thursday gs 6 majewski - c.ymcdn.com€¦ · the ominous octet of type 2 diabetes per ralph a....

9/23/2014

1

Update on Medications

to Treat Type 2 Diabetes

Wisconsin Academy of

Physician Assistants Fall Conference

October 9, 2014

Kathryn G. Majewski, MSHS, PA-C

Gundersen Health System – La Crosse Endocrinology Department

[email protected]

Disclaimer

• No conflicts of interests.

• No financial relationships with any

commercial interests.

• ADA & AACE info used with permission.

“Update”

• Currently for type 2 diabetes medications, we have 12 classes of agents:

– 16 oral agents

– 14 insulin options

– 5 other injectable options

– Plus numerous combination products

– & many more coming down the pipeline

• But we only have 45 minutes…

The Ominous Octet of Type 2 Diabetesper Ralph A. DeFronzo, MD – U of TX-San Antonio

Diabetes 58:4 (2009):773-795.

The Ominous Octet

Pancreas

• Beta cell dysfunction & failure

• Decreased insulin production

Small intestine

• Decreased incretin effect

Adipose

• Increased lipolysis, increased free fatty acid production

• Further impairs insulin secretion

Kidneys

• Increased reabsorption of glucose

Muscle

• Decreased glucose uptake

Brain

• Neurotransmitter dysfunction

• Affects appetite & weight

Liver

• Increased hepatic glucose production (stimulated by increased free fatty acids)

Islet-alpha cells

• Increased glucagon secretion

• Responsible for high fasting glucose levels

Diabetes 58:4 (2009):773-795.

With this in mind

• Choose meds that would address multiple

issues

• The natural history of diabetes is such that

over time it becomes more challenging to

control.

• Most people will require multi-drug therapy,

often from the time of diagnosis.

• Why not start sooner?

9/23/2014

2

Step-therapy for DM-2

The Foundation: Therapeutic Lifestyle Changes

Healthy food / beverage choices; regular activity; weight loss

Monotherapy – usually metformin

Dual drug therapy

metformin + GLP-1/DDP-4/TZD/?

Triple drug therapy

Insulin

+/- orals, GLP-1

It’s an UPDATE, so

we’ll start with the newest meds

SGLT-2sSodium-glucose co-transporter 2 inhibitors

Actions:

• Inhibits SGLT-2 in proximal convoluted tubule, reducing reabsorption of filtered glucose

• Lowers renal threshold for glucose

• Increases urinary excretion of glucose

• Causes osmotic diuresis

At present, 3 options (more to follow):

• canagliflozin (Invokana)

• dapagliflozin (Farxiga)

• empagliflozin (Jardiance)

SGLT-2s work here

Diabetes 58:4 (2009):773-795.

SGLT-2s

Advantages:

• Low risk of hypoglycemia –works only with hyperglycemia

• Lose about 400 calories per day via urine glucose– 4-6 pound wt loss

• Decreases BP by about 5 points on average– Diuretic effect

• Can be used early or late in the disease process

Disadvantages:

• May increase LDL by 4-8 points

• Don’t use with eGFR <45 (canaglifozin, empagliflozin) or < 60 (dapagliflozin)

• Increased risk of genital fungal infections & UTI, especially in those prone to such infxns

• Hypotension in elderly, with dehydration, etc.

• Increased urination & thirst, maybe constipation

• Increased risk of hyperkalemiawith canagliflozin, especially in CKD patients

SGLT-2s

Contradictions:

• eGFR < 60 (dapagliflozin)

• eGFR < 45 (canaglifozin, empagliflozin)

• Need to monitor creatinine & eGFR in folks using SGLT-2s– May cause slight increase

in creatinine & slight decrease in eGFR, especially in the elderly

Precautions:

• eGFR 45-59 (canaglifozin, empagliflozin)

• Use of loop diuretic– Reduce dose of loop

• Elderly

• Low systolic BP

• Issues re: dehydration– Athletes, outdoor work,

elderly, cognitively challenged, etc

• Pregnancy category C

9/23/2014

3

SGLT-2s

• Could be a good option for truck drivers with

CDL but will test positive for urine glucose, so

need to send documentation re: this when

they get their DOT physical.

