treatment of dm t-2: then and now a 30 year overview

Treatment of DM T-2: Then and Now

A 30 Year Overview

D. Kotun, PA-C, Ed.D. for WC Regional CME Day 2

Historical PerspectiveO 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 1922O Diabetic children rarely lived a year after diagnosisO 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)


Historical PerspectiveO 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 BestO Experiments started in summer of 1921O 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


Historical PerspectiveO First interventionsO 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.


Historical PerspectiveO Oral medications

O First came SulfonylureasO 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 ThiazolidinedionesO 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


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. OrO 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.


After SulfonylureasO General improvements

O The switch from increasing insulin to other mechanismsO Modifying insulin sensitivityO Delaying absorption of mealtime

glucoseO Inhibiting gluconeogenisisO Affecting the multiple biochemical

pathwaysO After the millennium, several new

medications came out


SulfonylureasO Sulfonylureas are insulin secretagogues (pancreas

spankers) – increase insulin outputO Orinase (tolbutamide); Tolinase (tolazamide); Diabinese

(chlorpropamide) O First generation – drawback was liver damage and

replacement by 2nd 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


BiguanidesO 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 safeO Lactic acidosis during metformin use is very rareO Very few hypoglycemic episodesO Modest weight loss O Successful at reducing macrovascular disease endpoints in patients who were

obese (UKPDS)

O Forms - Glucophage, Glucophage XR, Metformin XRO Very useful in patients who are obese with Type 2 DMO Weight loss and mild improvement of lipid profile O Hepatic insufficiency and CHF lead to increased risk of lactic acidosisO Some GI adverse effects increase dosage slowly and take after mealsO Monotherapy or combination

O Dosage up to 2 gm daily in the XR form and 2.5 gm of regularO Dose XR in the evening


MeglitinideO Short-acting insulin secretagogue

O Preprandial dosing potentially achieving more physiologic insulin release and less risk for hypoglycemia.

O Less efficacy than sulfonylureasO 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


Amino Acid DerivativesO Nateglinide (Starlix) – tabs 60 & 120mg (max

360mg/day)O Alone in drug naïve patients or with metformin

or TZDO Pre prandial O Caution with liver disease, adrenal

insufficiency, renal diseaseO Mimics endogenous insulin patterns with early

secretionO Controls mealtime glucose surgesO Monotherapy or in conjunction with metformin

or glitazones.


α- Glucosidase Inhibitors

O Acarbose (Precose) First one approved by FDAO 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 useO Monotherapy or in combination with other

treatment modalities.


ThiazolidinedionesO A great step forward, reducing or

delaying insulin use in DM T-2O Reduce insulin resistance in the

periphery (sensitize muscle and fat to the actions of insulin)O Possibly some slight hepatic effectO They activate peroxisome proliferator–

activated receptor (PPAR) gamma, a nuclear transcription factor that is important in fat cell differentiation and fatty acid metabolism


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 levelsO Very useful in insulin resistance.O May preserve beta cell function.O Positive effects on vasculature and inflammation.


ThiazolidinedionesO Require the presence of insulin to workO Decrease triglycerides and increase HDL, but they

may increase LDLO 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.


This takes us to just after the millennium

Many medications are available as combinations


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

releaseO Secretagogues cause non–glucose-dependent

insulin release and hypoglycemiaO Reduces glucagon and slows gastric emptying

O Combination with metformin or sulfonylurea O Modest weight loss probableO Administered by SubQ injections



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 controlO 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


O Liraglutide (Victoza) 6mg/ml 0.6 – 1.8 mg/dayO 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.



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.



O Dipeptidyl peptidase IV inhibitorsO 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)



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

incretinsO 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.


