The Effects of Hyperglycemia and Hypoglycemia on the Vasculature in Type 2 Diabetes Stephen N. Davis, MBBS, FRCP, MACP Professor and Chairman, Department of Medicine University of Maryland School of Medicine

Overview Prevalence of Diabetes, Obesity, and Cardiovascular Disease in the US Effects of Hyperglycemia and Hypoglycemia New Treatment Options for Type 2 Diabetes

1994 Methodology The percent of U.S. adults who are obese or who have diagnosed diabetes was determined by U.S.ing data from the Behavioral Risk Factor Surveillance System (BRFSS, available at http://www.cdc.gov/brfss). An ongoing, yearly, state-based telephone survey of the non-institutionalized adult population in each state, the BRFSS provides state-specific information on behavioral risk factors for disease and on preventive health practices. Respondents who reported that a physician told them they had diabetes (other than during pregnancy) were considered to have diagnosed diabetes. Self reported weight and height were U.S.ed to calculate body mass index (BMI): weight in kilograms divided by the square of height in meters. A BMI greater than or equal to 30 was considered to be obese. Rates were age-Adjusted U.S.ing the 2000 U.S. Standard Population.

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Prevalence of Obesity and Diabetes among US adults 2013 Obesity Diabetes Centers for Disease control and Prevention, 2014

Centers for Disease control and Prevention, 2014

Centers for Disease control and Prevention, 2014

1 out of 3 people will develop type 2 diabetes in their lifetime Centers for Disease control and Prevention, 2014

Centers for Disease control and Prevention, 2014

Sedentary Lifestyle & Slide Index L: DISCUSSION POINTS: McCalories!

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Natural History of Type 2 Diabetes Postprandial glucose 350 300 250 Glucose (mg/dL) Fasting glucose 200 150 100 50 Insulin resistance Relative b-cell Function Clinical Diagnosis of Diabetes Insulin level Pre-diabetes (IFG, IGT) Metabolic Syndrome -10 -5 Onset of DM 5 10 15 20 25 30 Years of Diabetes © 2002 International Diabetes Center. All rights reserved.

Pathophysiology of Type 2 Diabetes Pancreas Gut = Insulin Deficiency Impaired Secretion Carbohydrate Metabolism Hyperglycemia Muscle & Adipose Tissue = Insulin Resistance  Glucose Uptake  Hepatic Glucose Production Liver

Diabetes and Chronic Inflammation Obesity Chronic inflammation Diabetes Vascular diseases

Complications of Diabetes Over time, poorly managed Stroke Over time, poorly managed Diabetes can damage the cell’s ability to hold together, causing serious problems Heart Disease Neuropathy & Peripheral Vascular Disease Sores & Amputations As well as complications of pregnancy, dental disease, sexual dysfunction, depression, biochemical imbalances, inability to walk, susceptibility to disease

Tight glucose control can prevent or slow complications to diabetes (Keeping your glucose as close to normal as possible) Diabetic eye disease started in only one-quarter as many people. 75% Kidney disease started in only half as many people. 50% Nerve disease started in only one-third as many people. Neuropathy 66% Far fewer people who already had early forms of these three complications got worse.

Implications of tight diabetes control Achieving as close to normal values of 70 and 130 mg/dl before meals, and less than 180 mg/dl two hours after starting a meal, with a glycated hemoglobin level less than 7 percent Must pay more attention to diet and exercise and check blood sugar levels more often May feel better and have more energy Be able to increase and vary activities Costs of diabetes care could increase Possible weight gain Risks of hypoglycemia may increase

------------------------------ Ultrasound technology for measuring flow mediated dilation (FMD) of the brachial artery ------------------------------ FMD is a non-invasive measurement of endothelial function. -----------------------------

First artificial pancreas

The Artificial Pancreas – Refined Insulin Replacement/ Adjustment Image credit: http://www.kurzweilai.net/artificial-pancreas-the-way-of-the-future-for-treating-type-1-diabetes#!prettyPhoto Image credit: http://www.fda.gov/ucm/groups/fdagov-public/documents/image/ucm281573.gif