GLP-1 receptor agonists

AKA incretin mimetics• About 60% of post-meal insulin secretion is due to

effects of incretins. These effects are diminished in people with DM-2 & pre-diabetes.

Actions:

• Stimulates GLP-1 receptors, which enhances glucse-dependent insulin secretion

• Inhibits post-prandial glucagon release, so reduces heptatic glucose output

• In CNS, reduces appetite, promotes earlier satiety

• Slows gastric emptying

• Therefore weight loss


AKA incretin mimetics

• 5 options available, all with pen devices:

• exenatide (Byetta) – twice daily injection before meals

• liraglutide (Victoza) – once daily injection regardless of meals

• exenetide extended-release (Bydureon) – once weekly injection (new pen device)

• albiglutide (Tanzeum) – once weekly injection

• dulaglutide (Trulicity) – once weekly injection (just approved by FDA – not yet in stores as of 9-22-14)


Advantages:

• Low risk of hypoglycemia

• Appetite suppression

• Weight loss

• “I never knew before what it felt like to be full.”

• A motivator for further weight loss / healthier lifestyle

Disadvantages:

• Requires injection

• GI side effects are common– Nausea, diarrhea

– Usually transient

– Usually manageable

– May require dose adjustment

• Requires more education



Contraindications:

• Gastroparesis

• Chronic nausea, vomiting,

motility issues

• History of pancreatitis

• CrCl < 30

• Hx of medullary thyroid

carcinoma or MEN-2

– Black box warning re: risk

of thyroid tumors in rats

Precautions:

• Risk factors for

pancreatitis

• Chronic diarrhea

• Chronic abdominal pain

• Active peptic ulcer

GLP-1 receptor agonists work here

Diabetes 58:4 (2009):773-795.

9/23/2014

4

DPP-4 inhibitors: dipeptidyl peptidase-

4 inhibitors or incretin enhancers

Actions:

• Incretins have very short half-life – < 2 minutes in circulation

• DPP-4 inhibitors prolong the half-life of endogenous incretins by inhibiting their degradation

• Thereby increases post-prandial insulin secretion & decreases glucagon secretion

• Glucose-dependent action

DPP-4 inhibitors

Options:

• sitagliptin (Januvia)

• saxagliptin (Onglyza)

• linagliptin (Tradjenta)

• alogliptin (Nesina)

• All once-daily oral agents

• In stage 3 trials, a once-a-week version

DPP-4 inhibitors

Advantages:

• Oral, once daily


• Weight neutral

• No GI side effects

• Pregnancy category B

Disadvantages:

• Requires dose adjustment for renal disease with eGFR < 60

– Except linagliptin

• Post-marketing reports of hepatic failure with alogliptin, increased liver enzymes with sitagliptin

DPP-4 inhibitors

Contraindications:

Precautions:

• Hx of pancreatitis

• Risk factors for pancreatitis

• Potential slight increase risk of CHF, seen in 2 recent studies

Precautions:

• Decrease dose of sitagliptin, saxagliptin if eGFR < 50, alogliptin if eGFR < 60

• Decrease dose of saxagliptin if also taking strong cytochrome P450 3A4/5 inhibitors (ketoconazole, clarithromycin, etc)

DPP-4 inhibitors work here Just so you know…

Because they over-lap in their functions,

you should use

EITHER a GLP-1

OR a DPP-4,

not both at the same time.

9/23/2014

5

OK, you have the new stuff.

Let’s go back to

the old stuff.

Underlying theme of DM-2

is insulin resistance

• Starts long before person meets criteria for diagnosis of DM-2 or even pre-diabetes

• Suspect it in the right person

• Screen for it regularly

• Jump on it & treat it aggressively from the start

• Remember that HTN = insulin resistance

• Remember that high triglycerides & low HDL = insulin resistance

Screen with A1c

• First measurable defect is elevated post-

prandial glucose

• Will cause rise in A1c long before rise in

fasting glucose

• An A1c > 5.7% = pre-diabetes & deserves tx

• An A1c > 6.5% = diabetes & deserves tx

• For both, tx = therapeutic lifestyle changes +

medication

By the time they meet criteria for

diagnosis of DM-2, 50% of beta

cells have been destroyed.

