This is especially true for younger diabetics. However, the milestone study does not allow reliable comparison between different antidiabetic drugs.
The UK Prospective Diabetes Study (UKPDS) was milestone in the treatment of type 2 diabetes mellitus. This study, which lasted 20 years, was carried out on over 5,000 patients with newly manifested type 2 diabetes impressively showed that secondary diseases can be reduced through optimized blood sugar control. The data for this were first presented in 1998 at the European Diabetes Congress (EASD) in Barcelona. In short, mean HbA1c decrease from 7.9 to 7.0 percent resulted in 25 percent reduction for microvascular and twelve percent reduction for all diabetes-related endpoints in the sulfonylurea / insulin group.
In the relatively small group of 342 obese patients who were initially treated with metformin, there was 32 percent reduction in Diabetes-related endpoints, decrease in myocardial infarction by 39 percent and 36 percent reduction in all-cause mortality.
The reduction in microvascular diseases at 29 percent was similar to that in the sulfonylurea / insulin group, but this effect was - possibly also due to the small number of cases in the metformin group - not significant. The presentation of the UKPDS results in 1998 had thus provided definitive proof that better blood sugar control in people with type 2 diabetes leads to significant reduction in diabetes complications.
Similar to the previous large type 1 -Diabetes study DCCT (Diabetes Control and Complications Trial), further follow-up was also planned for UKPDS - but without any therapeutic influence. In 2008 - ten years after the first presentation in Barcelona - the results of the UKPDS follow-up were published. Almost over the entire period, namely from the second to the tenth year of follow-up, the HbA1c values in the originally different treatment arms were congruent.
One could now have assumed that the risk in the different groups in this one too Period would align. But this was not so; Interestingly, the initially intensively treated patients took their micro- and macrovascular risk reduction almost completely with them over the next ten years.
This is especially true for younger diabetics. However, the milestone study does not allow reliable comparison between different antidiabetic drugs.
The UK Prospective Diabetes Study (UKPDS) was milestone in the treatment of type 2 diabetes mellitus. This study, which lasted 20 years, was carried out on over 5,000 patients with newly manifested type 2 diabetes impressively showed that secondary diseases can be reduced through optimized blood sugar control. The data for this were first presented in 1998 at the European Diabetes Congress (EASD) in Barcelona. In short, mean HbA1c decrease from 7.9 to 7.0 percent resulted in 25 percent reduction for microvascular and twelve percent reduction for all diabetes-related endpoints in the sulfonylurea / insulin group.
In the relatively small group of 342 obese patients who were initially treated with metformin, there was 32 percent reduction in Diabetes-related endpoints, decrease in myocardial infarction by 39 percent and 36 percent reduction in all-cause mortality.
The reduction in microvascular diseases at 29 percent was similar to that in the sulfonylurea / insulin group, but this effect was - possibly also due to the small number of cases in the metformin group - not significant. The presentation of the UKPDS results in 1998 had thus provided definitive proof that better blood sugar control in people with type 2 diabetes leads to significant reduction in diabetes complications.
Similar to the previous large type 1 -Diabetes study DCCT (Diabetes Control and Complications Trial), further follow-up was also planned for UKPDS - but without any therapeutic influence. In 2008 - ten years after the first presentation in Barcelona - the results of the UKPDS follow-up were published. Almost over the entire period, namely from the second to the tenth year of follow-up, the HbA1c values in the originally different treatment arms were congruent.
One could now have assumed that the risk in the different groups in this one too Period would align. But this was not so; Interestingly, the initially intensively treated patients took their micro- and macrovascular risk reduction almost completely with them over the next ten years.Thus, “legacy effect” could be shown in people with type 2 diabetes, similar to earlier in the EDIC study on type 1 diabetes - which can be understood as kind of blood sugar memory.
< p> Various hypotheses have been made about the pathophysiological mechanisms of this “legacy effect” of the UKPDS, but ultimately also of the DCCT / EDIC study. The attempt to explain the accumulation of AGEs (advanced glycation endproducts) seems to be particularly interesting: Put simply, in hyperglycemia, more sugar residues accumulate on proteins and thereby change the physiological function of these biomolecules.AGE-modified proteins can accumulate in the body through long-term hyperglycaemia processes and in this way still exert their harmful effect long after an improvement in the glucose metabolism. Applied to the results of the UKPDS, this could mean that the higher glucose load in the conventionally treated group continues to have an effect for many years after the intervention through the accumulation of AGE products.
