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• W2083025587 abstract "Readers of this journal need little reminding of the close association between obesity and type 2 diabetes. The majority of our patients with type 2 diabetes are obese at the time of diagnosis or have been so at some time before in their lives ((1)). Both the degree and duration of obesity are risk factors for type 2 diabetes ((2), (3)). With what frequency obesity is itself a direct cause of diabetes, or whether these two morbid conditions, both characterized by insulin resistance, are parallel consequences of a prime mover are still debatable ((4), (5), (6)). That caloric restriction ((7)) and even modest weight loss ((8)) ameliorates hyperglycemia is, however, not debatable. With individual patient ((9)) and clinic ((10)) exceptions, most patients unfortunately cannot sustain such therapy and reap the benefits for very long ((8), (9), (10), (11), (12), (13), (14)). In my opinion, this recidivism is a fundamental symptom of type 2 diabetes that arises in the context of obesity. Truly rational pharmacotherapy will only emerge when we understand the crucial metabolic abnormality(s) that underlie and link this combination. Until then, if we cannot cure or even control obesity reliably, we are obliged to treat hyperglycemia vigorously and to achieve better results than we have ((15)). The recently published and long-awaited results of the United Kingdom Prospective Diabetes Study (UKPDS) now provides powerful support for this assertion ((16), (17)). Patients with type 2 diabetes are less likely to suffer the acute metabolic complications of diabetes, ketoacidosis, or severe hypoglycemic episodes induced by exogenous insulin than are those who have type 1 diabetes. But as the incidence of type 2 diabetes has been steadily rising to almost epidemic proportions, the prevalence of resultant diabetic retinopathy, nephropathy, and neuropathy has increased concomitantly. Fifty percent of cases of proliferative retinopathy and 80% of cases of macular edema result from type 2 diabetes ((18)). Half of the chronic dialysis that is necessitated by diabetic nephropathy is accounted for by patients with type 2 diabetes ((19)). Many of the lower extremity amputations in diabetic persons are contributed to by peripheral sensory neuropathy ((20), (21)). The Diabetic Control and Complications Trial (DCCT) demonstrated unequivocally that maintaining blood glucose close to normal with intensive treatment would prevent or delay diabetic retinopathy, nephropathy, and neuropathy in type 1 diabetes ((22)). Because prospective epidemiological studies, especially the Wisconsin Epidemiologic Study of Diabetic Retinopathy ((23)), had demonstrated very similar relationships between hyperglycemia and diabetic retinopathy in type 2 diabetes as in type 1 diabetes, many observers were (somewhat speculatively) willing to extrapolate the conclusions of the DCCT to type 2 diabetes ((24), (25), (26), (27), (28), (29)). Subsequently, a smaller scale Japanese randomized control trial ((30)) reproduced the DCCT results in type 2 diabetic patients; however, the subjects in that trial were not obese and had reached a state of insulin deficiency that required exogenous insulin treatment. Therefore this trial did not prove that aggressive pursuit of normal glycemia was as warranted in typical obese insulin-resistant, western type 2 diabetes as in type 1 diabetes. Until the introduction of metformin in 1995 ((31)), the only pharmacologic therapy available for type 2 diabetes in the United States was sulfonylurea drugs and insulin, both of which lead to weight gain ((6)), an obvious adverse effect in patients already struggling with obesity. In addition, sulfonylurea drugs still had to be prescribed under a residual cloud of suspicion originating with the University Group Diabetes Program observation that tolbutamide treatment was associated with an increased risk of cardiovascular death ((32)). Moreover, insulin itself was accused of playing a causative role in the development of atherosclerosis ((33)) and resultant cardiovascular events and mortality ((34)). Thus, aggressive treatment of hyperglycemia in patients with type 2 diabetes was certainly not the rule, judging by reported HbA1c results ((15)). However, we now have data from the UKPDS that should guide us in establishing firm therapeutic targets and reassure us in using certain therapeutic agents ((16), (17)) as we struggle with type 2 diabetes. The UKPDS was a randomized clinical trial begun in 1977 that was primarily designed to compare the effects of conventional treatment (originally called Diet Policy) with intensive drug treatment (originally called Active Policy) on the development of cardiovascular and microvascular complications. The 5102 research subjects had newly diagnosed type 2 diabetes by World Health Organization criteria. Their mean age was 53 years, mean weight 77.5 kg, and mean body mass index 27.5 kg/m2; importantly, 52% of them were overweight by the then used criterion of exceeding 120% of desirable body weight. Within the intensive treatment group, a secondary objective was to compare the efficacy of sulfonylurea drugs and insulin by randomly assigning the subjects to these agents. Finally, in the intensive treatment group the overweight subjects that were recruited in the original 15 (of an eventual 23) clinics were also randomly assigned to metformin. This 15-clinic cohort was analyzed separately, although those subjects assigned to Diet Policy, insulin, and sulfonylureas were also included in the main analysis. In the course of the average 10-year follow-up, in order to achieve fasting plasma glucose targets of <108 mg/dL in the intensive treatment group, and <270 mg/dL in the conventional treatment group, the investigators had to employ all of the drugs in subjects of the Diet Policy group, use insulin in all the other treatment groups, and use combination therapy of metformin with sulfonylurea drugs in many subjects of non-insulin treatment groups. The overall median HbA1c was 7.0% with intensive therapy, 7.9% with conventional therapy, and was 7.4% in the obese metformin monotherapy group. The potential confounding effects of these therapeutic crossovers have been pointed out ((35)). Nevertheless, despite the fact that 80% of the conventionally treated Diet Policy patients and 42% of their treatment time were “contaminated” by the necessary administration of the very drugs for which these individuals were originally assigned to be the control group, clear cut and highly statistically significant differences in important complications outcomes were observed. Most