ADVANCE Endpoints. Primary outcome. Secondary outcomes

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2 ADVANCE Trial-NEJM 11,140 type 2 patients with h/o microvascular or macrovascular disease or 1 vascular disease risk factor Control A1c to 6.5% vs standard tx Intensive arm received gliclazide XL 30 to 120mg daily then addition of metformin, TZD, acarbose, basal insulin, prandial insulin Median 5 year followup period

3 ADVANCE Endpoints Primary outcome Composite # of macrovascular events (CV death, nonfatal MI or nonfatal stroke) Composite # of microvascular events (worsening nephropathy, retinopathy) Secondary outcomes Myriad

4 Combined events 18.1% in intensive, 20% in standard, HR 0.9 CI , 0.98, p=0.01

5 Major Major microvascular events: HR 0.86 ( CI, p=0.01) I vs S

6 Major macrovascular events: HR 0.94 ( CI, p=0.32) I vs S

7 Nephropathy results Reduction in new or worsening nephropathy (HR 0.79, CI, p=0.006) I vs S Mostly due to reduction in development of macroalbuminuria (HR 0.70, CI, p<0.001 I vs S) Reduction in new-onset microalbuminuria (HR=0.91, CI, p=0.02)

8 ADVANCE results More hospitalizations in intensive group (44.9% vs 42.8%) with some excess due to hypoglycemia Severe Hypoglcyemia rate 2.7% intensive vs 1.5% standard HR 1.86, CI, p < I vs S

9 ADVANCE Conclusions An intensive glucose control strategy involving gliclazide lowered the A1c average to 6.5% in a broad range of type 2 patients Reduced the incidence of combined primary outcomes micro/macro events Main contributor to 10% RRR for primary outcome related to 21% RRR of new or worsening nephropathy No evidence of change to macrovasc events Intensive treatment increased hypos and increased rate of hospitalization

10 ACCORD Trial-NEJM Type 2 patients with starting A1c of 7.5%, with CV disease, anatomical evidence of significant atherosclerosis, albuminuria,, or at least 2 CV risk factors 10,251 patients, median age 62 years (40-79 if CV disease, yo if not), 8.1% A1c Primary outcome: Composite of Nonfatal MI/stroke, and CV-related death Stopped 17 months early, on 2/6/08

11 ACCORD results Intensive group (goal A1c sub-6%) maintained an avg A1c of 6.4%, with approx 1.4% reduction over 4 months Standard group (goal A1c of %) 7.9%) maintained an avg A1c of 7.5%, with approx 0.6% reduction over 4 months

12 Intensive=5%, standard=4%, HR 1.22( ) p=0.04 CV death: Intensive=2.6%, standard=1.8%, HR 1.35 ( ) p=0.02

13 Composite data: Intensive=6.9%, standard=7.2%, HR 0.9 ( ), p=0.16 Nonfatal Myocardial infarction: Intensive=3.6%, standard=4.6%, HR 0.76 ( ) p=0.004

14 ACCORD Results Hypoglycemia requiring med asst Intensive 10.5% vs Standard 3.5%, p<0.001 Weight gain > 10 kg since baseline Intensive 27.8% vs Standard 14.1%, p<0.001

15 ACCORD Conclusions Targeting A1c < 6% increased the rate of death from any cause after a mean of 3.5 years as compared with targeting 7-7.9% 7 7.9% in patients with a median 8.1% A1c and either previous CV events or multiple CV risk factors. Identified a previously unrecognized risk of intensive glucose lowering in high-risk patients with type 2 diabetes and high A1c, due either to the approach used for rapidly lowering A1cs or to the levels that were achieved.