Solved and outstanding questions
< p> Fifteen years after the UKPDS results were published, the European Diabetes Congress took place again this year in Barcelona. On this occasion, symposium was again dedicated to the world's most discussed diabetes therapy study - especially on the questions: What conclusions can be drawn retrospectively from this milestone study today? And which questions have remained open despite this extensive investigation?The question, for example, whether certain antihyperglycemic substance group has an advantage over another cannot be answered clearly with UKPDS. This is because the largest intervention arm includes sulfonylureas and insulin equally - and the effects of the two substances cannot be differentiated.
Furthermore, the evaluation was carried out after the initial therapy, which, however, was frequently changed during the intervention phase. In the sulfonylurea group, for example, sulfonylureas were only actually given in 83 percent of the study patient years, and in the case of insulin it was only 74 percent. And patients in the glibenclamide group, for example, received combination with other substances such as metformin or insulin in 30 percent of the study patient years.
The UKPD study - although often interpreted differently - does not allow reliable comparison between different antidiabetic drugs , since the therapy often deviated from the original assignment to drug group during the course of the study.
Discourse on sulfonylureas
Also the discussion initiated by UKPDS of possible increased mortality when combining metformin with sulfonylurea is still not "off the table" for good.Thus, “legacy effect” could be shown in people with type 2 diabetes, similar to earlier in the EDIC study on type 1 diabetes - which can be understood as kind of blood sugar memory.
< p> Various hypotheses have been made about the pathophysiological mechanisms of this “legacy effect” of the UKPDS, but ultimately also of the DCCT / EDIC study. The attempt to explain the accumulation of AGEs (advanced glycation endproducts) seems to be particularly interesting: Put simply, in hyperglycemia, more sugar residues accumulate on proteins and thereby change the physiological function of these biomolecules.AGE-modified proteins can accumulate in the body through long-term hyperglycaemia processes and in this way still exert their harmful effect long after an improvement in the glucose metabolism. Applied to the results of the UKPDS, this could mean that the higher glucose load in the conventionally treated group continues to have an effect for many years after the intervention through the accumulation of AGE products.
Solved and outstanding questions
< p> Fifteen years after the UKPDS results were published, the European Diabetes Congress took place again this year in Barcelona. On this occasion, symposium was again dedicated to the world's most discussed diabetes therapy study - especially on the questions: What conclusions can be drawn retrospectively from this milestone study today? And which questions have remained open despite this extensive investigation?The question, for example, whether certain antihyperglycemic substance group has an advantage over another cannot be answered clearly with UKPDS. This is because the largest intervention arm includes sulfonylureas and insulin equally - and the effects of the two substances cannot be differentiated.
Furthermore, the evaluation was carried out after the initial therapy, which, however, was frequently changed during the intervention phase. In the sulfonylurea group, for example, sulfonylureas were only actually given in 83 percent of the study patient years, and in the case of insulin it was only 74 percent. And patients in the glibenclamide group, for example, received combination with other substances such as metformin or insulin in 30 percent of the study patient years.
The UKPD study - although often interpreted differently - does not allow reliable comparison between different antidiabetic drugs , since the therapy often deviated from the original assignment to drug group during the course of the study.
Discourse on sulfonylureas
Also the discussion initiated by UKPDS of possible increased mortality when combining metformin with sulfonylurea is still not "off the table" for good.Specifically, it is about the observation that adding metformin to an existing sulfonylurea therapy increased the overall mortality by 60 percent over period of 6.6 years.
Only 268 patients were randomized to the combination therapy. This means that the absolute number of all-cause mortality was very low for statistical purposes. This, as well as documented differences in age and fasting blood sugar in the therapy arms, place the results on an uncertain basis. Numerous retrospective follow-up studies have since been published on this topic. But even in them the results are not unambiguous, so that there remains certain residual uncertainty with regard to an increased mortality when combining metformin with sulfonylureas.
Interestingly, exactly this topic was taken up at this year's EASD Congress: Two were presented there Retrospective analyzes once again link the sulfonylureas to increased mortality. The main author, Prof. Dr. med. Craig Currie, pharmacoepidemiologist at Cardiff University, concludes: “In my opinion, the safety of sulfonylureas requires an urgent assessment by health authorities.” The observational data did not allow any definitive conclusions to be drawn. "It is certainly not irrefutable evidence, but regulators and scientific societies should take this advice seriously and initiate studies to test this," said Currie in Barcelona.
