nearly 15 years earlier, and despite ending the study in very good control, after we released these patients to the primary care providers for their diabetes care, there was a substantial rise in HbA1c levels over time ... illustrating the difficulty of controlling HbA1c values to this level in this advanced diabetes population,” Dr. Reaven said.
15-year outcomes
At the final 15-year follow up, with the HbA1c levels similar in the groups, nearly all benefits seen at 10 years were lost. Event rates for the CVD primary composite outcome were 51.8 and 47.3 per 1,000 patient-years in the intensive care and standard care groups, respectively (HR, 0.91; P = .23), and event rates for the renal composite outcome were 88 and 85 per 1,000 patient-years (HR, 0.90; P = .55).
Similarly, no differences were seen at 15 years in the secondary VADT-F outcomes of any major diabetes outcome, (HR, 0.90; P = .16), cardiovascular death (HR, 0.94; P = .61), or death from any cause (HR 1.02; P = .81), and no differences were seen in the individual components of the composite outcomes, the investigators said.
The same was true for other outcomes, including hospitalizations and health-related quality of life, Dr. Reaven said.
Ocular events studied in the VADT-F included cataract extraction, laster photocoagulation, vitrectomy, and intravitreal injections, with the latter three constituting a retinal event composite for which there was a difference of “very borderline significance (HR, 0.84; P = .053),” said Dr. Emanuele of Hines (Ill.) VA Hospital and Loyola University of Chicago.
There was no difference between groups for cataract extraction. (HR, 1.16; P = .30) or in participants’ self reported vision at 15 years, he added.
Additional analyses showed that there were no treatment interactions for results based on baseline differences in diabetes duration, prior CV events, or risk scores.
In essence, there was no evidence of a legacy effect, Dr. Reaven said, noting that the findings are “relatively consistent” with those from other recent glucose-lowering trials, including ACCORDION and ADVANCE-ON, which also showed no legacy benefits of intensive glucose lowering.
Dr. Emanuele also concluded that no prolonged legacy effect was apparent for renal and other microvascular outcomes.
The lack of a legacy effect at 15 years, however, shouldn’t discount the benefits seen at the 10-year follow-up because there are other ways to look at “legacy,” Hertzel C. Gerstein, MD, said during an independent “clinical perspective” commentary on the VADT and VADT-F findings.
“Another way to define ‘legacy’ is what happens after the active clinical trial ends, and if you think of it that way, there is a legacy,” said Dr. Gerstein, a professor and Population Health Institute chair in diabetes research at McMaster University and Hamilton Health Sciences, Ontario, Canada.
That is, the intensive glycemic control led to significant improvements at 10-year follow-up. While he acknowledged “that’s just semantics,” he stressed that a number of important lessons have been learned from the VADT and VADT-F – not the least of which relate to mediation analyses that showed the benefit seen at 10 years can be explained, at least statistically, by the differences in HbA1c levels achieved during those intervening 10 years of follow-up.
For example, the 10-year cardiovascular outcome hazard ratios changed from 0.83 with a P value of .04 to 0.86 with a P value of .12 (after controlling for time-varying HbA1c levels) and to 0.94 with a P value of .53 (after controlling for time-varying cumulative mean HbA1c), he said, noting that similar findings have been reported from prior trials.
The VADT design
The VADT was designed to evaluate whether an intensive glycemic control regimen could reduce the incidence of major cardiovascular events compared with standard care in patients with T2DM; secondary objectives included differences in additional cardiovascular, renal, and other outcomes.
Subjects, who were enrolled from 20 VA medical centers beginning in December 2000, were aged 41 years or older (mean of about 60 years) and had failed to respond to a maximum dose of at least one oral agent and/or daily insulin. Patients were excluded if they had HbA1c less than 7.5%, had had a cardiovascular event in the previous 6 months, had advanced congestive heart failure, had severe angina, had a life expectancy of less than 7 years, had a body mass index over 40 kg/m2, had serum creatinine less than 1.6 mg/dL, or had an alanine transaminase level greater than 3 times the upper limit of normal, according to Wyndy L. Wiitala, PhD, of the VA Center for Clinical Management Research in Ann Arbor, Michigan.
