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Treatment of DM T-2: Then and Now A 30 Year Overview.

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Presentation on theme: "Treatment of DM T-2: Then and Now A 30 Year Overview."— Presentation transcript:

1 Treatment of DM T-2: Then and Now A 30 Year Overview

2 Historical Perspective O Before Banting and Best O -Egyptians treated diabetes "with a combination of ground earth, water, bones, wheat, and lead" (Yuwiler 15) -In the nineteenth century, physicians tried other common healing practices, such as bleeding, cupping or blistering patients. -In the nineteenth and twentieth centuries, "opium seemed to reduce the despair of dying [diabetic] patients" (Yuwiler 16) O Before 1922 O Diabetic children rarely lived a year after diagnosis O Five percent of adults died within two years, and less than 20 percent lived more than ten (Berger 57) O Untreated diabetics faced blindness, loss of limbs, kidney failure, stroke, heart attack and death (Yuwiler 12) D. Kotun, PA-C, Ed.D. for WC Regional CME Day2

3 Historical Perspective O Insulin comes out O Oct. 1920, Toronto, Canada; Dr. Frederick Banting, an unknown surgeon with a bachelor's degree in medicine, thought that the pancreatic digestive juices could be harmful to the secretion produced by the islets of Langerhans O Cells producing antidiabetic secretions could be extracted from the pancreas without being harmed O 1921, Banting took his idea to Professor John Macleod at the Univ. of Toronto, a leading figure in the study of diabetes in Canada. Macleod didn't think much of Banting's theories, but Banting managed to convince him that his idea was worth trying. Macleod gave Banting a laboratory, some equipment and ten dogs O Banting’s assistant, a medical student by the name of Charles Best O Experiments started in summer of 1921 O In late 1921, biochemist Bertram Collip, joined the team with the task of trying to purify the insulin enough for testing on animals and humans O In January 1922 in Toronto, Canada, a 14-year-old boy, Leonard Thompson, was chosen as the first person with diabetes to receive insulin. O 1923 Nobel Prize went to Banting and Macleod O Banting was upset as he felt that Best should be the one to share the prize D. Kotun, PA-C, Ed.D. for WC Regional CME Day3

4 Historical Perspective O First interventions O Banting, Macleod, and the rest of the team patented insulin extract giving away all their rights to the University of Toronto, which used the income to fund new research O Very soon after the discovery of insulin, the medical firm Eli Lilly started large-scale production of the extract O As soon as 1923, the firm was producing enough insulin to supply the entire North American continent. D. Kotun, PA-C, Ed.D. for WC Regional CME Day4

5 Historical Perspective O Oral medications O First came Sulfonylureas O glyburide (Diabeta®), glipizide (Glucotrol®), and glimepiride (Amaryl®) O Biguanides O Metformin (Glucophage®; Glucophage® XR) is the only biguanide FDA-approved for use in the United States O Thiazolidinediones O Rosiglitazone (Avandia ® ) and pioglitazone (Actos ® ) are the two thiazolidinediones FDA-approved for use in the United States. Troglitazone (Rezulin ® ) was removed from the market due to hepatotoxicity D. Kotun, PA-C, Ed.D. for WC Regional CME Day5

6 Current criteria for the diagnosis of diabetes O A1C ≥6.5% O FPG ≥126 mg/dL (7.0 mmol/L) O No caloric intake for at least 8 h. Or O Two-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT) O Glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. Or O In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L). O In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing. D. Kotun, PA-C, Ed.D. for WC Regional CME Day6

7 After Sulfonylureas O General improvements O The switch from increasing insulin to other mechanisms O Modifying insulin sensitivity O Delaying absorption of mealtime glucose O Inhibiting gluconeogenisis O Affecting the multiple biochemical pathways O After the millennium, several new medications came out D. Kotun, PA-C, Ed.D. for WC Regional CME Day7