Patients with newly manifested disease were entered into the UKPDS Type 2 diabetes and with mean age of 53 years included. Approximately 7.5 percent already had macrovascular diseases when randomized. Large cardiovascular outcome studies in type 2 diabetes, such as ACCORD1, ADVANCE2 and VADT3, which followed later, differed considerably in that older patients with mean duration of diabetes of around ten years were enrolled and one third of them already had cardiovascular diseases. In this study collective, there was no reduction in cardiovascular events due to an almost normoglycemic setting with HbA1c values well below seven percent. In ACCORD and ADVANCE, completely different collective was examined, and stricter glycemic target values were also pursued.
Based on the results of these studies, no general recommendation can be made today for an HbA1c lowering well below seven percent in patients with Long-standing type 2 diabetes and significant cardiovascular disease will be given more. This is especially true when drugs with hypoglycaemia potential are used.
All of the studies mentioned above have shown therapy-related limitations.Specifically, it is about the observation that adding metformin to an existing sulfonylurea therapy increased the overall mortality by 60 percent over period of 6.6 years.
Only 268 patients were randomized to the combination therapy. This means that the absolute number of all-cause mortality was very low for statistical purposes. This, as well as documented differences in age and fasting blood sugar in the therapy arms, place the results on an uncertain basis. Numerous retrospective follow-up studies have since been published on this topic. But even in them the results are not unambiguous, so that there remains certain residual uncertainty with regard to an increased mortality when combining metformin with sulfonylureas.
Interestingly, exactly this topic was taken up at this year's EASD Congress: Two were presented there Retrospective analyzes once again link the sulfonylureas to increased mortality. The main author, Prof. Dr. med. Craig Currie, pharmacoepidemiologist at Cardiff University, concludes: “In my opinion, the safety of sulfonylureas requires an urgent assessment by health authorities.” The observational data did not allow any definitive conclusions to be drawn. "It is certainly not irrefutable evidence, but regulators and scientific societies should take this advice seriously and initiate studies to test this," said Currie in Barcelona.
Patients with newly manifested disease were entered into the UKPDS Type 2 diabetes and with mean age of 53 years included. Approximately 7.5 percent already had macrovascular diseases when randomized. Large cardiovascular outcome studies in type 2 diabetes, such as ACCORD1, ADVANCE2 and VADT3, which followed later, differed considerably in that older patients with mean duration of diabetes of around ten years were enrolled and one third of them already had cardiovascular diseases. In this study collective, there was no reduction in cardiovascular events due to an almost normoglycemic setting with HbA1c values well below seven percent. In ACCORD and ADVANCE, completely different collective was examined, and stricter glycemic target values were also pursued.
Based on the results of these studies, no general recommendation can be made today for an HbA1c lowering well below seven percent in patients with Long-standing type 2 diabetes and significant cardiovascular disease will be given more. This is especially true when drugs with hypoglycaemia potential are used.
All of the studies mentioned above have shown therapy-related limitations.Even in UKPDS, patients treated with sulfonylureas and human insulin had significantly higher hypoglycaemia rates and weight gain. Considering that most people with type 2 diabetes are overweight or obese, further therapy-related weight gain seems undesirable from the perspective of those affected and the therapist.
Metformin is metabolically neutral
Clinically relevant is the increased risk of hypoglycaemia, which leads to more emergency missions and hospital admissions and, in extreme cases, to death. There was also an association between the occurrence of severe hypoglycaemia and cardiovascular events in the ACCORD, ADVANCE and VADT studies. From this it follows that primarily substances that do not induce hypoglycaemia and ideally also do not cause therapy-related weight gain should be preferred.
As early as 1998, the authors of the UKPDS therefore concluded that metformin, due to the reduction in macrovascular endpoints, the lower hypoglycaemia rate and weight neutrality should primarily be used in the therapy of obese patients with type 2 diabetes. As result, metformin was recommended as primary drug therapy in national and international guidelines - initially only for overweight and now generally -.