For good.

Be nice to your beta cells –

you only get so many.

Preserve those beta cells!

• By addressing the reason for their early demise

– Hyperglycemia

– Insulin resistance

– Over-working the beta cells

– They eventually burn out & quit working

• Help keep them working happily longer by giving metformin.

• Avoid using meds that will help them burn out sooner, like sulfonylureas.

9/23/2014

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Metformin

Actions:

• Decreases hepatic glucose output

• Reduces gluconeogenesis & glycogenolysis

• Increases peripheral glucose uptake & utilization

• Enhances insulin sensitivity

• Decreases intestinal glucose absorption

• Does not affect insulin production

• Antiatherogenic effects (DeFronzo)

Metformin

Options:

• metformin – twice daily with meals

• metformin extended-release – once daily with a meal

• In combination pills with many other DM meds

• We generally use 500 mg tablets, as the larger once are often too large to swallow.– 500 mg daily x several days, then 1000 mg daily x

several days, then 1500, then 2000 long term

Metformin

Advantages:

• Does not cause hypoglycemia

• Weight neutral

• Generally well tolerated

• On the $4 lists

• Plays nicely with others

• Good evidence it reduces risk of progression from IGT to DM


Disadvantages:

• GI side effects fairly common

• Nausea, loose stools, usually mild & short term– Some metformin is better

than no metformin

• Potential B-12 deficiency

• Lactic acidosis – rare but serious

Metformin

Contraindications:

• Significant CKD– d/c if creatinine

• > 1.4 women,

• > 1.5 men

• Clinically significant CHF

• Hypoperfusion (sepsis, MI, etc)

• Dehydration (GI losses, elderly, dementia, etc)

• Significant liver disease

Precautions:

• Stop temporarily if:• Dehydration for any reason

• Surgery or procedure (colonoscopy prep)

• Need for contrast dye for imaging studies

• Hospitalization

• Gastroenteritis

Lactic acidosis secondary to metformin

Preventable! Choose the right pts for the drug.

• Rare (3 cases per 100,000 pt-yr – most of whom had underlying contraindications to metformin)

• Lactate levels >5 mmol/L• Decreased blood pH• Increased anion gap• Increased lactate/pyruvate ratio. • Electrolyte disturbances • Treatment with hemodialysis• 40% mortality

Diabetes Care July 2004 vol. 27 no. 7 1791-1793

Metformin works here

Diabetes 58:4 (2009):773-795.

9/23/2014

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Another oldy but a goody

• For the right person, anyway…

• TZDs or thiazolidinediones

TZDs

Actions:

• Enhance insulin sensitivity in muscle & fat by increasing glucose transporter expression

• Increase glucose disposal by muscle

• Decrease glucose output from liver

Options:

• pioglitazone (Actos)

• rosiglitazone (Avandia)

• But these 2 are very different from each other

TZDsAdvantages:

• Once-daily oral

• Low risk hypoglycemia

• Pio improves lipids, lowers triglycerides, raises HDL

• Pio improves fatty liver –very common in DM-2

• Relatively safe in renal failure

• Preserves beta cell fxn

• Improves albumin excretion

• Improves vascular smooth muscle proliferation

Disadvantages:

• Takes 2-3 months to see full effect

• Fluid retention, therefore weight

gain in some

• Can push someone over the fence

into CHF - warn pt & d/c drug if wt

gain &/or edema

• Possible increased risk of fracture,

esp women 50+ yo

• Post-marketing reports of hepatic

failure – monitor if at increased risk

• Don’t use with gemfibrozil or

rifampin

• Pregnancy category C Peripheral (subQ) fat is associated with improvement of insulin sensitivity, whereas

central or visceral fat is the bad fat that is associated with insulin resistance.Vasc Health Risk Manag 2010; 6: 671-690.

