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The Multifaceted Roles of Adipose Tissue—Therapeutic Targets for Diabetes and Beyond PowerPoint Presentation
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The Multifaceted Roles of Adipose Tissue—Therapeutic Targets for Diabetes and Beyond

The Multifaceted Roles of Adipose Tissue—Therapeutic Targets for Diabetes and Beyond

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The Multifaceted Roles of Adipose Tissue—Therapeutic Targets for Diabetes and Beyond

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  1. Banting Medal for Scientific AchievementAward Dr. Philipp E. Scherer The Multifaceted Roles of Adipose Tissue—Therapeutic Targets for Diabetes and Beyond • Adiponectin or a adipocyte-derived factor can be: • Anti-apoptotic (Cardiac Myocytes, Beta cells, Podocytes) • Pro-angiogenic • Anti-atherogenic • Anti-inflammatory • Pro-adipogenic • Cause improvements in hepatic insulin sensitivity • Improve wound healing

  2. Similarities and differences between ADA and AHA Lipid guidelines by Dr Robert H Eckel • Dr Robert Eckel reiterated that the ACC/AHA and ADA are in agreement for most of the recommendations • The ADA also endorse the statin recommendations of ACC/AHA Following are some of the differences • ASCVD risk calculator is not endorsed as it was not adequately tested • Screening • At time of diagnosis • Initial medical evaluation • Age 40 and periodically (1-2 years)

  3. Highlights • Treatment • Lifestyle • Decrease saturated fat, trans fat and cholesterol • Omega-3 fatty acids, viscous fiber, plant sterols/stanols • Weight loss (if indicated) • Increase physical activity • Lifestyle (intensive) and optimise glucose control for increased TG (≥ 150 mg/dl and/or HDL <40 mg/dl (men) and <50 mg/dl (women) • To consider agents beyond statins like fibrates especially for TG

  4. Lipid management in T2DM By Jennifer G. Robinson • Maximize statin therapy • Manage other risk factors • When considering adding non-statin therapy • High risk patients • Maximize statin therapy and lifestyle first • Use of nonstatins shown to reduce ASCVD events when added to statins • In completely statin intolerant patients, use of nonstatins shown to reduce ASCVD events as monotherapy (Niacin, gemfibrozil, fenofibrate, bile acid sequestrants if TG <300 mg/dl)

  5. New Concepts and treatments of Diabetic Dyslipidemia • Epidemiologic, experimental and genetic studies implicate TG-rich lipoproteins & HDL in the pathogenesis of atherosclerotic CVD • In the post statin era RCTs have failed to show a significant CVD benefit with TG lowering or HDL raising treatment • In the case of fibrates and fish oil there is evidence that individuals with hypertriglyceridemia and/or low HDL-c may benefit • Therapies targeting HDL should focus on improved function rather than alterations in static levels • More effective therapies including those that target the underlying pathophysiology of diabetic dyslipidemia are needed • RCTs need to be conducted in this patient population to adequately test that hypothesis

  6. Anti-anginal drug Ranolazine Safely Lowers HbA1c in Diabetic Patientsby Dr Robert H Eckel • Phase 3 trial to determine the safety and effectiveness of ranolazine for glycemic control • T2DM patients with a baseline HbA1c level ranging from 7% to 10% • Arm 1: Ranolazine 1000 mg twice daily (n=465) • Arm 2: Ranolazine with Glimepiride (n= 215) • Ranolazine monotherapy reduced HbA1c levels 0.56% compared with placebo by 24 weeks • Fasting plasma glucose levels were also significantly reduced in the ranolazine-treatment arm

  7. Highlights • At week 12: 50% increase in the number of patients who achieved an HbA1c <7% with ranolazine • A significant reduction in fasting and 3-hour postprandial glucagon levels • In another arm, patients were treated with glimepiride 4 mg • The addition of ranolazine reduced HbA1c levels 0.5% compared with placebo at 24 weeks with reduction in FPG • Nearly twice as many patients in the glimepiride/ranolazine arm achieved HbA1c levels <7% compared with the glimepiride only arm • When ranolazine was added to metformin, however, there was no effect on HbA1c levels • This effect was seen as metformin dose was halved in the arm in which it was used in combination with ranolazine • This was done as ranolazine decreases the renal clearance of metformin

  8. Triple therapy improves glycemia in type 1 diabetes by Dr. Nitesh D. Kuhadiya • A retrospective analysis of 10 patients on CGMS treated with insulin, liraglutide and dapagliflozin • At baseline, patients had been receiving liraglutide added to insulin therapy for 11 months • Mean HbA1c, 8%; mean age, 56 years; mean age of diabetes diagnosis, 29 years; mean BMI: 29 kg/m2 • Dapagliflozin 5 mg daily was added at baseline and increased to 10 mg at 1 week