A total of 818 patients in the standard care group and 837 in the intensive treatment group completed the study with up to 7.5 years of total follow-up (median, 5.6 years). The groups were similar in age; both were mostly male, which is expected for a VA population; and the average HbA1c level was 9.4% in both groups. Other clinical measures, including lipids, blood pressure, and estimated cardiovascular risk were also similar between the two groups.
“The VADT was designed so that the only planned difference between the treatment groups was the level of glycemic control,” Dr. Wiitala said.
All patients with a BMI of 27 kg/m2 or greater were started on metformin plus rosiglitazone, and those with a BMI less than 27 kg/m2 were started on glimepiride plus rosiglitazone. Those in the intensive therapy arm were started on maximal doses, and those in the standard therapy arm were started on half the maximal doses. Insulin was added for patients in the intensive-therapy group who did not achieve HbA1c below 6%, as well as for those in the standard-therapy group with a level of less than 9%.
Any subsequent medication changes were determined according to protocol guidelines and local assessment, and investigators were allowed to use any approved drug at their discretion.
“The use of medications between the two groups was similar, with differences in dose and insulin intensity only,” Dr. Wiitala said, adding that all other aspects of treatment, including blood pressure control, lipid control, aspirin therapy, diet, and nutrition, were “nearly identical” in the two groups.
The VADT-F design
The negative findings from the VADT raised “a number of questions, which really provided the rationale for the VADT follow-up study,” Dr. Reaven said.
“Would the post-VADT follow-up reveal an emerging cardiovascular benefit? This was particularly relevant as there was an indication that the group differences were increasing toward the end of the study, and benefits in cardiovascular outcomes, as we know, take a fair amount of time,” he said, adding that since the glucose separation seen in the treatment groups was greater than that seen in other recent studies involving patients with advanced T2DM and remained that way for an extended period of time, the follow-up study provided an excellent opportunity to examine whether there was a legacy or other effects.
The VADT-F continued to follow the VADT patients after the intervention ended in 2008; at that time, patients returned to normal care with no further intervention by the research team, Dr. Wiitala said, noting that participants were followed using national data sources, annual mail surveys, and targeted chart reviews.
The 10-year interim analysis was reported in 2015, and the 15-year final analysis, which is currently under review, represents the longest follow-up of patients with advanced T2DM with high risk for cardiovascular disease, she said.
Clinical perspective and future directions
“These results suggest that there are modest long-term cardiovascular disease benefits of therapies directed toward bringing glucose control to near-normal range in high-risk type 2 diabetes and that substantial and continuous glucose separation may be required to maintain these improvements,” Dr. Reaven concluded, adding that “recent studies demonstrating cardiovascular benefit with diabetes agents that only achieve modest improvements in glycemic control highlight the importance of also considering nonglycemic approaches to reducing cardiovascular disease events and mortality in these patients.”
Similarly, Dr. Emanuele concluded that there is a delayed beneficial effect of intensive glycemic control on kidney outcomes but that the effect dissipates as glycemic separation wanes.
However, in his commentary at the meeting, Dr. Gerstein stressed that the findings add value; in addition to showing, via mediation analyses, that HbA1c levels statistically explain the differences seen between the intensive and standard therapy arms at 10 years, the VADT and VADT-F findings also underscore the veracity of the ADA’s recommended target of HbA1c less than 7%, albeit “with all sorts of caveats.”
“But one point to make is that clinical trials do not tell you how to treat the patient in front of you. [They] just tell you what works on average for the average patient. ... You have to take the information you get from randomized trials and put it into your brain as a doctor and treat the patient,” he said.
He and several colleagues further explained this concept in a recent editorial (Diabetes Care. 2018 Jun;41[6]:1121-4) penned in response to new guidance statements published by the American College of Physicians advocating for relaxation of HbA1c control goals in patients with T2DM.
“The ACP proposal may encourage a step backward at a time when accumulating evidence from randomized, controlled trials calls for movement forward in the treatment of diabetes,” they wrote in the editorial entitled “A1c targets should be personalized to maximize benefits while limiting risks.”