Sodium Glucose Co-Transporter 2 Inhibitors

O Canagliflozin (Invokana) - new to the marketO 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


Sodium Glucose Co-Transporter 2 Inhibitors

O Dapagliflozin (Farxiga) – 5 & 10 mg (max 10 mg)O Approved in Europe firstO Both can cause heavy glucosuria (70gm/day)O Once a day 100 – 300 mg before first mealO Renal complications may occur – hydration

and RFT monitoring are importantO Possible hypotension with ACE, ARB

O FDA recommended against approval (2012)


Bile Acid SequestrantsO Colesevelam HCl (Welchol) – lowers

triglyceridesO Adjunct to metformin, sulfonylureas,

or insulinO Effect on DPP-4 inhibitors or TZDs

unknownO Only use in DM T-2


Amylin Analog/Amylinomimetic

O Pramintide (Symilin) – injection 0.6 mg/ml O Adjunct to mealtime insulinO Decreases GI absorption of glucose O Not for the hypomotile (gastroparesis)O Dose 15 mcg up to 120 mcg (usual is 60 mcg)

O ActionO Delays gastric emptyingO Prevents postprandial rise in plasma glucagonO Increases satiety leading to decreased caloric

intake and potential weight lossO Not to be mixed with insulin, and reduce

preprandial, short acting insulin by ½


Dopamine Receptor AgonistO Bromcryptine (Cycloset) – 0.8mg tab

(4.8max)O Adjunct to diet and exercise in T-2

onlyO With food in A.M.

O Adjust antihypertensive medsO There may be a CNS component to

DM T-2 and in the future neurological modifiers may emerge as a treatment modality


Common Sense Treatment

O First steps are lifestyle changesO 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

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

Results from metformin substudy in the United Kingdom Prospective Diabetes Study

Blood pressure substudy in the United Kingdom Prospective Diabetes Study


Complicating FactorsO NephropathyO RetinopathyO NeuropathyO HypertensionO Dyslipidemias ↑ trig & LDL; ↓ HDLO Coronary Artery DiseaseO Peripheral Arterial DiseaseO Amyloid deposition in Islet cells


Adjunctive ActionsO Nutrition therapy - ↓

Etoh, and Na+, 7% wt loss

O Education O Physical activityO Psychosocial

assessment O Bariatric surgeryO ImmunizationsO BP controlO Lipid Management

O Antiplatlet agentsO Smoking cessationO CVD treatmentO NephropathyO RetinopathyO Foot careO Preconception careO Geriatric conditionsO Cystic fibrosis - DM


The FutureO Improved access and knowledge

O Including quality measurementsO Pumps with implanted monitoring

systemsO Lower cost technology

O Islet cell or pancreatic transplantsO Mechanical pancreasO Genetic engineeringO Organ cloningO CNS modifiers

D. Kotun, IMC Grand Rounds 25 Sep 2014

Technological Advances• Tricorder X prize finalists:

– Used smartphone first– Now the hardware is becoming more

streamlined


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)


Technological Advances• Ipad sized device (Gene-RADAR®) can diagnose:

– Ebola, e. coli, TB, AIDS, HIV, – Cost predicted to be about $20.00


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


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


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


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


BibliographyO Yuwiler, Janice M. Insulin. Detroit: Lucent Books, 2005. Print. Great

Medical DiscoveriesO Berger, Melvin. “Frederick Grant Banting.” Famous Men of Modern

Biology. New York: Thomas Y. Crowell Company, 1968. 56-73. Print.O The Discovery of Insulin". Nobelprize.org. Nobel Media AB 2014. Web. 1

Oct 2014. http://www.nobelprize.org/educational/medicine/insulin/discovery-insulin.html

O http://www.diabetesnet.com/about-diabetes/diabetes-medications/sulfonylureas#sthash.RDOPOby3.dpuf

O 2014 American Diabetes Association, Executive Summary: Standards of Medical Care in Diabetes - 2014 http://creativecommons.org/licenses/by-nc-nd/3.0/

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 06/25/2014 19:32:56 http://www.globalrph.com/amylin-agonists.htm

http://www.nobelprize.org/educational/medicine/insulin/discovery-insulin.html



http://www.diabetesnet.com/about-diabetes/diabetes-medications/sulfonylureas



http://creativecommons.org/licenses/by-nc-nd/3.0/



http://www.globalrph.com/amylin-agonists.htm



treatment of dm t-2: then and now a 30 year overview

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