16 ACCORD Conclusions Preliminary nonprespecified exploratory analyses of severe hypoglycemic episodes, differences in drug use (including rosi), weight change, and other factors did not identify an explanation of the mortality findings Proposed reasons include the magnitude or speed of A1c reduction, changes in drug regimens and in rate of hypoglycemia, in adverse effects due to an undetected interaction of various drug classes used at high doses

17 ADVANCE vs ACCORD Lower A1c goal in ACCORD Faster reduction to goal in ACCORD Higher degree of statin/asa use in ACCORD Much higher use of rosiglitazone in ACCORD 92% intensive, 58% standard ACCORD 17% intensive, 11% standard ADVANCE 77% intensive also on insulin in ACCORD More weight gain and hypoglycemia in ACCORD

18 NEJM Editorial opinions Most appropriate goal A1c = 7% Lower individual goals if primary prevention of macrovascular and/or reduction in microvascular events desired Higher individual goal in high risk patients who are prone to hypoglycemia Not satisfied that hypoglycemia, predominant use of rosi, and weight gain not responsible for changes Some of the ACCORD study population (no existing CVD or baseline A1c < 8%) did better with intensive treatment and paradoxical decrease in nonfatal MI Increased need to get all patients onto appropriate statin,, HTN, ASA therapy

19 THE VA Diabetes Trial (VADT) Study of 1791 US Veterans, average age 60 years old and average A1c =9.5% Randomized to intensive tx (A1c<7%) or standard tx (A1c 8-9%) 8 to study differences in CVD events such as stroke, MI, CHF, bypass, CV death Achieved A1c intensive 6.9%, vs standard 8.4% but saw no benefit, severe hypo pts at highest risk for CV death Baseline level of coronary calcium strongest determinant of future CVD, and intensive glycemic tx appeared more favorable in those with less disease Mirrors ADVANCE/ACCORD, but stressed importance to ID patients with less advanced vascular disease which may help determine who may benefit from more aggressive glucose lowering

20 Heart2D trial Examined effects of postprandial hyperglycemia on type 2 diabetes patients after acute MI Patients (n = 557) in prandial group received insulin lispro before each meal. Patients (n = 558) in the basal group received NPH insulin BID or insulin glargine Qday Compared prandial with basal insulin strategy by assessing for any subsequent cardiovascular event, including CV death, nonfatal stroke or MI, and hospitalization for coronary syndromes or bypass Mean blood glucose levels showed significantly smaller 2-hour postprandial excursions in the prandial than in the basal group ( (P <.0001). However, the rate of subsequent CV events during the study was similar in both treatment groups: 181 prandial,, 174 basal (hazard ratio [HR],.98)

21 DCCT analysis of A1c + GV Analyzed data from DCCT to assess the effect of HbA1c variability on the risk of retinopathy and nephropathy. The mean HbA1c and the variability of HbA1c following stabilization of glycemia were compared with the risk of retinopathy and nephropathy Evaluation showed that variability in HbA1c added to the risk of development or progression in both retinopathy (HR=1.54 for every 1% increase in HbA1c SD, 95% CI , p=0.02) and nephropathy (HR=1.42, 95% CI , p=0.05) Variability in HbA1c adds to the mean value in predicting microvascular complications in type 1 diabetes; fluctuations in glycemia as measured by A1c seem to be contributory to the development of retinopathy and nephropathy in type 1 diabetes.

22 CVD in Pediatrics Children who survive cancer are a high-risk group for CVD Steinberger/NIH study looked at 350 such children vs 350 healthy sibling controls Related to growth hormone deficiency associated with insulin resistance and adiposity in childhood cancer survivors Lack of followup post cancer, though at risk for developing early heart disease and diabetes Late cancer effect increasing CV risk includes abnormal lipids, HTN, obesity, and insulin resistance

23 Joslin Weight Loss Study 12-week weight-loss program for T2DM, 85 patients with type 2 diabetes, mean age 54 years. Average weight was 235 pounds, mean BMI was 38.4, mean HbA1c was 7.5%, and mean waist circumference was 46.7 inches. After 12 weeks, resulted in an average weight loss of 24.6 pound, a waist circumference reduction of 3.6 inches, & mean drop of 0.9% in A1C to 6.6%. After 1 year of follow-up, weight remained down by >18 pounds -- a long-term loss of 7.6%. However, A1C levels increased to approx 7.4%. The mainstays of the "Why WAIT?" program are a low carb diet & tailored exercise. Includes significant calorie reduction and reduce carbs to 40% and protein to 30-40% of calories. Led to a reduction in need for medications with a 65% reduction in medical costs, or about $560 per year per patient