Effect of pioglitazone on fat

TZDs & bladder cancer

• Recent studies have shown potential increase risk of bladder cancer

– In folks on TZD the longest & on the highest doses

• Smokers are up to 7 x higher risk of bladder cancer than non-smokers

• Risk of bladder cancer in general population of non-smokers is low

– Increasing the risk of a low risk condition is still a very low risk

• I’ll consider 15-30 mg of pio daily for non-smoker

TZDs

Contraindications:

• Class III-IV CHF

• Significant edema

• Significant liver disease

• +/- osteoporosis

• Hx of bladder cancer

Precautions:

• CHF

• Hepatic disease

• Heavy alcohol use

• Smokers

• Advanced age

9/23/2014

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TZDs work here

Diabetes 58:4 (2009):773-795.

Sulfonylureas

Actions:

• Stimulate pancreatic insulin secretion, regardless of blood glucose level

Options:

• 1st generation SUs – no longer in use

• 2nd generation SUs

– glyburide (Diabeta, Glynase, Micronase)

– glipizide (Glucotrol)

– glimepiride (Amaryl)

Sulfonylureas

Advantages:

• Inexpensive

Disadvantages:

• High risk of

hypoglycemia,

especially nocturnal

• After initial drop in A1c,

will see gradual rise

over time

• Increases rate of beta

cell demise

What’s the big deal with hypoglycemia?

• Typical DM-2 pt is obese. They eat too much & sit too much.

• Drop their sugar too low even once & they’ll:

– eat when they’re not hungry, so gain weight

– eat more than they should, so gain weight

– be less active because they fear low sugars due to activity

– skip or reduce med doses because of fear of low sugars

• If the sugar is low enough to cause symptoms, it’s low enough

to kill brain cells. We only have so many brain cells, right?

• Hypoglycemia triggers adrenaline response, raises BP & heart

rate. Folks with DM are at much higher risk of CV events.

• Sxs of low sugar often masked by beta blockers

Sulfonylureas

Contraindications:

• Renal disease

(especially glyburide)

• Sulfa allergy

• Severe liver disease

• Frail elderly, as

hypoglycemia increases

risk of falls & MI

Precautions:

• Drug interaction with

sulfa antibiotics,

NSAIDs, ACE-inhibitors,

fluoxetine, many others

can increase risk of

hypoglycemia


Sulfonylureas

• Recommend they not be used

• If you MUST use one, choose glimepiride

– Least likely to cause hypoglycemia

• Glyburide is dangerous & should be taken off the market – negative cardiovascular effects – much more likely to cause hypoglycemia

– If it were a new drug, it would never achieve FDA approval. You’ll also find it on the Beers’ list.

• SUs have maximal effect at half the maximum recommended dose, so don’t go to the max

9/23/2014

9

Sulfonylureas work here

Diabetes 58:4 (2009):773-795.

Meglitanides

Actions:

• Stimulates pancreatic insulin secretion

• Rapid onset & short action, unlike SUs

• Mimics natural insulin response to meals

Options:

• nateglinide (Starlix)

• repaglinide (Prandin)

Meglitanides

Advantages:

• Very fast acting

• Very short acting


• Doesn’t cause nocturnal hypoglycemia

• An option for folks with irregular mealtimes

• Weight neutral

Disadvantages:

• Frequent dosing – at start of each meal

• May cause slight increase in serum uric acid

Meglitanides

Contraindications:

• Coadministration with gemfibrozil

Precautions:

• Use with caution with moderate-severe liver disease – hasn’t been studied

• NSAIDs, MAO-inhibitors, non-selective beta blockers may increase risk of hypoglycemia

• Severe renal disease, use lower dose


Meglitanides work here

Diabetes 58:4 (2009):773-795.