8 Sulfonylureas O Sulfonylureas are insulin secretagogues (pancreas spankers) – increase insulin output O Orinase (tolbutamide); Tolinase (tolazamide); Diabinese (chlorpropamide) O First generation – drawback was liver damage and replacement by 2 nd generation agents O Glyburide (Micronase, DiaBeta, Glynase), Glipizide (Glucotrol, Glucotrol XL) O Second-generation agents; potent with fewer drug interactions than first-generation agents. Was used in the UKPDS. O May cause more physiologic insulin release with less risk for hypoglycemia and weight gain than other sulfonylureas O Glimepiride (Amaryl) O Third-generation sulfonylurea - more physiologic insulin release than some of the older agents. O Due to cardiac potassium channel effects, greater potential safety in patients with ischemic heart disease. O Only sulfonylurea approved for concomitant use with metformin or insulin D. Kotun, PA-C, Ed.D. for WC Regional CME Day8

9 Biguanides O Biguanides – First big step since insulin and secretagogs O reduce hepatic glucose production and increase glucose utilization in the periphery O Phenformin was taken off the market in the U.S. 1970s because risk of lactic acidosis O Metformin has proven effective and safe O Lactic acidosis during metformin use is very rare O Very few hypoglycemic episodes O Modest weight loss O Successful at reducing macrovascular disease endpoints in patients who were obese (UKPDS) O Forms - Glucophage, Glucophage XR, Metformin XR O Very useful in patients who are obese with Type 2 DM O Weight loss and mild improvement of lipid profile O Hepatic insufficiency and CHF lead to increased risk of lactic acidosis O Some GI adverse effects increase dosage slowly and take after meals O Monotherapy or combination O Dosage up to 2 gm daily in the XR form and 2.5 gm of regular O Dose XR in the evening D. Kotun, PA-C, Ed.D. for WC Regional CME Day9

10 Meglitinide O Short-acting insulin secretagogue O Preprandial dosing potentially achieving more physiologic insulin release and less risk for hypoglycemia. O Less efficacy than sulfonylureas O Repaglinide (Prandin) O Use in patients at increased risk for hypoglycemia needing aninsulin secretagogue. O Control of postprandial spikes O Alone or in conjunction with metformin or glitazones. O Bolus causing therefore good with meals D. Kotun, PA-C, Ed.D. for WC Regional CME Day10

11 Amino Acid Derivatives O Nateglinide (Starlix) – tabs 60 & 120mg (max 360mg/day) O Alone in drug naïve patients or with metformin or TZD O Pre prandial O Caution with liver disease, adrenal insufficiency, renal disease O Mimics endogenous insulin patterns with early secretion O Controls mealtime glucose surges O Monotherapy or in conjunction with metformin or glitazones. D. Kotun, PA-C, Ed.D. for WC Regional CME Day11

12 α- Glucosidase Inhibitors O Acarbose (Precose) First one approved by FDA O Also miglitol (Glycet) 50mg tabs (max 300mg) O Prolong the absorption of carbohydrates. O Titrate slowly to reduce gastrointestinal intolerance. O Modest effect on glycemic control is modest controls postprandial spikes O High degree of GI adverse effects (flatulence) limit use O Monotherapy or in combination with other treatment modalities. D. Kotun, PA-C, Ed.D. for WC Regional CME Day12

13 Thiazolidinediones O A great step forward, reducing or delaying insulin use in DM T-2 O Reduce insulin resistance in the periphery (sensitize muscle and fat to the actions of insulin) O Possibly some slight hepatic effect O They activate peroxisome proliferator– activated receptor (PPAR) gamma, a nuclear transcription factor that is important in fat cell differentiation and fatty acid metabolism D. Kotun, PA-C, Ed.D. for WC Regional CME Day13

14 Thiazolidinediones O Pioglitizone (Actos) 15 – 45mg qd (max 45mg) O Rosiglitazone (Avandia) 4-8mg qd or bid (max 8mg) O Only available via a restricted access program O Insulin sensitizer, stimulating glucose uptake in skeletal muscle and adipose tissue. O Monotherapy or with sulfonylureas and/or metformin and insulin. O Lowers plasma insulin levels O Very useful in insulin resistance. O May preserve beta cell function. O Positive effects on vasculature and inflammation. D. Kotun, PA-C, Ed.D. for WC Regional CME Day14

