Temporal trends in the initiation of glucose-lowering medications after a first-time myocardial infarction - a nationwide study between 1997 and 2006

Type 2 diabetes is a well-established risk factor for cardiovascular disease and is common among patients with acute myocardial infarction (MI), where the prevalence is as high as 20%[1]. Previous studies have shown that abnormal glucose metabolism is more common than normal glucose tolerance among patients with MI and that abnormal glucose tolerance is an important predictor of impaired long-term outcome in these patients[2‐4]. Thus, among patients with MI without known diabetes up to 65% exhibit abnormal glucose regulation when challenged with an oral glucose tolerance test (OGTT) and 25% of these have values diagnostic for diabetes and 40% have impaired glucose tolerance[5]. Focus on the adverse prognosis carried by diabetes in post-MI patients has increased over the years, causing new guidelines to be developed in 2007. These recommend that patients without diabetes admitted with MI are investigated with an OGTT within 3 months post MI[5, 6]. However, information regarding the actual number of patients receiving glucose-lowering medications (GLM) after first-time MI on a population basis is lacking. We therefore conducted the present nationwide register-based study to investigate the temporal trends in the initiation of GLM following hospitalization for first-time MI between 1997 and 2006.

Our study demonstrated an increase in the incidence rate of GLM initiation within the first year after first-time MI from 19.6 per 1000 person years in 1997 to 27.6 per 1000 person-years in 2001. Following year 2001 the incidence rates stabilized. The increased probability of initiating GLM after a first-time MI was confirmed in adjusted Cox-analyses. A similar trend in the increased incident rate in GLM initiation was demonstrated in the general population from 2.8 per 1000 person years in 1997 to 4.0 per 1000 person years in 2004. Corresponding to the MI population a stabilisation in incidence rate was observed in the general population after 2004. The international diagnostic criteria for diabetes was changed from a fasting blood glucose value of 7.0 mM to 6.1 mM in 1997, marking the initiation of this nation-wide observational study, why we cannot exclude the possibility that an unknown proportion of the increased incidence of diabetes during the period from 1997 until 2001 was in fact due to the subsequent implementation in clinical practice of these novel diagnostic criteria in Denmark. However, it should be noted that the criteria on diabetes/pre-diabetes was not changed in Denmark during the study period,[10], opposite to what happened in the US in 2003, where the cut-off point of impaired fasting glucose was further lowered to 5.6 mmol/L by the American Diabetes Association (ADA)[11]. Nevertheless, the theoretical possibility that the increased general use of GLM during the period from 1997 until 2001 to some (unknown) extent may be due to the implementation more stringent diagnostic criteria for diabetes, in fact support and substantiate the main conclusion of the current work being that diabetes remain disproportionately under diagnosed and under treated among the high risk proportion of patients developing diabetes after a MI.

Previously, studies in MI patients have documented that abnormal glucose metabolism before discharge is more frequent than normal glucose metabolism [2, 3, 12]. Indeed, the Euro Heart Survey on Diabetes and the Heart with data from 25 countries disclosed unrecognized diabetes in 22% of patients with acute coronary syndrome according to results of the OGTT [3, 13]. In addition, Norhammar et al. conducted a small-scale prospective study of 181 consecutively admitted MI patients without known diabetes, where an OGTT was performed at discharge and again 3 months later. According to the OGTT, 35% and 40% had impaired glucose tolerance at discharge and after 3 months, respectively and 31% and 25% had previously undiagnosed diabetes [11]. Similar results were also found by Egstrup et al [2, 14].

These results indicate that a large proportion of post-MI patients have undiagnosed diabetes or develop diabetes during admission or within a short time-span after discharge. We therefore anticipated that a much larger proportion of patients would have initiated GLM shortly after discharge for MI, than observed in our current study. There are numerous possible explanations for this discrepancy. First, diabetes in many patients was probably left undiagnosed, because the majority of patients presented with normal fasting glucose values and therefore in accord with contemporary guidelines, did not undergo an OGTT, although many would here have impaired glucose tolerance or overt diabetes [2]. Importantly, however, because our study was conducted prior to publication of prevailing international guidelines, these numbers should not be interpreted as representing a predominant negligence from clinicians. Second, guidelines regarding management of newly detected diabetes at the time of the study generally recommended lifestyle intervention and dietary treatment as first-line treatment. Therefore it is conceivable that a substantial number of patients not initiating GLM were in fact being managed by non pharmacological intervention. However, since diabetes is well-established as an important independent long-term prognostic factor after MI that predicts increased mortality even 17 years after MI,[15] our study underscores the importance of an aggressive diagnostic and therapeutic approach in diabetes patients with MI. It is highly unlikely that lifestyle interventions were sufficient for all diabetes patients not initiating GLM to have reached target blood glucose values, and our results indicate that a considerable number of post-MI patients do not receive GLM as appropriate. This is, however, only an assumption as we e.g. do not have any measurements of blood glucose values during and after hospitalization.