  9. Highlights • At the end of 12 weeks of triple therapy, reductions were seen in • Mean hba1c (0.66%, p = 0.0004) • Mean glucose level (28 mg/dl, P = 0.016) • Mean body weight (2 kg, P = 0.02) • Mean BMI (1 kg/m2, P = 0.02) • Total insulin dose was 0.7 u/kg daily and was unchanged from baseline • An 11% increase in time spent in the target glycemic range of 70 mg/dL to 160 mg/dL was seen • While time spent with glycemic levels greater than 160 mg/dL decreased by 13% (P < .05 for both) • No additional hypoglycemia was observed (< 70 mg/dL)

  10. Dulaglutide Provides Greater Blood Sugar Reduction as Compared to Liraglutide • Phase 3, randomized, parallel-arm, placebo-controlled, 52-week study • Comparison of safety and efficacy of once-weekly dulaglutide 0.75 mg to once-daily liraglutide 0.9 mg • Conducted in 487 Japanese T2DM patients with average baseline A1C of 8.1%, • Primary objective: To evaluate whether dulaglutide 0.75 mg was superior to placebo in reducing A1C from baseline at 26 weeks • A comparison of dulaglutide and liraglutide at 26 and 52 weeks was also done • Patients initially assigned to placebo were switched to dulaglutide 0.75 mg at 26 weeks for the remainder of the trial

  11. Highlights • At 52 weeks, dulaglutide 0.75 mg demonstrated statistically greater A1C reductions compared to liraglutide 0.9 mg (-1.39 percent vs. -1.19 percent) • Dulaglutide 0.75 mg provided statistically greater reductions in the average self-monitored blood glucose levels compared to liraglutide 0.9 mg (-53.1 mg/dL vs. -46.8 mg/dL) • Dulaglutide 0.75 mg significantly lowered average post-meal blood glucose levels from baseline compared to liraglutide 0.9 mg (-63.7 mg/dL vs. -55.4 mg/dL) • Mean body weight did not change in either treatment group and both agemts were well-tolerated in the study

  12. Canagliflozin + Metformin XR Superior to Either monotherapy • Phase 3, 26-week study, 1,186 T2DM patients inadequately controlled with diet and exercise randomized to • Canagliflozin 100 mg in combination with metformin XR (median 2,000mg/day) • Canagliflozin 300 mg in combination with metformin XR • Canagliflozin 100 mg • Canagliflozin 300 mg • Metformin XR

  13. Highlights • Both Cana + Met group: statistically superior HbA1C reductions (-1.77 and -1.78, respectively) vs. patients receiving either canagliflozin 100mg (-1.30), 300mg (-1.37) , or metformin XR (-1.42) alone • Patients taking canagliflozin in combination with metformin XR also had a significant reduction in weight compared to patients treated with metformin XR alone

  14. Real-World Data on Canagliflozin in Managed Care Setting • To describe the characteristics, treatment utilization, and outcomes of patients treated with canagliflozin in the real world within the first 6 months of it being commercially available • Retrospective cohort study from Optum Research Database (ORD) involving 3234 patients • Cana 100 mg (N=2141), Cana300 mg (N=1093) • Patients treated with canagliflozin when first available in the US typically had poorly controlled HbA1c levels at baseline and had received multiple prior antihyperglycemic agents • Following the first canagliflozin claim, they had an improvement in HbA1c levels and used fewer antihyperglycemic agents

  15. Highlights

  16. Impact of Canagliflozin Added on to Insulin and Metformin in Type 2 Diabetes: A Substudy of the CANVAS Trial • Substudy of CANVAS • 432 patients with T2DM at high risk of CVD with a mean age of 61 years & mean A1C of 8.2% • All patients were taking an insulin dose of at least 30 IU/day and a metformin dose of at least 2000 mg/day • The study group’s mean FPG was 166 mg/dL, the mean BMI was 34.9 kg/m2, and the mean insulin dose was 93 IU per day

  17. Highlights • Compared with the 146 patients taking placebo, A1C went down significantly for patients at both the 100 mg and 300 mg doses • All 3 groups started with a mean baseline A1C of 8.2% • A1C level for placebo group went up by 0.03% • A1C for the group taking 100 mg went down by 0.64% • A1C for group taking 300 mg went down 0.79% • Both doses of canagliflozin produced better results for FPG, body weight, and SBP than metformin and insulin alone