Findings from those trials, including the VADT and VADT-F, continue to increase diabetes insights and inform care, and while there is not yet a statin-like “prescribe-and-go” treatment for diabetes, the findings represent a step in the right direction, Dr Gerstein said.
“All you have to do is look at all the clinical trials that are happening. We’re going to get there. ... This is not the end of the end, this is the beginning of the next phase,” he said.
The VADT and VADT-F were funded by the VA Cooperative Studies Program, the ADA, and the National Institutes of Health/National Eye Institute. Medication and additional support were provided by Aventis, GlaxoSmithKline, and Novo Nordisk Pharmaceuticals, which provided funding and supplies, and by Abbott Laboratory, Amylin, Eli Lily, Kos, Roche, and the University of Chicago, which also provided supplies. Dr. Reaven is an advisory panel member for Sanofi and has received research support from AstraZeneca and Novo Nordisk. Dr. Gerstein has received grants or other research support, honoraria, and/or consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi. Dr. Wiitala and Dr. Emanuele reported having no disclosures.
ORLANDO – , according to final results from the VADT follow-up study (VADT-F).
Participants in the randomized, controlled VADT, which compared the effects of intensive versus standard glucose control in more than 1,700 patients with type 2 diabetes mellitus (T2DM), did not experience a significant improvement in the primary cardiovascular disease (CVD) outcome – a composite of myocardial infarction, stroke, cardiovascular death, new congestive heart failure, cardiovascular surgery or inoperable coronary artery disease, and ischemic amputation – after a median of 5.6 years of active treatment (hazard ratio, 0.88; P = .14). Nor did they experience significant improvement in secondary cardiovascular outcomes, including cardiovascular death and death from any cause (HRs, 1.32 and 1.07, respectively), or in a renal composite outcome (HR, 0.85), according to the findings published in 2009 (N Engl J Med. 2009 Jan 8;360[2]:129-39).
This was despite a rapid and statistically significant separation of hemoglobin A1c (HbA1c) levels between the treatment groups, Peter Reaven, MD, noted during a presentation of the final follow-up data at the annual scientific sessions of the American Diabetes Association.
Approximately 6 months after the start of the VADT, median HbA1c levels decreased from more than 9% in both groups to 6.9% and 8.4% in intensive and standard treatment groups, respectively (a median separation of 1.5%), said Dr. Reaven, director of the diabetes research program at the Phoenix VA Health Care System and a professor of clinical medicine at the University of Arizona in Phoenix.
“This was maintained throughout the study period,” he said. “All other risk factors during this period of time were equal between the two treatment groups.”
10-year outcomes
However, 10-year interim data from VADT-F, published in the New England Journal of Medicine (2015 Jun 4;372[23]:2197-206), showed a delayed benefit in these outcomes among those in the intensive control group: The incidence of the primary CVD composite outcome was reduced by 17% (HR, 0.83; P = .04) in favor of the intensive therapy at that time, Dr. Reaven said.
The incidence of the renal composite outcome, which included estimated glomerular filtration rate less than 54 mL/min per 1.73m2, sustained macroalbuminuria, and end-stage renal disease, was reduced by 32% (HR, 0.68; P = .008), said Nicholas Emanuele, MD, who presented the VADT-F renal and microvascular outcomes at the ADA meeting.
At that 10-year follow-up, HbA1c levels in the intensive and standard treatment groups had nearly equalized (although they remained slightly better in the intensive treatment group), and eventually, the levels stabilized at about 8.2% in both groups through the end of the 15-year follow-up, the investigators said.
“So it was still lower by nearly 1.2 hemoglobin percent units, compared to baseline values nearly 15 years earlier, and despite ending the study in very good control, after we released these patients to the primary care providers for their diabetes care, there was a substantial rise in HbA1c levels over time ... illustrating the difficulty of controlling HbA1c values to this level in this advanced diabetes population,” Dr. Reaven said.
15-year outcomes
At the final 15-year follow up, with the HbA1c levels similar in the groups, nearly all benefits seen at 10 years were lost. Event rates for the CVD primary composite outcome were 51.8 and 47.3 per 1,000 patient-years in the intensive care and standard care groups, respectively (HR, 0.91; P = .23), and event rates for the renal composite outcome were 88 and 85 per 1,000 patient-years (HR, 0.90; P = .55).
