Treatment of DM T-2:
Then and Now
A 30 Year Overview
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)
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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
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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.
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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
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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
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.
O
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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
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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 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
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Biguanides
O
Biguanides – First big step since insulin and secretagogs
O
O
O
Metformin has proven effective and safe
O
O
O
O
O
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
O
O
O
O
O
O
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
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
O
Dose XR in the evening
D. Kotun, PA-C, Ed.D. for WC Regional CME Day
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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
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Amino Acid Derivatives
O Nateglinide (Starlix) – tabs 60 & 120mg (max
360mg/day)
O Alone in drug naïve patients or with metformin or
O
O
O
O
O
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.
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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 Day
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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 Day
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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
O
O
O
O
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
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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 heartrelated 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 Day
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This takes us to just after
the millennium
Many medications are available as combinations
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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
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Glucagon-Like Peptide 1
Receptor Agonists (Incretins)
O
O
O
O
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
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
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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
O
O
O
O
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
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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.
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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)
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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 Day
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Sodium Glucose CoTransporter 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 Day
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Sodium Glucose CoTransporter 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)
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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
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Amylin
Analog/Amylinomimetic
O Pramintide (Symilin) – injection 0.6 mg/ml
O
O
O
O
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)
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
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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 Day
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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
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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 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
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Adjunctive Actions
O Nutrition therapy - ↓
Na+,
O
O
O
O
O
O
O
Etoh, and
7% wt
loss
Education
Physical activity
Psychosocial
assessment
Bariatric surgery
Immunizations
BP control
Lipid Management
D. Kotun, PA-C, Ed.D. for WC Regional CME Day
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
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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
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Technological Advances
• Tricorder X prize finalists:
– Used smartphone first
– Now the hardware is becoming more
streamlined
D. Kotun, IMC Grand Rounds 25 Sep 2014
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
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
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
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
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
–D. Easy
toGrand
read
results
Kotun, IMC
Rounds
25 Sep 2014
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
D. Kotun, PA-C, Ed.D. for WC Regional CME Day
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D. Kotun, PA-C, Ed.D. for WC Regional CME Day
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Bibliography
O
O
O
O
O
O
O
Yuwiler, Janice M. Insulin. Detroit: Lucent Books, 2005. Print. Great Medical
Discoveries
Berger, Melvin. “Frederick Grant Banting.” Famous Men of Modern Biology. New
York: Thomas Y. Crowell Company, 1968. 56-73. Print.
The Discovery of Insulin". Nobelprize.org. Nobel Media AB 2014. Web. 1 Oct 2014.
http://www.nobelprize.org/educational/medicine/insulin/discovery-insulin.html
http://www.diabetesnet.com/about-diabetes/diabetesmedications/sulfonylureas#sthash.RDOPOby3.dpuf
2014 American Diabetes Association, Executive Summary: Standards of Medical
Care in Diabetes - 2014 http://creativecommons.org/licenses/by-nc-nd/3.0/
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 06/25/2014 19:32:56 http://www.globalrph.com/amylin-agonists.htm
D. Kotun, PA-C, Ed.D. for WC Regional CME Day
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