Management of Hypoglycemia Prevention Treatment: 15 gm oral carbohydrate, measure glucose 15 min later If more severe, 25 gm glucose iv, or 1 mg glucagon, sc or im Short-term increase of glycemic target may be useful to interrupt the vicious cycle Slide 40 Efforts should be made to prevent hypoglycemia by rational treatment choice and awareness of factors which increase risk. Mild-to-moderate hypoglycemia should be treated by ingesting 15 gm or carbohydrate and measuring blood glucose levels 15 minutes later. In patients treated with alpha glucosidase inhibitors, this must be taken in the form of glucose. Severe hypoglycemia, requiring assistance from an outside party should be treated with intravenous glucose or glucagon (sc or im) and followed by glucose ingestion to replenish liver glycogen. If a patient experiences repeated hypoglycemic episodes a short-term increase of glycemic targets may be useful to interrupt the vicious cycle.

Novel Treatment Options Reduce Blood Sugar without Causing Hypoglycemia

Exenatide (Byetta®, Bydureon®), GLP-1 Agonists The Benefits: Improvement in the HbA1c Reduction in FBG No significant hypoglycemia Weight loss Reduction in biomarkers of cardiovascular risk Exenatide (Byetta®, Bydureon®), albiglutide (Tanzeum®), dulaglutide (Trulicity®), liraglutide (Victoza®)

Dipeptidyl peptidase-4 inhibitors The Benefits: Oral agent Improvement in the HbA1c Reduction in FBG No significant hypoglycemia Reduction in biomarkers of cardiovascular risk Sitagliptin (Januvia®), saxagliptin (Onglyza®), linagliptin (Tradjenta®), alogliptin (Nesina®) Medscape Diabetes. 2006;8(1) © 2006  Medscape

Sodium-glucose Cotransporter-2 Inhibitors The Benefits: Improvement in the HbA1c Reduction in FBG No hypoglycemia Reduction in BP Weight loss Reductions in cardiovascular/all-cause mortality Canagliflozin (Invokana®), empagliflozin (Jardiance®), dapagliflozin (Farxiga®) U.S. Food and Drug Administration

Empagliflozin/linagliptin (Glyxambi®) SGLT-2 & DPP-4 inhibitor 1. ↑ insulin production 2. ↓ sugar production 3. Removes some sugar

Newly approved long-acting insulin analogs for treatment of diabetes Insulin Glargine U300 (Toujeo) Insulin degludec U-200 (Tresiba) flex touch insulin pen Both as effective as Lantus glargine but significantly less night-time low blood sugars

Concentrated long-acting basal insulins Humulin-R U500 Insulin Degludec U200 Insulin glargine U300 Duration of Action 6-10 hours 42 hours >30 hours Half-life 4 hours 25 hours 18-19 hours Steady state -- 2-3 days 5 days Weight gain (T1DM) +4.9kg +0.2kg -0.6kg (T2DM) -0.11kg +0.2kg HbA1c from baseline -1.6% (T2DM) -0.4% (T1DM) -0.4% (T1DM) -1.3% (T2DM) -0.8% (T2DM)

A long-acting human insulin analogue administered subcutaneously Similar efficacy and safety as glargine

Insulin degludec (Tresiba®) vs. insulin glargine Lower rate of hypoglycemia Lower rate of nocturnal hypoglycemia Similar efficacy

Toujeo® Compared to Glargine Lower rate of severe hypoglycemia

Insulin Patch A thin silicon patch 100+ microneedles – each the size of an eyelash Enzymes on the microneedles sense blood glucose levels. When glucose levels increase, the enzymes trigger a rapid release of insulin into the tissue. In the future – as with the artificial pancreas - glucagon will also be incorporated into this device.

Summary Type 2 diabetes and obesity are increasing yearly. Hyperglycemia and hypoglycemia both damage blood vessels. New treatments for type 2 diabetes reduce the risk of hyperglycemia and hypoglycemia