Similarly, no differences were seen at 15 years in the secondary VADT-F outcomes of any major diabetes outcome, (HR, 0.90; P = .16), cardiovascular death (HR, 0.94; P = .61), or death from any cause (HR 1.02; P = .81), and no differences were seen in the individual components of the composite outcomes, the investigators said.
The same was true for other outcomes, including hospitalizations and health-related quality of life, Dr. Reaven said.
Ocular events studied in the VADT-F included cataract extraction, laster photocoagulation, vitrectomy, and intravitreal injections, with the latter three constituting a retinal event composite for which there was a difference of “very borderline significance (HR, 0.84; P = .053),” said Dr. Emanuele of Hines (Ill.) VA Hospital and Loyola University of Chicago.
There was no difference between groups for cataract extraction. (HR, 1.16; P = .30) or in participants’ self reported vision at 15 years, he added.
Additional analyses showed that there were no treatment interactions for results based on baseline differences in diabetes duration, prior CV events, or risk scores.
In essence, there was no evidence of a legacy effect, Dr. Reaven said, noting that the findings are “relatively consistent” with those from other recent glucose-lowering trials, including ACCORDION and ADVANCE-ON, which also showed no legacy benefits of intensive glucose lowering.
Dr. Emanuele also concluded that no prolonged legacy effect was apparent for renal and other microvascular outcomes.
The lack of a legacy effect at 15 years, however, shouldn’t discount the benefits seen at the 10-year follow-up because there are other ways to look at “legacy,” Hertzel C. Gerstein, MD, said during an independent “clinical perspective” commentary on the VADT and VADT-F findings.
“Another way to define ‘legacy’ is what happens after the active clinical trial ends, and if you think of it that way, there is a legacy,” said Dr. Gerstein, a professor and Population Health Institute chair in diabetes research at McMaster University and Hamilton Health Sciences, Ontario, Canada.
That is, the intensive glycemic control led to significant improvements at 10-year follow-up. While he acknowledged “that’s just semantics,” he stressed that a number of important lessons have been learned from the VADT and VADT-F – not the least of which relate to mediation analyses that showed the benefit seen at 10 years can be explained, at least statistically, by the differences in HbA1c levels achieved during those intervening 10 years of follow-up.
For example, the 10-year cardiovascular outcome hazard ratios changed from 0.83 with a P value of .04 to 0.86 with a P value of .12 (after controlling for time-varying HbA1c levels) and to 0.94 with a P value of .53 (after controlling for time-varying cumulative mean HbA1c), he said, noting that similar findings have been reported from prior trials.
The VADT design
The VADT was designed to evaluate whether an intensive glycemic control regimen could reduce the incidence of major cardiovascular events compared with standard care in patients with T2DM; secondary objectives included differences in additional cardiovascular, renal, and other outcomes.
Subjects, who were enrolled from 20 VA medical centers beginning in December 2000, were aged 41 years or older (mean of about 60 years) and had failed to respond to a maximum dose of at least one oral agent and/or daily insulin. Patients were excluded if they had HbA1c less than 7.5%, had had a cardiovascular event in the previous 6 months, had advanced congestive heart failure, had severe angina, had a life expectancy of less than 7 years, had a body mass index over 40 kg/m2, had serum creatinine less than 1.6 mg/dL, or had an alanine transaminase level greater than 3 times the upper limit of normal, according to Wyndy L. Wiitala, PhD, of the VA Center for Clinical Management Research in Ann Arbor, Michigan.
A total of 818 patients in the standard care group and 837 in the intensive treatment group completed the study with up to 7.5 years of total follow-up (median, 5.6 years). The groups were similar in age; both were mostly male, which is expected for a VA population; and the average HbA1c level was 9.4% in both groups. Other clinical measures, including lipids, blood pressure, and estimated cardiovascular risk were also similar between the two groups.
“The VADT was designed so that the only planned difference between the treatment groups was the level of glycemic control,” Dr. Wiitala said.