So, in the real world, here’s

how I do it

9/23/2014

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In general,

• Start with lifestyle modification – even before dxof pre-diabetes in people at higher risk

• Start metformin at time of dx of pre-DM or DM to preserve beta cell function, which has already dropped substantially

• Add a GLP-1 if they need weight loss

– Or a DPP-4 if they are normal wt or decline injectables

• Add TZD if not high risk for CHF, not smoker

• Add SGLT-2 or add basal insulin, later prandialinsulin

Official guidelines

American Diabetes Association – ADA

• Updated every January

• Lots of choices & lots of good info, but not much guidance re: meds

• http://professional.diabetes.org/ResourcesForProfessionals.aspx?cid=84160

American Association of Clinical Endocrinologists

• Updated 2013

• Focused on physiology

• Emphasizes therapies that don’t cause hypoglycemia &/or weight gain, which are major safety & compliance barriers

• https://www.aace.com/publications/algorithm

At diagnosis, AACE recommends

• If A1c is < 7.5%

– Start with metformin (& lifestyle, of course)

• If A1c is > 7.5%

– Start with metformin + another agent

• If A1c is > 9%

– If no sxs, start with dual- or triple-drug oral therapy

– If sxs, start with basal insulin, at least short term, till s/sx dehydration resolve, to protect kidneys

Add-on therapy should target a

different physiology issue

Diabetes 58:4 (2009):773-795.

Choose therapy for the individual

• First step is to consider contraindications• Metformin in CKD, pioglitazone in CHF, etc.

• Next, evaluate patient values & preferences• Desire / need for weight loss?

• Is hypoglycemia especially dangerous for that person?

• Fear of injections?

• Financial burden? Insurance issues?

• Age – be much more aggressive with younger pts

• Get patient “buy-in”. It helps a lot with compliance.

• Remember, each patient is the captain of their own health care team.

Choose goals of therapy

for that individual

• Based on their preferences, lifestyle, age, co-morbidities, risk factors, etc.

• A1c goals:

– Generally < 7%

– < 6.5% for healthy pts without concurrent illness

& at low risk for hypoglycemia

– < 7.5% for pts with cardiac disease, but only if you can do that with NO hypoglycemia

– < 8% for elderly, frail, with NO hypoglycemia

– Adjust goals over time to fit pt’s current situation

9/23/2014

11

The financial burden

• Brand name drugs almost always have a co-pay discount program

– www.(insert brand name here).com

• Hot competition in some classes, so can get co-pay fully paid by the pharma company

• These programs apply to non-govt-funded insurance plans (including the exchanges)

• Many pharma companies change rules for pt assistance programs for those in Medicare –D donut hole

A gift for you

www.fingertipformulary.com

• Choose the drug

• Choose your state

• Choose patient’s insurance plan (non-Medicare & Medicare plans)

• Shows you tier for that drug

• Gives link for plan’s full formulary

• Quick & easy to do in exam room

• Saves time/hassle, frustration & improves compliance

The bottom line:

• Start early in the disease process

• Be aggressive with therapy to preserve beta cell function

• Go at it from several different directions with medications

• Weight loss

• Weight loss

• Weight loss

• Close follow up

For your patients who will

only go the “natural” route

• SGLT-2s were derived from the bark of apple

trees

• Metformin was derived from the French lilac

plant

• GLP-1s were derived from saliva from lizards

• Obesity is not natural. Weight loss is good!

For the sake of completeness,

I am including the following

information on your handouts, but

will not have time to discuss this

during the presentation.

9/23/2014

12

Insulins

Actions:

• Insulin replacement therapy

• Reduces blood glucose

• Gives beta cells a rest to some extent

Dosing options:

• Vial & syringe

• Pen device

• Same price with most insurance plans

Insulin options

The preferred plan:• Long-acting basal insulins:

– glargine (Lantus), detemir (Levemir)

• Rapid-acting prandial insulins:– lispro (Humalog), aspart (NovoLog), glulisine (Apidra)

• U-500 R insulin for those severely insulin resistant (>200 u / day)– Be sure you know what you’re doing with it before prescribing U-500 – it’s a

completely different ball game & totally unlike standard Regular insulin.

