Early Glycemic Control and
Magnitude of HbA1c Reduction Predict Cardiovascular Events and Mortality: Population-Based Cohort Study of 24,752 Metformin Initiators. Elisabeth Svensson,1 Lisbeth M. Baggesen,1 Søren P. Johnsen,1 Lars Pedersen,1 Helene Nørrelund,1 Esben S. Buhl,2 Christiane L. Haase,2 and Reimar W Thomsen
We investigated the association of early achieved HbA1c level and magnitude of HbA1c reduction withsubsequentrisk ofcardiovascularevents ordeath inpatients with type 2 diabetes who initiate metformin.
RESEARCH DESIGN AND METHODS
This was a population-based cohort study including all metformin initiators with HbA1c tests inNorthern Denmark,2000–2012. Six months after metformin initiation, we classiﬁed patients by HbA1c achieved (<6.5% or higher) and by magnitude of
HbA1c change from the pretreatment baseline. We used Cox regression to examine subsequent rates of acute myocardial infarction, stroke, or death, controlling for baseline HbA1c and other confounding factors.
We included 24,752 metformin initiators (median age 62.5 years, 55% males) with a median follow-up of 2.6 years.
The risk of a combined outcome event gradually increased with rising levels of HbA1c achieved compared with a target HbA1c of <6.5%: adjusted hazard ratio (HR) 1.18 (95% CI 1.07–1.30) for 6.5–6.99%,
HR 1.23 (1.09–1.40) for 7.0–7.49%, HR 1.34 (1.14–1.57) for 7.5–7.99%, and HR 1.59 (1.37–1.84)for‡8%.Resultswereconsistentforindividualoutcomeeventsandrobust by age group and other patient characteristics.
A large absolute HbA1c reduction from baseline also predicted outcome: adjusted HR 0.80 (0.65–0.97) for D = 24, HR 0.98 (0.80–1.20) for D = 23, HR 0.92 (0.78–1.08) for D = 22, and HR 0.99 (0.89–1.10) for D = 21 compared with no HbA1c change (D = 0).
A large initial HbA1c reduction and achievement of low HbA1c levels within 6 months after metformin initiation are associated with a lower risk of cardiovas-cular events and death in patients with type 2 diabetes.
Lowering glycated hemoglobin (HbA1c) levels to ,7% (,53 mmol/mol) in most adults with type 2 diabetes has been a recommended target in treatment guide-lines for more than a decade (1–4) be-cause of the documented effect in reducing microvascular complications (5). In contrast, it remains debated whether even tighter glucose control (such as HbA1c ,6.5%) may bemore ben-eﬁcial or harmful (6) and what the true effect of tight early glucose control is on subsequentcardiovascular disease(7).
Although the large clinical randomized con-trolled trials have failed to show a clear beneﬁcial effect of early intensive glyce-mic control on cardiovascular events in type 2 diabetes (5), long-term follow-up studies from the UK Prospective Diabetes Study (UKPDS) (8) and Veterans study (9) have suggested a beneﬁcial cardiovascu-lar effect,termed “metabolicmemory”or “legacy effect.” (10) In observational re-search, most studies, but not all, suggest that having a low glycemic level mea-sured at some point of time is associated with fewer cardiovascular events and mortality in type 2 diabetes (11–18).
Some studies found a linear relationship between successively lower glycemic lev-els and fewer cardiovascular events (11,12,18), whereas others reported a J-orU-shapedcurve(14–16).Comparison of these studies is hampered by inclusion of case patients with prevalent diabetes with different time of diabetes duration and by different ways of measuring glyce-miccontrol.Onlytwooftheobservational studiesoncardiovascularriskbeganatthe diagnosisofdiabetes (15,18). Olssonetal. (18) found an overall increased risk of acute myocardial infarction with a time-updated HbA1c ,6.0% (42 mmol/mol) compared with 6–7%, whereas ¨Ostgren et al. (15) reported the lowest cardiovas-cular risk was seen with an early achieved HbA1c level of 6.8% (51 mmol/mol). Whether the magnitude of early HbA1c reduction predicts subsequent prognosis remains unknown.
Because current guidelines empha-size the importance of tight glycemic control early after diabetes diagnosis, before complications have occurred (4), further research is warranted on the association of early glycemic control with cardiovascular events, taking into account HbA1c at the initiation of metfor-min use. Thus, using real-life data from Danishmedicalregistries,weinvestigated the association of achieved HbA1c level and magnitude of HbA1c reduction with subsequent risk of myocardial infarction, stroke, and death in a population-based cohort of patients with incident type 2 diabetes initiating metformin treatment.
In this population-based study of 24,752 metformin initiators, attaining a stringent HbA1c goalof,6.5%within6monthswas associated with lower risk of cardiovascu-lar events and mortality, with the risk gradually increasing at higher HbA1c lev-els. A large magnitude of HbA1c reduction similarly was associated with a lower sub-sequent risk of adverse outcomes.
Our results corroborate ﬁndings from a few previous observational studies on early glycemic control showing lowered risk of macrovascular events (15,18), and also in the UKPDS trial (31), all in patients with newly diagnosed type 2 di-abetes. Olsson et al. (18), monitoring 101,799 patients from the Clinical Practice Research Data Link in the U.K. be-tween 1995 and 2011 from start of type 2 diabetes diagnoses, found an increased risk for myocardial infarction of ;60% (HR 1.6) at an HbA1c of 7–8% vs. 6–7%, with a median follow-up of 5.4 years (18). Our corresponding ﬁnding was slightly lower (HR 1.5 [95% CI 1.0– 2.1])comparingHbA1c of$8%vs.,6.5%, with a median follow-up of 2.6 years.