All patients with a BMI of 27 kg/m2 or greater were started on metformin plus rosiglitazone, and those with a BMI less than 27 kg/m2 were started on glimepiride plus rosiglitazone. Those in the intensive therapy arm were started on maximal doses, and those in the standard therapy arm were started on half the maximal doses. Insulin was added for patients in the intensive-therapy group who did not achieve HbA1c below 6%, as well as for those in the standard-therapy group with a level of less than 9%.
Any subsequent medication changes were determined according to protocol guidelines and local assessment, and investigators were allowed to use any approved drug at their discretion.
“The use of medications between the two groups was similar, with differences in dose and insulin intensity only,” Dr. Wiitala said, adding that all other aspects of treatment, including blood pressure control, lipid control, aspirin therapy, diet, and nutrition, were “nearly identical” in the two groups.
The VADT-F design
The negative findings from the VADT raised “a number of questions, which really provided the rationale for the VADT follow-up study,” Dr. Reaven said.
“Would the post-VADT follow-up reveal an emerging cardiovascular benefit? This was particularly relevant as there was an indication that the group differences were increasing toward the end of the study, and benefits in cardiovascular outcomes, as we know, take a fair amount of time,” he said, adding that since the glucose separation seen in the treatment groups was greater than that seen in other recent studies involving patients with advanced T2DM and remained that way for an extended period of time, the follow-up study provided an excellent opportunity to examine whether there was a legacy or other effects.
The VADT-F continued to follow the VADT patients after the intervention ended in 2008; at that time, patients returned to normal care with no further intervention by the research team, Dr. Wiitala said, noting that participants were followed using national data sources, annual mail surveys, and targeted chart reviews.
The 10-year interim analysis was reported in 2015, and the 15-year final analysis, which is currently under review, represents the longest follow-up of patients with advanced T2DM with high risk for cardiovascular disease, she said.
Clinical perspective and future directions
“These results suggest that there are modest long-term cardiovascular disease benefits of therapies directed toward bringing glucose control to near-normal range in high-risk type 2 diabetes and that substantial and continuous glucose separation may be required to maintain these improvements,” Dr. Reaven concluded, adding that “recent studies demonstrating cardiovascular benefit with diabetes agents that only achieve modest improvements in glycemic control highlight the importance of also considering nonglycemic approaches to reducing cardiovascular disease events and mortality in these patients.”
Similarly, Dr. Emanuele concluded that there is a delayed beneficial effect of intensive glycemic control on kidney outcomes but that the effect dissipates as glycemic separation wanes.
However, in his commentary at the meeting, Dr. Gerstein stressed that the findings add value; in addition to showing, via mediation analyses, that HbA1c levels statistically explain the differences seen between the intensive and standard therapy arms at 10 years, the VADT and VADT-F findings also underscore the veracity of the ADA’s recommended target of HbA1c less than 7%, albeit “with all sorts of caveats.”
“But one point to make is that clinical trials do not tell you how to treat the patient in front of you. [They] just tell you what works on average for the average patient. ... You have to take the information you get from randomized trials and put it into your brain as a doctor and treat the patient,” he said.
He and several colleagues further explained this concept in a recent editorial (Diabetes Care. 2018 Jun;41[6]:1121-4) penned in response to new guidance statements published by the American College of Physicians advocating for relaxation of HbA1c control goals in patients with T2DM.
“The ACP proposal may encourage a step backward at a time when accumulating evidence from randomized, controlled trials calls for movement forward in the treatment of diabetes,” they wrote in the editorial entitled “A1c targets should be personalized to maximize benefits while limiting risks.”
Findings from those trials, including the VADT and VADT-F, continue to increase diabetes insights and inform care, and while there is not yet a statin-like “prescribe-and-go” treatment for diabetes, the findings represent a step in the right direction, Dr Gerstein said.
“All you have to do is look at all the clinical trials that are happening. We’re going to get there. ... This is not the end of the end, this is the beginning of the next phase,” he said.