  18. Intranasal ‘Puff’ of Glucagon May Safely, Effectively Treat Hypoglycemia by Dr Jennifer Lynn Sherr • 45 pediatric T1DM patients received either IM or intranasal (IN) glucagon at 7 centres • The two youngest cohorts (4-<8; 8-<12 yrs) were randomized to one IM or two IN administrations • Oldest group (n=12, 12-<17 yrs): Received either 1 mg of IM glucagon or 3 mg intranasal glucagon in randomized crossover manner • Glucagon was administered 5 minutes after their blood glucose was lowered to <80 mg/dL

  19. Highlights • A sharp rise in glucose was observed in all age groups following either IM or IN dosing • Nausea (with or without vomiting) occurred with 67% of IM sessions v.s 42% of IN sessions

  20. Novel Combination therapy IDegLira for T2DM by Prof. John Buse • 26-week, phase III study compared the efficacy and safety of IDegLira vs. insulin glargine (IG) in T2DM uncontrolled on IG (20-50U) • Adults (n=557, A1c 7-10%) were randomized to either once-daily IDegLira or continued IG uptitration, both + metformin • Initial doses were 16 dose steps (16U IDeg + 0.6 mg Lira) for IDegLira (maximum 50 dose steps) and pre-trial dose for IG (mean 32U; no maximum). • Fasting self-measured blood glucose titration target was 71-90 mg/dL for both arms

  21. Highlights • Mean A1c decreased from 8.4 to 6.6% (IDegLira) and from 8.2 to 7.1% (IG) (p<0.001) • Mean fasting plasma glucose decreased similarly in both arms from 160 to 110 mg/dL • Weight decreased from 88.3 to 86.9kg (IDegLira) and increased from 87.3 to 89.1kg (IG) (p<0.001) • More subjects achieved the composite endpoints with IDegLira vs. IG • IDegLira was superior to IG in A1c reduction, risk of hypoglycemia and weight change • IDegLira offers clinical advantages over IG in intensifying therapy while minimising insulin dose requirements, in subjects uncontrolled on IG

  22. Bihormonal Bionic Pancreas Effective in Patients across various age & BMI ranges • Results of a comparative trial in 19 children (aged 6–11 years) with type 1 diabetes attending a diabetes summer camp were consolidated with past data • Glucose regulation by automated bihormonal (insulin and glucagon) bionic pancreas was compared with insulin pump therapy under medical supervision for 5 days each • The children chose their own meals and participated in all camp activities • Both groups of preadolescents were monitored remotely for severe hypoglycemia

  23. Highlights • After 24 hours of autonomous adaptation, the bionic pancreas • Produced a lower mean continuous glucose level compared with the insulin pump (138 ± 11 vs 168 ± 30 mg/dL; P < .001) • Less time spent <60 mg/dL (1.2% vs 2.8%; P < .001) • More time between 70 to 180 mg/dL (80.6% vs 57.6%; P < .001) • Less time spent >180 mg/dL (16.5% vs 36.3%; P < .001) • Hypoglycemia requiring oral carbohydrates was observed less frequently in children with the bionic pancreas compared with children with the insulin pump (once per 1.1 vs 1.8 days; P = .04)

  24. Using technology for better outcomes • Need for standardisation of CGM reports as there are different CGM devices producing different reports • A standard report for CGM based on Expert Panel Input was suggested i.e. Ambulatory Glucose Profile (AGP) • Based on the research at the International Diabetes Centre (IDC) AGP has been developed as a novel way to address data interpretation • Glucose data, collected over several days or weeks, are analysed as if they occurred within a single 24 hour period and plotted in a series of bands around the median • AGP is designed to be quick to generate and easy to interpret

  25. Highlights Conclusion • Data drives improvement • Use of SMBG and CGM data is associated with improved HbA1c values and positive behavior change • Presentation of data impacts use • Consistent definitions and visual display • A standard glucose report improves ease of use, interpretation, clinical and behavioral decision-making • Ambulatory glucose profile (AGP) is a standard glucose report

  26. A game as a tool for continuing medical education • 135 primary-care physicians (including 52 residents) were randomized in southern Brazil to receive education about insulin therapy from • The game (70 physicians) or • From traditional instruction (65 physicians) • The physicians replied to a questionnaire to assess their baseline knowledge, skills, attitudes, and satisfaction • Those who were randomized to the "game group" played the InsuOnLine game, which included patient-case scenarios, on their computers, at their own speed

  27. Highlights • The physicians in the control group attended 3 to 4 hours of traditional lectures with clinical-case discussions • The content of the game and the lectures was similar and based on guideline recommendations for insulin therapy • The primary outcome was insulin-prescribing skills and knowledge, as measured by a questionnaire • Secondary outcomes were beliefs about insulin and satisfaction with the activities

