Internal Medicine Grand Rounds: New Goals and Therapeutic Options for Type 2 Diabetes

Figures given are: number of people with diabetes in 2011 and predicted number of people that will have diabetes in 2030 according to IDF estimates. Percentage is the increase in diabetes from 2011 to 2030. “World” box acts as the legend is one of the greatest challenges of the 21st century, as seen in the global incidence and projections of diabetes epidemic worldwide 2011 and this is predicted to rise to 552 million by 2030 $465 billion in healthcare expenditure in 2011 – 11% of the total expenditure, and is expected to exceed $595 billion by 2030 This slide depicts the relationship over time of insulin resistance, beta-cell dysfunction, and hyperglcyemia Initially, hyperinsulinemia in the face of insulin resistance maintains glucose levels within the normal range. In time, insulin secretion falters, and blood glucose levels rise, initially in the post- prandial phase, but eventually in the fasting state. Patients initially develop ‘pre- diabetes’ –either impaired fasting glucose and/or impaired glucose tolerance, and as insulin secretion falters further, type 2 diabetes. Importantly, by the time diabetes is diagnosed, the patient has already lost half of his/her beta cell capacity between the development of diabetes and its vascular complications. The microvascular complications (retinopathy, nephropathy, and neuropathy) rarely occur before type 2 diabetes has already been established. In contrast, macrovascular disease, which has many other inputs (blood pressure, lipids), can occur in patients with insulin resistance or in the pre-diabetic phase Understanding cardiovascular (CV) outcome studies in type 2 diabetes mellitus (DM). These

data highlight the importance of balancing the benefits and risks of antidiabetes medications when making treatment decisions using agents that minimize the risk of hypoglycemia and weight gain and possibly lead to weight loss. ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release and Controlled Evaluation; ASCD = atherosclerotic cardiovascular disease; DCCT/EDIC = Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; HbA1c = hemoglobin A1c; PROACTIVE = PROspective pioglitAzone Clinical Trial In macroVascular Events; UKPDS = United Kingdom Prospective Diabetes Study; VADT = Veterans Affairs Diabetes Trial. From Diabetologia,36 modified with permission from Springer Publishing FIG. 1.  Mechanisms involved in the effect of hyperglycemia on superoxide anion production in the mitochondria of endothelial cells that lead to overactivation of pathways responsible for the metabolic memory of complications in diabetes. Epigenetic changes produced by histone methylation depicted in the lower right corner also contribute to the metabolic memory (see text for full explanation). AGEs, advanced glycation end-products; GAPDH, glyceraldehyde 3- phosphate dehydrogenase; H, histones; M, methylation; MCP-1, monocyte chemoattractant protein-1; NF-κB, nuclear factor κB; PARP, poly(ADP-ribose) polymerase; PKC, protein kinase C; RAGE, advanced glycation end- products receptors; ROS, reactive oxygen species; VCAM-1, vascular cell adhesion molecule-1 FIG. 1. Intracellular hyperglycemia induces overproduction of superoxide, a ROS, at the mitochondrial level as a possible cause of the metabolic memory of hyperglycemic stress after glucose