The VADT and VADT-F were funded by the VA Cooperative Studies Program, the ADA, and the National Institutes of Health/National Eye Institute. Medication and additional support were provided by Aventis, GlaxoSmithKline, and Novo Nordisk Pharmaceuticals, which provided funding and supplies, and by Abbott Laboratory, Amylin, Eli Lily, Kos, Roche, and the University of Chicago, which also provided supplies. Dr. Reaven is an advisory panel member for Sanofi and has received research support from AstraZeneca and Novo Nordisk. Dr. Gerstein has received grants or other research support, honoraria, and/or consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi. Dr. Wiitala and Dr. Emanuele reported having no disclosures.
ORLANDO – , according to final results from the VADT follow-up study (VADT-F).
Participants in the randomized, controlled VADT, which compared the effects of intensive versus standard glucose control in more than 1,700 patients with type 2 diabetes mellitus (T2DM), did not experience a significant improvement in the primary cardiovascular disease (CVD) outcome – a composite of myocardial infarction, stroke, cardiovascular death, new congestive heart failure, cardiovascular surgery or inoperable coronary artery disease, and ischemic amputation – after a median of 5.6 years of active treatment (hazard ratio, 0.88; P = .14). Nor did they experience significant improvement in secondary cardiovascular outcomes, including cardiovascular death and death from any cause (HRs, 1.32 and 1.07, respectively), or in a renal composite outcome (HR, 0.85), according to the findings published in 2009 (N Engl J Med. 2009 Jan 8;360[2]:129-39).
This was despite a rapid and statistically significant separation of hemoglobin A1c (HbA1c) levels between the treatment groups, Peter Reaven, MD, noted during a presentation of the final follow-up data at the annual scientific sessions of the American Diabetes Association.
Approximately 6 months after the start of the VADT, median HbA1c levels decreased from more than 9% in both groups to 6.9% and 8.4% in intensive and standard treatment groups, respectively (a median separation of 1.5%), said Dr. Reaven, director of the diabetes research program at the Phoenix VA Health Care System and a professor of clinical medicine at the University of Arizona in Phoenix.
“This was maintained throughout the study period,” he said. “All other risk factors during this period of time were equal between the two treatment groups.”
10-year outcomes
However, 10-year interim data from VADT-F, published in the New England Journal of Medicine (2015 Jun 4;372[23]:2197-206), showed a delayed benefit in these outcomes among those in the intensive control group: The incidence of the primary CVD composite outcome was reduced by 17% (HR, 0.83; P = .04) in favor of the intensive therapy at that time, Dr. Reaven said.
The incidence of the renal composite outcome, which included estimated glomerular filtration rate less than 54 mL/min per 1.73m2, sustained macroalbuminuria, and end-stage renal disease, was reduced by 32% (HR, 0.68; P = .008), said Nicholas Emanuele, MD, who presented the VADT-F renal and microvascular outcomes at the ADA meeting.
At that 10-year follow-up, HbA1c levels in the intensive and standard treatment groups had nearly equalized (although they remained slightly better in the intensive treatment group), and eventually, the levels stabilized at about 8.2% in both groups through the end of the 15-year follow-up, the investigators said.
“So it was still lower by nearly 1.2 hemoglobin percent units, compared to baseline values nearly 15 years earlier, and despite ending the study in very good control, after we released these patients to the primary care providers for their diabetes care, there was a substantial rise in HbA1c levels over time ... illustrating the difficulty of controlling HbA1c values to this level in this advanced diabetes population,” Dr. Reaven said.
15-year outcomes
At the final 15-year follow up, with the HbA1c levels similar in the groups, nearly all benefits seen at 10 years were lost. Event rates for the CVD primary composite outcome were 51.8 and 47.3 per 1,000 patient-years in the intensive care and standard care groups, respectively (HR, 0.91; P = .23), and event rates for the renal composite outcome were 88 and 85 per 1,000 patient-years (HR, 0.90; P = .55).
Similarly, no differences were seen at 15 years in the secondary VADT-F outcomes of any major diabetes outcome, (HR, 0.90; P = .16), cardiovascular death (HR, 0.94; P = .61), or death from any cause (HR 1.02; P = .81), and no differences were seen in the individual components of the composite outcomes, the investigators said.
The same was true for other outcomes, including hospitalizations and health-related quality of life, Dr. Reaven said.