24 Insulin Glargine and Retinopathy The safety of glargine was demonstrated in a 5-year 5 post-marketing study, in which there was no evidence of an increased risk of retinopathy with long-term glargine Involved 1,017 patients with type 2 diabetes randomized to glargine QD or NPH BID After 5 years, retinopathy progression was observed in 14.2% of glargine patients and in 15.7% in NPH, a non-significant difference Trend towards less weight gain (3.0 kg) with glargine than with insulin therapy (4.3 kg). In addition, significantly fewer episodes of hypoglycemia occurred in glargine-treated patients.

25 Not ready for Prime time new tx SGLT-2 2 inhibitors Partial inhibition of glucose reabsorption in proximal renal tubules, producing glucosuria: dapagliflozin Glucokinase Activators Augment insulin secretion & hepatic glucose extraction by activating GK, a glucose sensor in the beta-cell and liver: RO Glucagon Receptor Antagonist Reduce hepatic glucose production Sirtuins Proteins associated with increased lifespan/metab efficiency. Promoting these might help to mimic effects of caloric restriction and exercise

26 More new stuff 11-beta beta-hydroxy steroid dehydrogenase inhibitors Activation of this enzyme in fat cells leads to conversion of cortisone to cortisol,, implicated in metabolic syndrome, use in 30 patients improved insulin sensitivity, improved lipids ARISE trial/succinobucol Anti-inflammatory/Anti inflammatory/anti-oxidative oxidative therapy 6144 pts with confirmed ACS had reduced rate of CV death, cardiac arrest, MI and stroke, higher rates of A.fib and diarrhea

27 New options in current classes DPP IV inhibitors Alogliptin, saxagliptin GLP-1s Liraglutide,, Byetta once weekly

28 Exhibit hall features Medtronic CGM/dashboard integration A remote glucose sensor/baby monitor from Medtronic in concept phase Omnipod + CGM Glycomark: : $10 test, similar to A1c but specific for postprandial BG evaluation PreDx: : blood test that utilizes biomarkers to predict 5 year risk of getting T2DM

29 Educator specific info Conversation Maps survey 65% of educators report improved patient self-management with its use 80% report that it makes group facilitation more interactive and engaging 60% report increase in patient interest in DM education and willingness to learn 40% believe the most effective learning tool 90% would recommend to peers

30 A1c=eAG Estimated average glucose to be reported in place of A1c, determined by 507 patients and 2700 BGs each eag (mg/dl) = 28.7 x A1C : A1C of 6% equals eag of 126 mg/dl A1C of 6.5% equals eag of 140 A1C of 7% equals eag of 154 A1C of 7.5% equals eag of 169 A1C of 8% equals eag of 183 A1C of 8.5% equals eag of 197 A1C of 9% equals eag of 212 A1C of 9.5% equals eag of 226 A1C of 10% equals eag of 240

31 Endo shortage-abstract abstract Study done to investigate why medical students are not choosing to specialize in endocrinology. Survey to medical school students from 47 US medical schools, resulting in 524 participants. Only seven students (1.3%) expressed an interest in endocrinology and only 3 of those were interested in diabetes. Students cited the challenges of inadequate compensation (34.9%), lack of procedures (37.9%), and modifying patient behavior (46%) as central factors in deterring them from specializing in diabetes. In contrast, 48.8% cited the social importance of diabetes care and the pandemic status (33.4%) as reasons to enter the field, indicating awareness of the societal need. These data suggest that due to lack of financial incentives, few US students plan to enter the field of endocrinology, and the burden of care for patients with diabetes will fall even more to the primary care providers than it is today.

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33 New insulin formulations Transdermal insulin Used as a basal insulin replacement in 8 pts, with appropriate change in serum insulin level Intranasal insulin Reduction in post meal BGs seen in 5 patients, less hypos than rapid analog Oral insulin Hepatic-directed vesicle insulin (HDVI) significantly reduced postprandial BG in 6 patients

34 Despite valiant efforts of the research group the insulin suppository still has one major drawback