normalization. Overproduction of ROS is the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications, such as polyol pathway flux, increased AGE formation, activation of protein kinase C, and increased hexosamine pathway flux Mitochondrial proteins are glycated in hyperglycemia, and this effect induces mitochondria to overproduce superoxide anion, a condition that does not depend on glycemic levels Binding of AGEs to RAGE results in generation of intracellular ROS generation, which promotes the expression of RAGE themselves. mtDNA may influence gene expression and at the same time may contribute to an overgeneration of free radicals at the mitochondrial level These self-maintaining conditions, leading to a persistent oxidative stress generation independent of the actual glycemic levels, may contribute to the appearance of the metabolic memory FIG. 2. Kaplan-Meier curves for time to primary macrovascular end point by clinical categories of CAC (0–10 [A], 11–100 [B], 101– 400 [C], and >400[D]) in those randomized to the standard (Std) or intensive (Int) therapy arm. Differences between treatment groups were significant in A (P 0.03). Shown above the x-axes are the total numbers of participants at risk at baseline and the beginning of each follow-up year through year 6 calcified coronary atherosclerosis may determine cardiovascular disease events in response to intensive glycemic control within the Veterans Affairs Diabetes Trial (VADT) RESEARCH DESIGN AND METHODS At baseline, 301 type 2 diabetic participants in the VADT, a randomized trial comparing the effects of intensive versus standard glucose lowering on cardiovascular events, had baseline coronary atherosclerosis assessed by coronary artery calcium (CAC) measured by computed tomography. Participants were followed over the 7.5-year study for development of cardiovascular end points RESULTS During a median follow-up duration of 5.2 years, 89 cardiovascular events occurred Although intensive glucose-lowering therapy did not significantly reduce cardiovascular events in the substudy cohort as a whole, there was evidence that the response was modified by baseline CAC, as indicated by significant P values for treatment by log(CAC + 1) interaction terms in unadjusted and multivariable-adjusted models (0.01 and 0.03, respectively) Multivariable-adjusted hazard ratios (HRs) for the effect of treatment indicated a progressive diminution of benefit with increasing CAC Avoiding ‘glucocentricity’ is key in the comprehensive management of the patient with T2DM. Cardiovascular risk factor reduction must incorporate blood pressure and lipid control, in addition to, where indicated, anti- platelet therapy Depiction of the elements of decision-making used to determine appropriate efforts to achieve glycaemic targets. Greater concerns about a particular domain are represented by increasing height of the ramp Thus, characteristics/predicaments towards the left justify more stringent efforts to lower HbA1c, whereas those towards the right are compatible with less stringent efforts. Where possible, such decisions should be made in conjunction with the patient, reflecting his or her preferences, needs and values This ‘scale’ is not designed to be applied rigidly but to be used as a broad construct to help guide clinical decisions. Adapted with permission from Ismail-Beigi et al [ref 20] Fixed dose combinations