Ocular events studied in the VADT-F included cataract extraction, laster photocoagulation, vitrectomy, and intravitreal injections, with the latter three constituting a retinal event composite for which there was a difference of “very borderline significance (HR, 0.84; P = .053),” said Dr. Emanuele of Hines (Ill.) VA Hospital and Loyola University of Chicago.
There was no difference between groups for cataract extraction. (HR, 1.16; P = .30) or in participants’ self reported vision at 15 years, he added.
Additional analyses showed that there were no treatment interactions for results based on baseline differences in diabetes duration, prior CV events, or risk scores.
In essence, there was no evidence of a legacy effect, Dr. Reaven said, noting that the findings are “relatively consistent” with those from other recent glucose-lowering trials, including ACCORDION and ADVANCE-ON, which also showed no legacy benefits of intensive glucose lowering.
Dr. Emanuele also concluded that no prolonged legacy effect was apparent for renal and other microvascular outcomes.
The lack of a legacy effect at 15 years, however, shouldn’t discount the benefits seen at the 10-year follow-up because there are other ways to look at “legacy,” Hertzel C. Gerstein, MD, said during an independent “clinical perspective” commentary on the VADT and VADT-F findings.
“Another way to define ‘legacy’ is what happens after the active clinical trial ends, and if you think of it that way, there is a legacy,” said Dr. Gerstein, a professor and Population Health Institute chair in diabetes research at McMaster University and Hamilton Health Sciences, Ontario, Canada.
That is, the intensive glycemic control led to significant improvements at 10-year follow-up. While he acknowledged “that’s just semantics,” he stressed that a number of important lessons have been learned from the VADT and VADT-F – not the least of which relate to mediation analyses that showed the benefit seen at 10 years can be explained, at least statistically, by the differences in HbA1c levels achieved during those intervening 10 years of follow-up.
For example, the 10-year cardiovascular outcome hazard ratios changed from 0.83 with a P value of .04 to 0.86 with a P value of .12 (after controlling for time-varying HbA1c levels) and to 0.94 with a P value of .53 (after controlling for time-varying cumulative mean HbA1c), he said, noting that similar findings have been reported from prior trials.
The VADT design
The VADT was designed to evaluate whether an intensive glycemic control regimen could reduce the incidence of major cardiovascular events compared with standard care in patients with T2DM; secondary objectives included differences in additional cardiovascular, renal, and other outcomes.
Subjects, who were enrolled from 20 VA medical centers beginning in December 2000, were aged 41 years or older (mean of about 60 years) and had failed to respond to a maximum dose of at least one oral agent and/or daily insulin. Patients were excluded if they had HbA1c less than 7.5%, had had a cardiovascular event in the previous 6 months, had advanced congestive heart failure, had severe angina, had a life expectancy of less than 7 years, had a body mass index over 40 kg/m2, had serum creatinine less than 1.6 mg/dL, or had an alanine transaminase level greater than 3 times the upper limit of normal, according to Wyndy L. Wiitala, PhD, of the VA Center for Clinical Management Research in Ann Arbor, Michigan.
A total of 818 patients in the standard care group and 837 in the intensive treatment group completed the study with up to 7.5 years of total follow-up (median, 5.6 years). The groups were similar in age; both were mostly male, which is expected for a VA population; and the average HbA1c level was 9.4% in both groups. Other clinical measures, including lipids, blood pressure, and estimated cardiovascular risk were also similar between the two groups.
“The VADT was designed so that the only planned difference between the treatment groups was the level of glycemic control,” Dr. Wiitala said.
All patients with a BMI of 27 kg/m2 or greater were started on metformin plus rosiglitazone, and those with a BMI less than 27 kg/m2 were started on glimepiride plus rosiglitazone. Those in the intensive therapy arm were started on maximal doses, and those in the standard therapy arm were started on half the maximal doses. Insulin was added for patients in the intensive-therapy group who did not achieve HbA1c below 6%, as well as for those in the standard-therapy group with a level of less than 9%.
Any subsequent medication changes were determined according to protocol guidelines and local assessment, and investigators were allowed to use any approved drug at their discretion.