notably, the cumulative incidence of an aggregated microvascular outcome (any of fatal or nonfatal renal failure, vitreous hemorrhage, or retinal photocoagulation) was reduced 25% by intensive treatment (p < 0.0099). Many individual retinal and renal outcomes such as photocoagulation and doubling of serum creatinine were significantly reduced. A 16% reduction in an aggregated myocardial infarction outcome (fatal or nonfatal myocardial infarction or sudden death) of borderline statistical significance (p < 0.052) was also observed with intensive treatment. Of great importance, neither sulfonylurea drugs nor insulin increased the incidence of myocardial infarctions, laying to rest the concerns cited above. The aggregate microvascular outcome was also decreased by intensive treatment in the separately analyzed obese cohort, but the difference was not statistically significant. This may be attributed to a lower sample size in the obese substudy than in the complete trial (1362 vs. 3876 subjects), a smaller difference in HbA1c (0.6% vs. 0.9%), and possibly a lower retinopathic event rate in the obese subjects (unpublished data). From a bariatric perspective, weight gain occurred with sulfonylurea drugs and insulin, as compared to conventional therapy. The cost of insulin therapy was an average weight gain over 10 years of about 6.5 kg, which was 4.0 kg more than the weight gain of the conventionally treated patients. Weight tended to plateau thereafter. If we assume an average loss of height of 3 cm over the span of study time, with insulin treatment, the average BMI increased about 2.5 units to approximately 30 kg/m2. Although this was not a negligible change, it only barely brought patients into the weight range where mortality increases exponentially ((36)). On the other hand, this weight gain plus a (relatively low) yearly prevalence of severe hypoglycemic episodes of 2.5% to 3% of patients per year may have acted as a brake on insulin dosage. Although the single highest insulin dosage reported was 400 units per day, the insulin dose for patients with BMI > 35 kg/m2 averaged 36 units at 3 years and 60 units at 12 years. Overall insulin doses in the intensively treated group, irrespective of BMI, were hardly heroic, averaging 0.27 units per kilogram per day at 3 years and 0.42 units per kilogram per day at 12 years. A reluctance to increase insulin doses more aggressively resulted in a median HbA1c of 7.1% with insulin treatment vs. 6.7% with chlorpropamide, 7.2% with glyburide, and 7.4% with metformin. These data suggest that if we wish to lower glycemia closer to normal (<6.1%), we will probably need to use larger doses of insulin in monotherapy ((6)) and more often combine insulin with oral drugs that improve responses to insulin ((37), (38), (39), (40)). In several respects the UKPDS results with metformin therapy ((17)) deserve special mention. Within the obese cohort study, metformin was associated with a 29% reduction in the risk of aggregated microvascular complications, but this was not statistically significant (p < 0.19). This nonsignificant result may be explained by the same reasons offered above for the similar outcome of intensive treatment with insulin and sulfonylurea drugs in the obese cohort. On the other hand, metformin monotherapy was associated with significant reductions in any diabetes-related event (32% lower, p < 0.0023), diabetes-related death (42% lower, p < 0.017), all-cause mortality (36% lower, p < 0.011), and myocardial infarction (39% lower, p < 0.010). This unique effect of metformin on myocardial infarction and mortality is not readily explained by blood glucose lowering, which was less than that achieved with insulin and sulfonylurea drugs in the main trial. This beneficial effect of metformin may have been mediated by reduction in insulin resistance ((40)), in plasminogen activator inhibitor-1 levels ((40), (41)), or by some presently unknown mechanism. It is noteworthy that metformin monotherapy was the only UKPDS treatment that did not produce weight gain ((17)). Unfortunately, the luster of metformin as a preferred treatment of type 2 diabetes with obesity was dimmed by another secondary and relatively small study that was later imbedded in the UKPDS ((17)). Overweight and normal weight subjects whose fasting plasma glucose levels could no longer be maintained within the target range with a sulfonylurea drug alone were randomly assigned either to add or not to add metformin. Unexpectedly, diabetes-related death was increased by 96% (p < 0.039) and all-cause mortality was increased 60% (p < 0.041) by the addition of metformin to a sulfonylurea drug. This adverse effect of metformin on mortality was not substantiated by other analytical strategies that included merging the data of the metformin monotherapy trial with those of the sulfonylurea-metformin combination trial, by a formal meta-analysis of the two trials, or by an epidemiological analysis that involved all other metformin-treated patients in the UKPDS. Nevertheless, only another randomized control trial that is conducted in sulfonylurea failure patients and that compares the addition of metformin to the addition of a placebo to the sulfonylurea drugs for many years can completely remove the new uncertainty regarding the safety of this combination ((42)). In summary, I believe that the overall UKPDS results mandate aggressive treatment of obese patients with type 2 diabetes and that treatment should aim for a HbA1c level of <7.0%, in order to prevent significant morbidity from retinopathy, nephropathy, and probably neuropathy. We need not avoid the use of insulin or sulfonylurea drugs when these are required to achieve this glycemic target. Metformin monotherapy may be particularly efficacious in decreasing cardiovascular complications in obese patients with type 2 diabetes. If the mechanism does involve effects on insulin resistance, it is important that we study the effect of thiazolidinedione drugs by a randomized control trial in obese type 2 diabetic patients, because one drug of this class, troglitazone, reduces peripheral insulin resistance much more than does metformin ((43)). If we can't lower weight consistently, which is the preferred treatment, we must still lower blood glucose with the drugs at hand while we await the results of further studies to determine the selective benefits of lowering insulin resistance." @default.
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• W2083025587 title "Implications of the United Kingdom Prospective Diabetes Study for Patients with Obesity and Type 2 Diabetes" @default.
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