Major discussion point:

Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26:2929-2940 FIG. 5. GLP-1 actions on peripheral tissues GLP-1 acts directly on the endocrine pancreas, heart, stomach, and brain, whereas actions on liver and muscle are direct and/or indirect Another study demonstrating the glucose- lowering effect of GLP-1 infusion in type 2 diabetes involved 7 patients and 6 age- and BMI-matched control subjects with normal glucose tolerance (NGT).1 subjects) was infused at a rate of 1.2 pmol/kg per minute from 10:00 pm until 5:00 pm the following day. For measurement of plasma glucose levels, blood was drawn hourly throughout the night and intermittently during the day Nondiabetic subjects underwent an identical protocol on one occasion, without GLP-1 infusion. On each test day, subjects ate a standardized meal for breakfast, lunch, and a mid-afternoon snack at 8:00 am, 12:00 pm, and 3:00 pm, respectively diabetes, to levels comparable to those of the control subjects. In contrast, glucose levels in the diabetic patients remained elevated during the saline infusion 21 During that first year, 14% of the patients gained at least 1 kg/[m.sup.2], 32% lost at least

1 kg/[m.sup.2], and 53% ha no weight change At baseline, the patients’ average ag was 58 years, half were men, and average BMI was 3 kg/[m.sup.2]. One-third received at least one antidiabete drug. At a median follow-up of 4.6 years, 423 patien had died overall and 197 were cardiovascular deaths. The patients who added at least 1 kg/[m.sup.2] during the first year of follow-up remained at an elevated BMI throughout the study. They also had higher levels of he moglobin [A.sub.Ic] and higher rates of treatment with insulifik and sulfonylurea sulfonylurea /sul·fo·nyl·urea/ (sul?fo-nil-u-re´ah) any of a class of compounds that exert hypoglycemic activity by stimulating the islet tissue to secrete insulin; used to control hyperglycemia in patients with type 2 diabetes mellitus  drugs compared with the patients who lost weight or didn’t change weight. All patients had similar patterns for blood pressure and cholesterol levels throughout follow-up..   Data Source: Data came from a review of 8,486 patients of 84 primary-care practices in Sweden Ultimately, more intensive insulin regimens may be required (see Figure 3.) rapid progression from a 2-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycaemia (e.g. HbA1c ≥10.0-12.0%) beginning with insulin if patient presents with severe hyperglycemia (≥300-350 mg/dl [≥16.7-19.4 mmol/l]; HbA1c ≥10.0-12.0%) with or without catabolic features (weight loss, ketosis, etc) Earlier and more aggressive intervention may improve patients’ chances of reaching treatment goal. This figure depicts a conceptual approach to treatment of patients with type 2 diabetes mellitus. Compared with conventional therapy, early and aggressive management of hyperglycemia is more likely to result in attainment of glycemic controls. HbA1c = hemoglobin A1c; OAD = oral antidiabetes agents. From Int J Clin Pract,62 with permission from Blackwell Publishing Ltd OBJECTIVE: To examine the scope and underpinnings of psychological insulin

resistance (PIR) across eight Western nations, with special attention to the potential influence of beliefs about insulin and broader patient beliefs regarding medications and diabetes METHODS: A total of 1400 subjects with insulin-naïve, type across eight nations completed an online survey. The survey assessed willingness to start insulin, beliefs about insulin and current medications, and diabetes-related emotional distress RESULTS: The majority of respondents were male (59.3%), years and mean diabetes duration was 6.1 years. A total of 17.2% reported they would be years and mean diabetes duration was 6.1 years. A total of 17.2% reported they would be Aim: To assess the effect of a 4-week adjunctive therapy of exenatide twice-daily or

sitagliptin (100 mg/day) in response to a standardised breakfast meal challenge in 48 men or women with T2D receiving insulin glargine + metformin Study design and methods: Single-centre, randomised, open- label, active comparator-controlled study with a three arm parallel group design, consisting of: screening, 4-8 week run-in period, 4- week treatment period, and follow-up Results: HbA1c significantly period, 4- week treatment period, and follow-up Results: HbA1c significantly glargine+metformin+exenatide arm. Reductions of -1.5 ± 0.7% and -1.2 ± 0.5%, respectively, were observed in the glargine+metformin+sitagliptin arm and the glargine+metformin arm Note that Ligthelm 2006 and Hirao 2007 only pushed A1C down as far as ~8 mmol/l compared to Note that Ligthelm 2006 and Hirao 2007 only pushed A1C down as far as ~8 mmol/l compared to PREFER was ~7 mmol/l OBJECTIVE— Safety and efficacy of biphasic insulin aspart 70/30 (BIAsp 70/30, prebreakfast and presupper) were compared with once-daily insulin glargine in type 2 diabetic subjects inadequately controlled on oral antidiabetic drugs (OADs) AND METHODS— This 28-week parallel-group study randomized 233 insulin-naive patients with HbA1c values 8.0% on 1,000 mg/day metformin alone or in combination with other OADs. Metformin was adjusted up to 2,550 mg/day before insulin therapy was initiated with 5–6 units BIAsp 70/30 twice daily or 10–12 units glargine at bedtime and titrated to target blood glucose (80–110 mg/dl) by algorithm-directed titration RESULTS— A total of 209 subjects completed the study. At study end, the mean HbA1c value was lower in the BIAsp 70/30 group than in the glargine group (6.91 1.17 vs 7.41 1.24%, P0.01). The HbA1c reduction was greater in the BIAsp 70/30 group than in the glargine group (2.790.11 vs.2.360.11%, respectively; P0.01), especially for subjects with baseline HbA1c 8.5% (3.13 1.63 vs. 2.60 1.50%, respectively; P 0.05). More BIAsp 70/30 –treated subjects reached target HbA1c values than glargine-treated subjects (HbA1c [McCall AL, 2002, p.207A]