“The use of medications between the two groups was similar, with differences in dose and insulin intensity only,” Dr. Wiitala said, adding that all other aspects of treatment, including blood pressure control, lipid control, aspirin therapy, diet, and nutrition, were “nearly identical” in the two groups.
The VADT-F design
The negative findings from the VADT raised “a number of questions, which really provided the rationale for the VADT follow-up study,” Dr. Reaven said.
“Would the post-VADT follow-up reveal an emerging cardiovascular benefit? This was particularly relevant as there was an indication that the group differences were increasing toward the end of the study, and benefits in cardiovascular outcomes, as we know, take a fair amount of time,” he said, adding that since the glucose separation seen in the treatment groups was greater than that seen in other recent studies involving patients with advanced T2DM and remained that way for an extended period of time, the follow-up study provided an excellent opportunity to examine whether there was a legacy or other effects.
The VADT-F continued to follow the VADT patients after the intervention ended in 2008; at that time, patients returned to normal care with no further intervention by the research team, Dr. Wiitala said, noting that participants were followed using national data sources, annual mail surveys, and targeted chart reviews.
The 10-year interim analysis was reported in 2015, and the 15-year final analysis, which is currently under review, represents the longest follow-up of patients with advanced T2DM with high risk for cardiovascular disease, she said.
Clinical perspective and future directions
“These results suggest that there are modest long-term cardiovascular disease benefits of therapies directed toward bringing glucose control to near-normal range in high-risk type 2 diabetes and that substantial and continuous glucose separation may be required to maintain these improvements,” Dr. Reaven concluded, adding that “recent studies demonstrating cardiovascular benefit with diabetes agents that only achieve modest improvements in glycemic control highlight the importance of also considering nonglycemic approaches to reducing cardiovascular disease events and mortality in these patients.”
Similarly, Dr. Emanuele concluded that there is a delayed beneficial effect of intensive glycemic control on kidney outcomes but that the effect dissipates as glycemic separation wanes.
However, in his commentary at the meeting, Dr. Gerstein stressed that the findings add value; in addition to showing, via mediation analyses, that HbA1c levels statistically explain the differences seen between the intensive and standard therapy arms at 10 years, the VADT and VADT-F findings also underscore the veracity of the ADA’s recommended target of HbA1c less than 7%, albeit “with all sorts of caveats.”
“But one point to make is that clinical trials do not tell you how to treat the patient in front of you. [They] just tell you what works on average for the average patient. ... You have to take the information you get from randomized trials and put it into your brain as a doctor and treat the patient,” he said.
He and several colleagues further explained this concept in a recent editorial (Diabetes Care. 2018 Jun;41[6]:1121-4) penned in response to new guidance statements published by the American College of Physicians advocating for relaxation of HbA1c control goals in patients with T2DM.
“The ACP proposal may encourage a step backward at a time when accumulating evidence from randomized, controlled trials calls for movement forward in the treatment of diabetes,” they wrote in the editorial entitled “A1c targets should be personalized to maximize benefits while limiting risks.”
Findings from those trials, including the VADT and VADT-F, continue to increase diabetes insights and inform care, and while there is not yet a statin-like “prescribe-and-go” treatment for diabetes, the findings represent a step in the right direction, Dr Gerstein said.
“All you have to do is look at all the clinical trials that are happening. We’re going to get there. ... This is not the end of the end, this is the beginning of the next phase,” he said.
The VADT and VADT-F were funded by the VA Cooperative Studies Program, the ADA, and the National Institutes of Health/National Eye Institute. Medication and additional support were provided by Aventis, GlaxoSmithKline, and Novo Nordisk Pharmaceuticals, which provided funding and supplies, and by Abbott Laboratory, Amylin, Eli Lily, Kos, Roche, and the University of Chicago, which also provided supplies. Dr. Reaven is an advisory panel member for Sanofi and has received research support from AstraZeneca and Novo Nordisk. Dr. Gerstein has received grants or other research support, honoraria, and/or consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi. Dr. Wiitala and Dr. Emanuele reported having no disclosures.
EXPERT ANALYSIS FROM ADA 2018