15 Thiazolidinediones O Require the presence of insulin to work O Decrease triglycerides and increase HDL, but they may increase LDL O Decrease HbA(1c) level about 1.5 % O FDA alert on May 21, 2007 – rosiglitazone may cause increased risk of myocardial infarction (MI) and heart- related deaths. O Rosiglitazone was associated with an increased risk of stroke, heart failure, and all-cause mortality and an increased risk of the composite of AMI, stroke, heart failure, or all-cause mortality. D. Kotun, PA-C, Ed.D. for WC Regional CME Day15

16 This takes us to just after the millennium Many medications are available as combinations D. Kotun, PA-C, Ed.D. for WC Regional CME Day16

17 Glucagon-Like Peptide 1 Receptor Agonists (Incretins) O Incretin-mimetics O Mimics the endogenous incretin, glucagonlike peptide-1 (GLP-1) O It stimulates glucose-dependent insulin release O Secretagogues cause non–glucose-dependent insulin release and hypoglycemia O Reduces glucagon and slows gastric emptying O Combination with metformin or sulfonylurea O Modest weight loss probable O Administered by SubQ injections D. Kotun, PA-C, Ed.D. for WC Regional CME Day17

18 Glucagon-Like Peptide 1 Receptor Agonists (Incretins) O Exenatide (Byetta) 250mcg/ml 5 – 10mcg bid IM (dose increase after 1 month) O Suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. O Adjunctive therapy to metformin or a sulfonylurea without achieving glycemic control O Exenatide has greater ease of titration (only 2 possible doses, with most patients progressing to the higher dose) than does insulin. O However, exenatide is more expensive than high-dose glitazone therapy and requires twice-daily injections. O A long-acting formulation that is given once weekly has been developed and has been found to provide significantly greater improvement in glycemic control than does the twice-daily formulation O Exenatide ext-rel (Bydureon) 2mg/vial - 2mg/week D. Kotun, PA-C, Ed.D. for WC Regional CME Day18

19 Glucagon-Like Peptide 1 Receptor Agonists (Incretins) O Liraglutide (Victoza) 6mg/ml 0.6 – 1.8 mg/day O rDNA origin O Incretin mimetic agent that elicits glucagonlike peptide-1 (GLP-1) receptor agonist activity. O Activates GLP-1 receptor by stimulating G-protein in pancreatic beta-cells. O Increases intracellular cyclic AMP, causes insulin release with elevated glucose concentrations. O Indicated as adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. O Has not been studied in combination with insulin. D. Kotun, PA-C, Ed.D. for WC Regional CME Day19

20 Dipeptidyl Peptidase-4 Inhibitors O Sitagliptin (Januvia) 25, 50, 100mg tabs (100mg/day) O Slows inactivation of incretins, increasing and prolonging their action O Incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) increase in response to a meals O Rapidly inactivated by the enzyme, DPP-4. O Incretin hormones are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. O They increase insulin release and decrease glucagon levels in the circulation in a glucose-dependent manner. D. Kotun, PA-C, Ed.D. for WC Regional CME Day20

21 Dipeptidyl Peptidase-4 Inhibitors O Dipeptidyl peptidase IV inhibitors O Newest addition to available oral hypoglycemic agents O Sitagliptin - FDA approved October 2006 O DPP-4 degrades the endogenous incretins GLP-1 and glucose- dependent insulinotropic peptide (GIP). O Saxagliptin (Onglyza) 2.5 – 5 mg/day - FDA-approved July 2009 O Can be used as a monotherapy or in combination with metformin or a glitazone. O Given once daily and is weight neutral O Two others – Linagliptin (Tranjenta) 5mg/day and alogliptin (Nesina) 6.25, 12.5, 25mg (25mg/day) D. Kotun, PA-C, Ed.D. for WC Regional CME Day21