In agreement with the results cited above, treatment guidelines have recommended that all patients hospitalized with MI have a fasting glucose measurement during hospitalization, and are subjected to an OGTT three months after discharge [5, 6]. Furthermore, management of patients with diabetes with lifestyle interventions (including dietary treatment) alone is no longer considered to be first- line treatment. In addition to such interventions, patients with newly diagnosed diabetes should initiate treatment with metformin unless contraindicated [16]. Therefore, it would be of great interest to repeat the current study in the future, investigating the impact of the change of treatment guidelines in this real life population-scale setting.

During the 10 year study period a considerable increase in initiation of GLM in the general population was apparent. The incidence of diabetes in our study was in consistency with a previous study employing the Danish National Diabetes Register, where Carstensen et al. demonstrated an increase in the incidence of diabetes [17]. Whether the increase in incidence of diabetes in Denmark represents a true epidemiologic increment in diabetes rates is questionable, and other possible explanations include 1) increased diagnostic intensity due to an augmentation of the awareness of diabetes in the general population, and 2) a large undiagnosed population of patients with diabetes early in the study period was being diagnosed during the rest of the study period, and 3) a decrease in mortality rates in the general population leading to increased numbers of subjects at risk of diabetes. The extent to which these individual factors each contribute to the increase in incidence of diabetes is speculative. A very important discrepancy in our study compared with the study by Carstensen et al. was that we only documented an increase in incidence of patients with diabetes requiring GLM. Supplementary to the explanations outlined above, we speculate that an increased awareness during the 10 year study period of the importance of reaching normoglycaemia in diabetes patients with use of GLM may also contribute to our finding of increased incident diabetes.

We would have anticipated a steeper increase in incidence rate in the post-MI population compared to the general population. Indeed the incidence rates are much higher in the MI population than in the general population, which is not surprising, since MI patients are at much higher risk of developing diabetes and since diabetes is a risk factor for MI. If the higher incidence rates in the MI population compared to the general population were solely to be explained by a true increased awareness of diabetes in the MI population and not in the general population as a whole, a steeper, linear or even exponential increment of incident diabetes in the MI population would be expected. Since we did not find such steep increase, it is most likely that the increased initiation of GLM in the MI population was, in fact, primarily the effect of a general increased awareness of diabetes in the population as a whole.

Results from randomized controlled trials have conclusively demonstrated that the risk of microvascular complications can be reduced by intensive glycaemic control in patients with diabetes [18‐22]. Although the effect of intensive glycaemic control on macrovascular outcomes remains a matter of intense debate,[23‐25] the American Diabetes Association (ADA) currently stated that glycaemic control early in the course of type 2 diabetes may provide CVD benefits and that glycaemic control may play a greater role for CVD prevention in patients with a shorter duration of diabetes before macrovascular disease is established [26].

It is known that patients with diabetes and cardiovascular disease tend to have poorer glycaemic control than those with diabetes without cardiovascular disease, indicating the need for increased attention to glycaemic control in patients with cardiovascular disease [27]. The current results shows that when it comes to early GLM initiation in those with newly detected diabetes, there remains a considerable room for improvement in modern clinical practice.

The change in the pattern of type of GLM used in MI patients during the period is likely to reflect the results of the UKPDS as well as the Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction Study 1 signaling increased survival among users of metformin in general as well as the value of early insulin treatment after a recent MI [21, 28]. This has shown to be valid also for patients undergoing percutaneous intervention (PCI), in whom the use of metformin or thiazolidinediones seem to attenuate the re-stenosis formation [13]. Opposite, the effect of sulfonylureas or insulin on outcomes in MI patients treated with and without PCI seems to be less beneficial [29, 30]. The extent to which our findings of changes in clinical practice may change the long-time survival in Danish MI patients with diabetes remain to be determined.

Our study demonstrated an increase in incidence rates of GLM initiation within the first year post- MI. Parallel, a similar trend was observed in the general population. These results indicate that the increased initiation of GLM in the MI population was primarily the effect of a general increased awareness of diabetes in the population as a whole. From a public heath perspective, this study underscores a continuous need for diagnostic and therapeutic improvement in the care of MI patients that develop diabetes, and such strategy is likely to provide long-term benefits.