Presentation is loading. Please wait.

Presentation is loading. Please wait.

Treatment of DM T-2: Then and Now

Similar presentations


Presentation on theme: "Treatment of DM T-2: Then and Now"— Presentation transcript:

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

2 Historical Perspective
Before Banting and Best -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) Before 1922 Diabetic children rarely lived a year after diagnosis Five percent of adults died within two years, and less than 20 percent lived more than ten (Berger 57) 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 Day

3 Historical Perspective
Insulin comes out 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 Cells producing antidiabetic secretions could be extracted from the pancreas without being harmed 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 Banting’s assistant, a medical student by the name of Charles Best Experiments started in summer of 1921 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 In January 1922 in Toronto, Canada, a 14-year-old boy, Leonard Thompson, was chosen as the first person with diabetes to receive insulin. 1923 Nobel Prize went to Banting and Macleod 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 Day

4 Historical Perspective
First interventions 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 Very soon after the discovery of insulin, the medical firm Eli Lilly started large-scale production of the extract 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 Day

5 Historical Perspective
Oral medications First came Sulfonylureas glyburide (Diabeta®), glipizide (Glucotrol®), and glimepiride (Amaryl®) Biguanides Metformin (Glucophage®; Glucophage® XR) is the only biguanide FDA-approved for use in the United States Thiazolidinediones 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 Day

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

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

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

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

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

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

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

13 Thiazolidinediones A great step forward, reducing or delaying insulin use in DM T-2 Reduce insulin resistance in the periphery (sensitize muscle and fat to the actions of insulin) Possibly some slight hepatic effect 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 Day

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

15 Thiazolidinediones Require the presence of insulin to work
Decrease triglycerides and increase HDL, but they may increase LDL Decrease HbA(1c) level about 1.5 % FDA alert on May 21, 2007 – rosiglitazone may cause increased risk of myocardial infarction (MI) and heart-related deaths. 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. PPAR-alpha agonists[edit] PPARα (alpha) is the main target of fibrate drugs, a class of amphipathic carboxylic acids (clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate). They were originally indicated for cholesterol disorders and more recently for disorders that feature high triglycerides. Many of them increase the risk of cancer to the point where they eliminate the survival benefit of reduced heart disease.[citation needed] PPAR-gamma agonists[edit] PPARγ (gamma) is the main target of the drug class of thiazolidinediones (TZDs), used in diabetes mellitus and other diseases that feature insulin resistance. It is also mildly activated by certain NSAIDs (such as ibuprofen) and indoles, as well as from a number of natural compounds.[1][2] Known inhibitors include the experimental agent GW-9662. They are also used in treating hyperlipidaemia in atherosclerosis. Here they act by increasing the expression of ABCA1, which transports extra-hepatic cholesterol into HDL. Increased uptake and excretion from the liver therefore follows. Animal studies have shown their possible role in amelioration of pulmonary inflammation, especially in asthma.[3] They may cause fluid retention and heart failure in those with weak hearts. PPAR-delta agonists[edit] PPARδ (delta) is the main target of a research chemical named GW It has been shown that agonism of PPARδ changes the body's fuel preference from glucose to lipids,[4] but ironically improves metabolic syndrome (which is characterized by the body being unable to efficiently deal with glucose resulting in insulin resistance and sometimes diabetes). Dual and pan PPAR agonists[edit] A fourth class of dual PPAR agonists, so-called glitazars, which bind to both the α and γ PPAR isoforms, are currently under active investigation for treatment of a larger subset of the symptoms of the metabolic syndrome.[5][6] These include the experimental compounds aleglitazar, muraglitazar and tesaglitazar. In June 2013, saroglitazar was the first glitazar to be approved for clinical use.[7] In addition, there is continuing research and development of new dual α/δ and γ/δ PPAR agonists for additional therapeutic indications, as well as "pan" agonists acting on all three isoforms.[8][9] D. Kotun, PA-C, Ed.D. for WC Regional CME Day

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 Day

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

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

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

20 Dipeptidyl Peptidase-4 Inhibitors
Sitagliptin (Januvia) 25, 50, 100mg tabs (100mg/day) Slows inactivation of incretins, increasing and prolonging their action Incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) increase in response to a meals Rapidly inactivated by the enzyme, DPP-4. Incretin hormones are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. 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 Day

21 Dipeptidyl Peptidase-4 Inhibitors
Dipeptidyl peptidase IV inhibitors Newest addition to available oral hypoglycemic agents Sitagliptin - FDA approved October 2006 DPP-4 degrades the endogenous incretins GLP-1 and glucose-dependent insulinotropic peptide (GIP). Saxagliptin (Onglyza) 2.5 – 5 mg/day - FDA-approved July 2009 Can be used as a monotherapy or in combination with metformin or a glitazone. Given once daily and is weight neutral 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 Day

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

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

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

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

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

27 Dopamine Receptor Agonist
Bromcryptine (Cycloset) – 0.8mg tab (4.8max) Adjunct to diet and exercise in T-2 only With food in A.M. Adjust antihypertensive meds 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 Day

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

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

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

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

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 Day

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

44 Bibliography D. Kotun, PA-C, Ed.D. for WC Regional CME Day
Yuwiler, Janice M. Insulin. Detroit: Lucent Books, Print. Great Medical Discoveries Berger, Melvin. “Frederick Grant Banting.” Famous Men of Modern Biology. New York: Thomas Y. Crowell Company, Print. The Discovery of Insulin". Nobelprize.org. Nobel Media AB Web. 1 Oct 2014 American Diabetes Association, Executive Summary: Standards of Medical Care in Diabetes MPR Physician Assistant’s Edition, Fall 2014, Vol. 21, No. 3, Haymarket Media, Inc., New York, N.Y. 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 Day


Download ppt "Treatment of DM T-2: Then and Now"

Similar presentations


Ads by Google