22 Dipeptidyl Peptidase-4 Inhibitors O Another DPP-4 inhibitor, vildagliptin, is currently under review at the FDA. O Dipeptidyl peptidase IV (DPP-4) inhibitor. O Blocks the enzyme DPP-4, which is known to degrade incretins O Increases concentrations of active intact incretin hormones (GLP-1 and GIP). O The hormones stimulate insulin release in response to increased blood glucose levels following meals. O This action enhances glycemic control. O Indicated as adjunct to diet and exercise O Improves glycemic control in adults with type 2 diabetes mellitus. D. Kotun, PA-C, Ed.D. for WC Regional CME Day22

23 Sodium Glucose Co- Transporter 2 Inhibitors O Canagliflozin (Invokana) - new to the market O Promote urinary excretion of glucose, preventing tubular reabsorption via the sodium–glucose - O Once a day 100 – 300 mg before first meal O Renal complications may occur – hydration and RFT monitoring are important O Possible hypotension with ACE, ARB D. Kotun, PA-C, Ed.D. for WC Regional CME Day23

24 Sodium Glucose Co- Transporter 2 Inhibitors O Dapagliflozin (Farxiga) – 5 & 10 mg (max 10 mg) O Approved in Europe first O Both can cause heavy glucosuria (70gm/day) O Once a day 100 – 300 mg before first meal O Renal complications may occur – hydration and RFT monitoring are important O Possible hypotension with ACE, ARB O FDA recommended against approval (2012) D. Kotun, PA-C, Ed.D. for WC Regional CME Day24

25 Bile Acid Sequestrants O Colesevelam HCl (Welchol) – lowers triglycerides O Adjunct to metformin, sulfonylureas, or insulin O Effect on DPP-4 inhibitors or TZDs unknown O Only use in DM T-2 D. Kotun, PA-C, Ed.D. for WC Regional CME Day25

26 Amylin Analog/Amylinomimetic O Pramintide (Symilin) – injection 0.6 mg/ml O Adjunct to mealtime insulin O Decreases GI absorption of glucose O Not for the hypomotile (gastroparesis) O Dose 15 mcg up to 120 mcg (usual is 60 mcg) O Action O Delays gastric emptying O Prevents postprandial rise in plasma glucagon O Increases satiety leading to decreased caloric intake and potential weight loss O Not to be mixed with insulin, and reduce preprandial, short acting insulin by ½ D. Kotun, PA-C, Ed.D. for WC Regional CME Day26

27 Dopamine Receptor Agonist O Bromcryptine (Cycloset) – 0.8mg tab (4.8max) O Adjunct to diet and exercise in T-2 only O With food in A.M. O Adjust antihypertensive meds O There may be a CNS component to DM T-2 and in the future neurological modifiers may emerge as a treatment modality D. Kotun, PA-C, Ed.D. for WC Regional CME Day27

28 Common Sense Treatment O First steps are lifestyle changes O Review the social history to determine fit into the patient’s lifestyle O Referral to the appropriate specialists O Keep aware of the potential complications O Education, education, education D. Kotun, PA-C, Ed.D. for WC Regional CME Day28

29 Major findings from the primary glucose study in the United Kingdom Prospective Diabetes Study (UKPDS).

30 Results from metformin substudy in the United Kingdom Prospective Diabetes Study

31 Blood pressure substudy in the United Kingdom Prospective Diabetes Study

32 Complicating Factors O Nephropathy O Retinopathy O Neuropathy O Hypertension O Dyslipidemias ↑ trig & LDL; ↓ HDL O Coronary Artery Disease O Peripheral Arterial Disease O Amyloid deposition in Islet cells D. Kotun, PA-C, Ed.D. for WC Regional CME Day32

33 Adjunctive Actions D. Kotun, PA-C, Ed.D. for WC Regional CME Day33 O Nutrition therapy - ↓ Etoh, and Na +, 7% wt loss O Education O Physical activity O Psychosocial assessment O Bariatric surgery O Immunizations O BP control O Lipid Management O Antiplatlet agents O Smoking cessation O CVD treatment O Nephropathy O Retinopathy O Foot care O Preconception care O Geriatric conditions O Cystic fibrosis - DM

