Disclosures. Type 2 Diabetes. The New Epidemic: How Did We Get Here and What's to Come? Summary:

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1 Type 2. The New Epidemic: How Did We Get Here and What's to Come? Robert J. Rushakoff, MD Professor of Medicine University of California, San Francisco None Disclosures Type 2. The New Epidemic: How Did We Get Here and What's to Come? Age-Adjusted Prevalence of Obesity and Diagnosed 1994 Summary: A lot more diabetes Fewer Complications New diabetes medication may lead to even fewer complications 1

2 Age-Adjusted Prevalence of Obesity and Diagnosed 1996 Age-Adjusted Prevalence of Obesity and Diagnosed 1998 Age-Adjusted Prevalence of Obesity and Diagnosed 2000 Age-Adjusted Prevalence of Obesity and Diagnosed

3 Age-Adjusted Prevalence of Obesity and Diagnosed 2004 Age-Adjusted Prevalence of Obesity and Diagnosed 2006 Age-Adjusted Prevalence of Obesity and Diagnosed 2008 Age-Adjusted Prevalence of Obesity and Diagnosed

4 Top Ten Countries for Number of Adults with, Counties in the Top and Bottom Two Quintiles of Both and Obesity, 2007 MMWR 2009;58: Source: Data are from International Federation. IDF Atlas, 7th edition. Brussels, Belgium: International Federation, 2015; Burden of in California Conroy SM, Lee AK, Pendleton L, Bates JH. (2014). Burden of in California. Sacramento, California: Chronic Disease Control Branch, California Department of Public Health 4

5 Estimated lifetime risk of developing diabetes for individuals born in the United States in 2000 Insulin Resistance in SA: Pathogenesis At birth: increased insulin in cord blood Percent Total Non-Hispanic White Non-Hispanic Black Hispanic Men Women Diet: 5-day HFHC diet reduced insulin-stimulated glucose disposal rate in SA but not in Caucasians, indicating the rapid induction of insulin resistance in the former group. Over the past two decades total daily intake of fat has increased by 7 g in the rural areas and 6 g in the urban areas of India high intake of refined carbohydrates and high glycemic load is contributing to the increased insulin resistance and type 2 diabetes and metabolic syndrome in this population Narayan et al, JAMA, 2003 Relative HgA 1c Relative HgA 1c

6 Relative HgA 1c Relative HgA 1c Goals, Treatment and Outcomes Over 30 Years Goals, Treatment and Outcomes Over 30 Years HgA1c 9% Before DCCT, UKPDS Sulfonylurea Insulin NHANES % 8% After DCCT + Metformin NHANES % 7% After DCCT, UKPDS + TZD 1980s 1990s % Before DCCT, UKPDS Sulfonylurea Insulin NHANES % 8% After DCCT + Metformin NHANES % 7% After DCCT, UKPDS + TZD 1980s 1990s 1997 NHANES %? 6% + Incretin 2006 NHANES % What is appropriate for the patient + hypoglycemia Medication issues ACCORD

7 Crude and Age-Adjusted Incidence of End-Stage Renal Disease Related to Mellitus (ESRD-DM) per 100,000 Diabetic Population, United States, Crude and Age-Adjusted Percentage of Adults Aged 18 Years or Older with Diagnosed Reporting Visual Impairment, United States, Trends in Age- Standardized Rates of - Related Complications among U.S. Adults with and without Diagnosed, Declines in Lower Extremity Amputation in the US Medicare Population, Gregg EW et al. N Engl J Med 2014;370: Foot & Ankle International July 2013 vol. 34 no

8 Impact of Intensive Therapy for : Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS DCCT / EDIC* ACCORD ADVANCE VADT Kendall DM, Bergenstal RM. International Center 2009 UK Prospective Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024) Initial Trial Long Term Follow-up * in T1DM ACCORD: Action to Control Cardiovascular Risk in 10,251 Enrollees 60% male 40% female Mean age 62.2 Baseline HgA1c 8.1% BMI % macrovascular dx Duration DM: 10 years Majority of intensive group on 3-5 oral agents plus insulin Hypoglycemia 3 times greater in intensive group Primary and Secondary Outcomes ACCORD: Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups The Action to Control Cardiovascular Risk in Study Group. N Engl J Med 2008;358: The Action to Control Cardiovascular Risk in Study Group. N Engl J Med 2008;358:

9 Effect of a Multifactorial Intervention on Mortality in Type 2 Kaplan-Meier Estimates of the Risk of Death from Any Cause and from Cardiovascular Causes and the Number of Cardiovascular Events, According to Treatment Group Gaede P et al. N Engl J Med 2008;358: Cardiac Effects of Sulfonylurea Related Hypoglycemia Positive Side to TZDs 30 type 2 DM patients on sulfonylureas Mean HbA1c hour CGM Hypoglycemia (<63 mg/dl for >20 minutes) was detected in 9 of 30 subjects Episodes were typically nocturnal (67%) and asymptomatic (73%). Hypoglycemia associated QTc prolongation was seen in five of nine subjects with a large variation in individual response. Higher QT dynamicity, a poor prognostic factor in cardiac disease, was seen in subjects who experienced hypoglycemia compared with subjects who did not (0.193 vs for the nocturnal period; P = 0.01). This finding persisted after the hypoglycemic event. The rates of ventricular and supraventricular ectopy demonstrated a nonsignificant trend toward an increase during hypoglycemia Reduction in glucose Reduces BP Reduces albuminuria Reduces CRP Possible DM prevention Reduces NASH Reduces LFT Reduces IMT Reduces stent failure Reduces death after CHF Increases adiponectin Increases HDL Care 2017 Feb; dc