The similar ﬁndings, despite different categorization of HbA1c and use of different HbA1c measure (updated means vs. early glycemiccontrol),strengthensthevalidity of our results.
Our data show that achievement of stringent glycemic levels is possible in real life in at least some elderly patients with comorbidities and that reaching such levels predicts lower risk of vascular events and death.
Of note, elderly patients with complications who attained stringent HbA1c levels in our observa-tional study may have been selected by caregivers through criteria that are not well described in our data, for example, by having a low risk of hypoglycemia or high patient motivation and self-care (3). In accordance, the updated statement from the American Heart Association and the American Diabetes Association suggests stringent targets for selected in-dividual patients, including patients with a short disease duration (7).
A novel ﬁnding in our study was that the magnitude of early HbA1c reduction is an independent predictor of lower cardiovascular risk and death, also after taking pretreatment HbA1c level into account.
Nonetheless, in the subgroup of patients who had a low baseline HbA1c (,7.5%) before metformin initiation, a reduction in the order of22% tended to be associated with worse outcomes, consistent with ﬁndings from random-izedtrials (5).Asa result of thestatistical variation and imprecision of outcome HRs associated with limited size of the change in HbA1c subgroups, our ﬁndings should be interpreted with caution.
Overall, our ﬁndings suggest that rapid glycemic response may be used as a possible source of identiﬁcation of a subgroup of patients with a lower risk of adverse outcomes.It is possible thatrapid glycemic responders to therapy initiation (i.e., more easy-to-treat patients) may have a different pathological trajectory and a milder variant of type 2 diabetes than patients who are poor responders. It is also possible that it is the young patients with type 2 diabetes without complications that clinicians dare to treat intensively; for example , reduce HbA1c .10% to ,7%, supported by a re-cent study from Denmark (32). However, we observed a clear association between early control and improved outcomes also when restricted to people older than 70 years in our study. Moreover, we have previously observed that young patients, toa lesserextentthan older patients, reach an early glycemic control ,7% within 6 months, possibly related to the fact that the pretreatment HbA1c with young debut of diabetes often is high (33).
The strengths of this study include a population-based design within the comprehensive Danish public health care system, and accordingly, our data reﬂectactual clinical practicein diabetes care. Carstensen et al. (34) showed a high sensitivity and positive predictive value (.95%) for identifying patients with type 2 diabetes using Danish registries, with GP registration as the gold standard. Positive predictive values for important comorbidities are also documented as being high in the DNPR (25).
Furthermore, we have a comprehensive assessment of cardiovascular events and death, and validity of these codes are also high (26,27). We only looked at myocardial infarction, stroke, and death, yet other studies have found similar associ-ations with glycemia for heart failure, as summed in the meta-analysis by Erqou et al. (35) Finally, we only included metfor-min initiators, increasing the homogeneity of the population studied and representing the clinical practice today with metformin as the preferred initial pharmacological agent for type 2diabetes(4).Whether early glycemic control by other oral glucose-lowering drugs is associated with similar beneﬁts remains to be proven.
Study limitations included that only approximately half of all potentially eligible patients had HbA1c measurements within the right time frame around therapy start. The fact that patients with no HbA1c measurement available had low outcome risks suggests that this sub-groupmighthavebeenlesssevereatstart. Over time, the frequency of HbA1c mea-surements has increased, and because treatment guidelines have changed over time from initial lifestyle modiﬁcation to emphasizing early drug treatment, it is likely that patients had high HbA1c levels in the beginning of our study period primarily as a result of late initiation of medical therapy and that HbA1c mea-surements from recent years more re-liably reﬂect baseline glycemic control in newly diagnosed type 2 diabetes.
Nonetheless, analyses stratiﬁed by period of metformin initiation showed consistent results. Moreover, prescrip-tion redemption is only a marker of actual drug consumption. We also have to bear in mind that the guidelines have changed over time to encompass individ-ualized therapy (3,4). Pretreatment HbA1c levels have decreased substantially over time in Denmark and in other countries, and achievement of early glycemic control has improved (22).
Byregression analyses and stratiﬁcation, we were able to evaluate the effect of a range of possible confounders of the asso-ciationbetweenearlyglycemiccontroland cardiovascular events, and interestingly, few differences were seen comparing crude and adjusted results and in stratiﬁed analyses.Also,theanalysisadjustedforpo-tentialunmeasuredconfoundingbyeduca-tional level showed consistent results. We had no data on tobacco smoking but were able to adjust for a number of smoking-related diseases. Still, imperfectly mea-sured,unmeasured(e.g.,BMI,diet,physical activity, social support, motivation, and self-care), or unknown factors may have affected our risk estimates.
In conclusion, these real-world data provide evidence that not only achievement of early glycemic control but also the magnitude of HbA1c reductionp redicts decreased riskof cardiovascular outcomes and mortality in metformin initiators, in-dependent of baseline HbA1c levels at treatment initiation. Whereas causality is difﬁcult to prove in our observational study design, these results provide an early prediction tool for identiﬁcation of patient subgroups with type 2 diabetes that have increased risk for cardiovascular complications and death.
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