34 The Future O Improved access and knowledge O Including quality measurements O Pumps with implanted monitoring systems O Lower cost technology O Islet cell or pancreatic transplants O Mechanical pancreas O Genetic engineering O Organ cloning O CNS modifiers D. Kotun, PA-C, Ed.D. for WC Regional CME Day34

35 Technological Advances Tricorder X prize finalists: – Used smartphone first – Now the hardware is becoming more streamlined D. Kotun, IMC Grand Rounds 25 Sep 2014

36 Technological Advances Stool “sniffer” can diagnose and I.D. the individual strain of C. Diff. (Med. News Today, 2 Sep 14) – Also was a story from Finnish scientists who are developing a urine “sniffer” for prostate CA Google Glasses helped surgeons monitor vitals on simulated patients (non-GG users -82% less awareness) D. Kotun, IMC Grand Rounds 25 Sep 2014

37 Technological Advances Ipad sized device (Gene-RADAR®) can diagnose: – Ebola, e. coli, TB, AIDS, HIV, – Cost predicted to be about $20.00 D. Kotun, IMC Grand Rounds 25 Sep 2014

38 Technological Advances Cloud DX – Vitaliti necklace and cuff 11 physiological parameters with instant results on your tablet, stored in the cloud Danvantri – BP, temp, pulse ox, now Pending integration ECG, spirometry, glucose DMI – Developed with NASA and NIH – set of diagnostics BioDyn (Dynamical Biomarkers Group) – 5 Module system – patch D. Kotun, IMC Grand Rounds 25 Sep 2014

39 Technological Advances Final Frontier Medical Devices – Basil Leaf Technologies – DxtER – Uses data to diagnose specific conditions – Developers replicated a deconstructed Dx Process for 22 conditions User friendly Can make a “real” clinical diagnosis MESI Simplifying diagnostics – Wearable wristbands, modules, and questionnaire – See & Hear – Pee and Blood to gather data – Consolidated in a smartphone app give results in color D. Kotun, IMC Grand Rounds 25 Sep 2014

40 Technological Advances SCANADU – Moffitt Field, Calif. – Bluetooth monitors vital signs then sends data to a smartphone – Include “urine paddles” for pregnancy and health status – Dr. Walter De Brouwer says “can almost replace a clinic” SCANurse – London, UK – Interactive engagement with the user – Long term interaction – Easy to read results D. Kotun, IMC Grand Rounds 25 Sep 2014

41 Technological Advances Zensor – Belfast Northern Ireland – Wearable, non-invasive cardio event monitor – Sends via WiFi to a secure server for review Resp., pulse, temp., motion, blood, urine D. Kotun, IMC Grand Rounds 25 Sep 2014

42 D. Kotun, PA-C, Ed.D. for WC Regional CME Day42

43 D. Kotun, PA-C, Ed.D. for WC Regional CME Day43

44 Bibliography O Yuwiler, Janice M. Insulin. Detroit: Lucent Books, Print. Great Medical Discoveries O Berger, Melvin. “Frederick Grant Banting.” Famous Men of Modern Biology. New York: Thomas Y. Crowell Company, Print. O The Discovery of Insulin". Nobelprize.org. Nobel Media AB Web. 1 Oct O medications/sulfonylureas#sthash.RDOPOby3.dpuf medications/sulfonylureas#sthash.RDOPOby3.dpuf O 2014 American Diabetes Association, Executive Summary: Standards of Medical Care in Diabetes O MPR Physician Assistant’s Edition, Fall 2014, Vol. 21, No. 3, Haymarket Media, Inc., New York, N.Y. O McAuley, D., Pharm.D. 2014, GlobalRph, The Clinicans Ultimate Reference, updated 06/25/ :32:56 D. Kotun, PA-C, Ed.D. for WC Regional CME Day44


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