It is important to identify people with type 2 diabetes at the earliest opportunity, target good glucose control immediately after diagnosis, and maintain it as long as possible, to reduce the risks of heart attack and premature death following the years after diagnosis, say researchers from the UK Prospective Diabetes Study (UKPDS).
These findings — based on data extrapolated from the UKPDS — by Marcus Lind, professor at the University of Gothenburg, Sweden, and colleagues were published online July 7 in Diabetes Care.
“We used advanced methods to determine the statistical relationships” between early and delayed improvements in A1c values and subsequent myocardial infarctions and all-cause mortality 5 to 20 years later, senior author Rury R. Holman, MBChB, summarized in an email to Medscape Medical News.
“We saw simulated benefits for both MIs and all-cause mortality, with a greater benefit for all-cause mortality,” said Holman, emeritus professor of diabetic medicine, Radcliffe Department of Medicine, University of Oxford, UK.
And the “introduction of new glucose-lowering agents [following the UKPDS trial], especially those that do not induce hypoglycemia or weight gain, has made it easier to take advantage of this ‘legacy’ effect,” said Holman.
A1c targets should be those set by current guidelines according to a patient’s individual characteristics, he explained.
Invited to weigh in, Hertzel C. Gerstein, MD, who was not involved in the study, echoed these comments.
This new analysis “showed that an early reduction in A1c has greater long-term benefits on death and MI than a later reduction,” he said in an email.
“It stresses the importance of getting and maintaining glycemic control early in the disease, while also noting that there is a benefit (albeit much weaker) with delayed glucose control,” said Gerstein, a professor of medicine at McMaster University in Hamilton, Canada.
The current analysis differs from the Veterans Affairs Diabetes Trial (VADT) — which showed that glucose control soon after diagnosis had cardiovascular benefits 10 years later but not 15 years later — in that it is based on a model, not actual events, he noted.
It adds to our knowledge by showing that there is a loss of beneficial effect with delay in glucose control.
“The fact that the study was done in the presence of older drugs doesn’t change the importance of glucose control,” Gerstein noted.
“Indeed, the fact that the newer drugs make it easier to control glucose faster highlights the importance of taking advantage of this and doing it,” he stressed, in agreement with Holman.
Does Timing of Glycemic Control Matter?
UKPDS recruited individuals with newly diagnosed type 2 diabetes who were age 25 to 65 years during the period 1977-1991, Holman explained.
The trial randomized individuals who had fasting plasma glucose concentrations >6 and <15 mmol/L (>108 and <270 mg/dL) to receive either a conventional glycemic-control strategy (primarily with diet) or an intensive glycemic-control strategy, primarily with monotherapy with sulfonylurea, insulin, or (only for those with >120% of ideal body weight) metformin.
When the trial ended on September 30, 1997, the 3277 surviving participants entered a 10-year post-trial monitoring study, where they did not have to adhere to their previous glycemic-control strategies.
For the current study, the researchers developed a regression model based on data from more than 3000 patients in UKPDS, of whom 662 had a myocardial infarction (MI) and 775 died during follow-up.
The patients had a mean age of 53 at diabetes diagnosis and 38% were women.
Imposing a 1% lower A1c from the time of diabetes diagnosis was associated with an 18.8% lower risk of all-cause mortality 10 to 15 years later.
Delaying this reduction in A1c until 10 years after diabetes diagnosis was associated with a smaller 2.7% lower risk of all-cause mortality.
Similarly, imposing a 1% lower A1c at the time of diabetes diagnosis was associated with a 19.7% lower risk of MI, 10 to 15 years later.
Having a 1% lower A1c 10 years later was associated with a smaller 6.5% lower risk of MI during follow-up.
Expressed differently, the hazard ratios for MI per 1% increase in A1c were 1.13, 1.22, 1.27, and 1.31 at 5, 10, 15, and 20 years of follow-up, respectively.
And the hazard ratios for all-cause mortality per 1% increase in A1c were 1.08, 1.18, 1.28, and 1.36 at 5, 10, 15, and 20 years of follow-up, respectively.
“Our study found an [all-cause mortality] risk increase of >30% at 20 years per unit [A1c] increase compared with 10%–20% in previous studies,” the researchers write, and this difference “likely will increase even more for many patients over a lifetime horizon.”
Cardiovascular outcome trials of diabetic agents have likely underestimated the beneficial effects of glycemic control, they note, because they were generally only 3 to 5 years long.
“Given these large legacy effects, early detection of type 2 diabetes (screening) and glycemic optimization needs greater emphasis in guidelines, by health care providers, and in clinical practice to more effectively prevent long-term complications and achieve a more normal life-expectancy for people with type 2 diabetes,” Lind and colleagues conclude.
The study was supported by the Swedish State. Holman reports research support from AstraZeneca, Bayer, and MSD, and personal fees from Anji Pharmaceuticals, Bayer, Intarcia, MSD, Novartis, and Novo Nordisk. Lind has received research grants from DexCom and Novo Nordisk and has been a consultant for AstraZeneca, Boehringer Ingelheim, DexCom, Eli Lilly, MSD, and Novo Nordisk. The other researchers have disclosed no relevant financial relationships.
Gerstein reports being a member of advisory panels for Novo Nordisk, Pfizer, and Sanofi, and a consultant for Abbott, Covance, Eli Lilly, Kowa, and Sanofi. He reported receiving research support from AstraZeneca, Eli Lilly, Merck, Novo Nordisk, and Sanofi, and having other relationships with Boehringer Ingelheim, DKSH, Eli Lilly, Sanofi, and Zuellig Pharma.
Diabetes Care. Published online July 7, 2021. Abstract