The other substance classes used in the UKPDS - human insulin and sulfonylureas - are, however, because of undesirable effects such as weight gain and hypoglycemia induction are not quite as consistently advocated, especially since number of newer antidiabetic drugs that have lower risk of hypoglycemia (e.g. analog insulins, glitazones, incretin-based therapies and SGLT2 inhibitors) have now come onto the market.
Patient collectives different today
In summary, the UKPDS has shown that blood sugar-lowering therapy has positive effects in the medium and long term in newly manifested type 2 diabetes. The findings from this groundbreaking study have also led to the promotion of metformin as the drug of choice for the drug therapy of type 2 diabetes today (although the substance was still often considered dangerous at the time of the UKPDS intervention!).
The recommendation to aim for an HbA1c value below 7.0 percent in the event of new manifestation is essentially based on the findings of the UKPDS. Compared to ACCORD and ADVANCE, the UKPDS clearly shows that good metabolic control from the beginning of the disease is sensible and useful - here the patients obviously also take the positive effects of the glucose metabolism improvement with them over many years ("legacy" effect).
Together with ACCORD, ADVANCE and VADT, UKPDS has also shown that there are therapeutic limitations in the form of therapy-related weight gain and hypoglycaemia.Even in UKPDS, patients treated with sulfonylureas and human insulin had significantly higher hypoglycaemia rates and weight gain. Considering that most people with type 2 diabetes are overweight or obese, further therapy-related weight gain seems undesirable from the perspective of those affected and the therapist.
Metformin is metabolically neutral
Clinically relevant is the increased risk of hypoglycaemia, which leads to more emergency missions and hospital admissions and, in extreme cases, to death. There was also an association between the occurrence of severe hypoglycaemia and cardiovascular events in the ACCORD, ADVANCE and VADT studies. From this it follows that primarily substances that do not induce hypoglycaemia and ideally also do not cause therapy-related weight gain should be preferred.
As early as 1998, the authors of the UKPDS therefore concluded that metformin, due to the reduction in macrovascular endpoints, the lower hypoglycaemia rate and weight neutrality should primarily be used in the therapy of obese patients with type 2 diabetes. As result, metformin was recommended as primary drug therapy in national and international guidelines - initially only for overweight and now generally -.
The other substance classes used in the UKPDS - human insulin and sulfonylureas - are, however, because of undesirable effects such as weight gain and hypoglycemia induction are not quite as consistently advocated, especially since number of newer antidiabetic drugs that have lower risk of hypoglycemia (e.g. analog insulins, glitazones, incretin-based therapies and SGLT2 inhibitors) have now come onto the market.
Patient collectives different today
In summary, the UKPDS has shown that blood sugar-lowering therapy has positive effects in the medium and long term in newly manifested type 2 diabetes. The findings from this groundbreaking study have also led to the promotion of metformin as the drug of choice for the drug therapy of type 2 diabetes today (although the substance was still often considered dangerous at the time of the UKPDS intervention!).
The recommendation to aim for an HbA1c value below 7.0 percent in the event of new manifestation is essentially based on the findings of the UKPDS. Compared to ACCORD and ADVANCE, the UKPDS clearly shows that good metabolic control from the beginning of the disease is sensible and useful - here the patients obviously also take the positive effects of the glucose metabolism improvement with them over many years ("legacy" effect).
Together with ACCORD, ADVANCE and VADT, UKPDS has also shown that there are therapeutic limitations in the form of therapy-related weight gain and hypoglycaemia.These can now be avoided in many cases by differentiated diabetes therapy.
Since the patient collectives today differ considerably from the 80s and 90s with regard to the accompanying medication, it remains open in the end whether against the background of Improved accompanying therapy today, reduction in cardiovascular events through moderate blood sugar lowering with manageable study size and duration would be demonstrable. For long time to come, the UKPDS will therefore remain the only major therapeutic study that has been able to demonstrate such positive effects on diabetes-relevant endpoints.
Finally, one must consider: With reduction in glucose levels, type 2 diabetes is by no means complete treated. Hyperglycemia should also be seen as an indicator of complex metabolic disease that is not yet fully understood. The therapy of type 2 diabetes therefore includes much more than just good blood sugar control. ▄
Prof. Dr. med. Monika Kellerer Marienhospital Stuttgart
1 ACCORD = Action to Control Cardiovascular Risk in Diabetes Study
2 ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation
3 VADT = Veterans Affairs Diabetes Trial
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