10 Pioglitazone after Ischemic Stroke or Transient Ischemic Attack multicenter, double-blind trial 3876 patients who had had a recent ischemic stroke or TIA No diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index received either pioglitazone (target dose, 45 mg daily) or placebo. N Engl J Med 2016; 374: Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003). Pioglitazone can help prevent recurrence of stroke and progression into diabetes in those patients with insulin resistance and recent cardiovascular events. Bone mineral density should be closely monitored in patients taking pioglitazone due to high rates of bone fracture, hospitalizations, and surgeries. INCRETINS Incretin Drugs Gut factors that promote insulin secretion in response to nutrients Major incretins: GLP-1, CCK, GIP GLP Agonists Exenatide Liraglutide Semaglutide Albiglutide Taspoglutide Exenatide Lar Lixsenatide Dulaglutide DPP 4 Inhibitors Vildagliptin Sitagliptin Saxagliptin Alogliptin Linagliptin Dutogliptin Metogliptin Gemigliptin Anagliptin Trelagliptin Teneligliptin Omarigliptin (1/week) 10

11 GLP Agonists Exenatide Liraglutide Semaglutide Albiglutide Taspoglutide Exenatide Lar Lixsenatide Dulaglutide Incretin Drugs DPP 4 Inhibitors Vildagliptin Sitagliptin Saxagliptin Alogliptin Linagliptin Dutogliptin Metogliptin Gemigliptin Anagliptin Trelagliptin Teneligliptin Omarigliptin (1/week) Incretins (GLP-1): CVD ELIXA: Lixisenatide (N Engl J Med 2015; 373: ) neutral effect on heart failure and other cardiovascular problems Liraglutide (N Engl J Med 2016; 375: ) rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo Renal Glucose Reabsorption in Type 2 Renal Handling of Glucose (180 L/day) (900 mg/l)=162 g/day Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule Renal glucose reabsorption is increased in type 2 diabetes Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose J Intern Med. 2007;261: Glucose SGLT2 S1 SGLT1 90% S3 10% No Glucose 11

12 Rationale for SGLT2 Inhibitors Inhibit glucose reabsorption in the renal proximal tubule Resultant glucosuria leads to a decline in plasma glucose and reversal of glucotoxicity This therapy is simple and nonspecific Even patients with refractory type 2 diabetes are likely to respond SGLT2 Inhibitors Potential Advantages Weight loss Low risk of hypoglycemia Possible BP lowering effect Effect independent of insulin Concerns Polyuria Electrolyte disturbances Bacterial UTIs Fungal genital infections Euglycemic DKA Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 SGLT2 Inhibitors Amputations Increased risk for lower-limb amputations (toes)? Mechanism Limited data 3.4 year interim analysis of CANVAS rate of amputations per every 1000 patients 100 mg/day: mg/day: 5 Placebo: 3 Primary outcome: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke Zinman B et al. N Engl J Med 2015;373:

13 SGLT2 Inhibitors Bone Loss What is the only safe way to treat DM long-term? 714 elderly patients with type 2 diabetes (mean age, 64 years; range, years). At 2 years, Decreases in total hip BMD were seen with canagliflozin 100 and 300 mg versus placebo (-1.7%, -2.1%, -0.8%; differences of -0.9% and -1.2%) No bone loss at other sites, (normal age-related bone loss, ~ %/year). Fractures tended to occur as early as 12 weeks after initiating treatment and were primarily located in the distal parts of the upper and lower extremities. Why? SGLT2 inhibitors increase concentrations of phosphate in serum, probably via increased tubular reabsorption, which has the potential to adversely affect bone. SGLT2 inhibitors increase concentrations of parathyroid hormone (PTH). Sustained increases in PTH concentration enhance bone resorption and increase the risk for bone fractures. Don t develop it in the first place. CDC Medicare Funding Funding! Begins 1/1/2018 The 12 American month intervention Association for At least Educators 16 weekly core 1 hour America s sessions Health Insurance Medicare PlansPart B Black Women s BMI >24 (Asian Health >22) Imperative HbA1c 5.7 to 6.4 or FBS 110- National 125 Association of Chronic No Disease dx of type Directors 1 type 2 DM YMCA (can of the have USA hx gestational DM) No ESRD Payment structure - - TBD Must be recognized CDC Prevention Recognition Program Care, Diabetologia. 19 April 2012 [Epub ahead of print] 13

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