  28. Highlights • The mean insulin-therapy-knowledge score (% of right answers) improved from 52% at baseline to 85% after the traditional education (P < .001), and to 92% after the game-based education (P < .001) • The mean improved score was higher in the group that received game-based education than in the group that received traditional education • Almost all the participants (96%) found that the game was fun • Most participants considered the game to be more effective than attending a lecture to learn about insulin therapy

  29. Low Vitamin D Levels Common in Painful Diabetic Neuropathy • 45 T2DM patients — 17 with painful neuropathy, 14 with painless neuropathy, and 14 with no neuropathy — along with 14 healthy volunteers • All had vitamin D levels measured between May and September and answered questionnaires to assess sunlight exposure and neuropathy symptoms • They also underwent detailed clinical, neurophysiological, and lower-limb skin intra-epidermal nerve-fiber density (IENFD) assessments • They were divided into three groups based on the Neuropathy Impairment Score of the Lower Limb (NIS-LL) and the Douleur Neuropathique 4 (DN4)

  30. Highlights • After adjustment for age, BMI, and sunlight exposure, vitamin D levels were significantly lower in the painful-neuropathy group, at 34.34 nmol/L vs • 53.22 for painless neuropathy • 50.00 for no neuropathy • 64.95 for the healthy volunteers (P = .01) • Main group differences were significant between painful and painless neuropathy (P = .02) and painful neuropathy vs healthy controls (P = .002) • There was a significant positive correlation between vitamin D levels and sunlight exposure (P = .003)

  31. Diabetics Develop HF Sooner and Die Younger After HF: Fremantle Diabetes Study by Dr Timothy Davis • Community-based, observational study involving 1296 T2DM patients and followed for an average of 12 years • Mean age: 64 years, and duration of diabetes: 4 years • 8.6% of subjects had a prior hospitalization for heart failure • Of the 1185 individuals without HF at baseline, 31.8% were hospitalized for HF or died from HF during the follow-up period • T2DM patients were > 2 times more likely to develop HF (HR: 2.36) during the 12-year follow-up

  32. Highlights In conclusion • Diabetic patients have their first heart-failure event 4 to 5 years before individuals without diabetes • Diabetic patients die 4 years earlier after their heart-failure event • 30% of type 2 diabetics went on to develop or die from heart failure

  33. Sulfonylureas does not increase the risk of all-cause or cardiovascular mortality • A meta-analysis • 47 randomized, controlled clinical trials (>52 weeks duration) involving 37,650 patients in this latest meta-analysis • Overall, the use of a SU as first-line or second-line therapy was not associated with an increased risk of total mortality (odds ratio [OR] 1.12; 95% CI 0.96–1.30) or cardiovascular mortality (OR 1.12; 95% CI 0.87–1.52) • Similarly, there was no significant association with sulfonylurea use and the risk of MI or stroke

  34. TECOS: No CVD Risks or Heart Failure With Sitagliptin in High-Risk Diabetic Patients by Dr Eric Peterson • TECOS: Trial Evaluating Cardiovascular Outcomes with Sitagliptin • 14,671 patients with T2DM and established CVD randomized to sitagliptin or placebo on top of their existing therapy • Baseline HbA1c: ranging from 6.5% to 8.0% • Mean duration of diabetes: 11.6 years • Primary end point: cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina • Secondary end point: first confirmed event of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke

  35. Highlights

  36. Highlights: Kaplan–Meier Curves for Primary and Secondary Outcomes Among patients with T2DM and established CVD, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

  37. “Real World” effect of weight loss in T2DM: Why WAIT study • 129 obese patients with type 2 diabetes who took part in the Why WAIT (Weight Achievement and Intensive Treatment) • Participants were provided with • Structured menus of 1500 calories/day for women and 1800 calories/per day for men • A progressive, gradual, balanced, individualized exercise plan • Participants were switched to antihyperglycemic medications that cause weight loss or do not affect weight • At the end of the 12-week program: Weight loss of 9.7% • Average HbA1c dropped from 7.5% to 6.5%, & medication use fell by 50% to 60%

  38. After 1 year, the patients were divided into 2 groups, based on their weight loss: • Group A (n=61): Patients who not maintained a weight loss of at least 7% • Group B (n=68): Patients who had maintained this level of weight loss • After 5 years in Group A: • Patients maintained a weight loss of 3.5% • Mean HbA1c levels decreased to 6.7% at 12 weeks and then increased to 7.7% at 1 year and 8.0% at 5 years • After 5 years in Group B: • Patients had lost 9.0% of their initial weight • Mean HbA1c levels decreased to 6.49% at 12 weeks, and increased, but to a lesser extent, to 6.8% at 1 year and 7.3% at 5 years • increased to 7.7% at 1 year and 8.0% at 5 years In conclusion, weight loss when maintained results in durable A1c lowering in T2DM at 5 years

  39. Thank You