Used less often, but somewhat less expensive – often gives wider & more frequent fluctuations in blood glucose levels, more hypoglycemia

• Intermediate-acting insulins – twice daily dosing:– NPH (Humulin N, Novolin N)

• Short-acting prandial insulins:– Regular (Humulin R, Novolin R)

• Fixed-dose combinations– 70/30, 75/25, 50/50, etc – very limited flexibility, more low sugars

Insulin options

Used less often, but somewhat less expensive – often causes wider & more frequent fluctuations in blood glucose levels, more hypoglycemia

• Intermediate-acting insulins – twice daily dosing:– NPH (Humulin N, Novolin N)

• Short-acting prandial insulins:– Regular (Humulin R, Novolin R)

• Fixed-dose combinations– 70/30, 75/25, 50/50, etc – very limited flexibility, more

low sugars

Insulins

Advantages:

• Works quickly

• Once-daily basal insulin may be enough

• Plays nicely with other DM meds

• Many options, much flexibility with dosing

Disadvantages:

• Injections / hassle

• Must be open to monitoring, reporting sugars, frequent dose adjustments

• Significant risk of hypoglycemia

• VERY user dependent

• Takes dexterity, other physical & cognitive abilities

• Requires ongoing patient education

Insulins

Contraindications:

• None, other than the

universal previous

allergic reaction to the

drug

Precautions:

• Severe hypoglycemia

• Reduce dose with

severe renal or hepatic

disease

Insulins work here – sort of

Diabetes 58:4 (2009):773-795.

9/23/2014

13

Tips for insulin therapy• Always inject in the abdomen, not the extremities, to

improve absorption & consistent effectiveness

• If dose is > 50 units, split into 2 smaller doses in 2 separate locations to improve absorption & effectiveness

• If on prandial insulin, don’t use a sliding scale that says no insulin if sugar is less than … at mealtime– Give a base dose, & go up a bit or down a bit depending

upon their pre-meal sugar, but they need SOME prandialinsulin at each meal

• The most accurate “generic” meter & strips are the Relion brands from Wal-Mart. Relion insulins are also a less expensive option for folks without insurance.

Alpha-glucosidase inhibitors

Advantages:

• Weight neutral

• Does not cause

hypoglycemia

Disadvantages:

• Dosed at start of each

meal

• Significant GI issues,

especially flatulance

• May cause diarrhea,

abdominal discomfort

• Potential very low risk

of liver toxicity


Actions:

• Competitively blocks the enzyme alpha-

glucosidase in brush border of small intestine

– Therefore slows breakdown of carbohydrate to

glucose & delays intestinal glucose absorption

Options:

• acarbose (Precose)

• miglitol (Glyset)


Contraindications:

• Inflammatory bowel

disease

• Hx of intestinal

obstruction or at risk

• Colonic ulceration

Precautions:


Alpha glucosidase inhibitors work in

the gut, but does not involve incretins

Diabetes 58:4 (2009):773-795.

Bile acid sequestrant

Actions:

• May reduce hepatic insulin resistance

• Therefore, reduced hepatic glucose production

• May have effect on molecular mediators of

glucose metabolism

• May reduce intestinal glucose absorption

Options:

• colesevelam (Welchol)

9/23/2014

14


Advantages:

• Not systemically absorbed

• Weight neutral

• Does not cause hypoglycemia

• Lowers LDL about 20%

• May help IBS-diarrhea predominant sxs

• Safe in CKD, CHF

Disadvantages:

• Inconvenient dosing– Either 3 big pills bid or

powder mixed with liquid daily

• Can cause constipation & abdominal bloating

• Can interfere with absorption of some nutrients & some meds, esp OCPs & antibiotics

• Can increase triglycerides


Contraindications:

• Triglyceride > 500

• Hx of bowel obstruction

• Hx of triglyceride-

induced pancreatitis

Precautions:

• Triglyceride > 300

• Multiple drug

interactions re:

interfering with

absorption


Bile acid sequestrant works in the gut

but does not involve incretins

Diabetes 58:4 (2009):773-795.

Dopamine agonist

Actions:

• Uncertain; may centrally reverse many of the

metabolic changes associated with insulin

resistance & obesity

Option:

• bromocriptine (Cycloset)

Dopamine agonist

Advantages:


• Weight neutral

• Lowers risk of CV events

Disadvantages:

• Common side effects:

– Nausea, vomiting

– Headache

– Hypotension, SYNCOPE

– Dizziness

– Fatigue

– Confusion

– Depression

– Agitation / hallucinations

Dopamine agonist

Contraindications:

• Antipsychotic use

• Severe psychotic

disorder

• Breastfeeding

• Syncope

• Use of ergot

medications

• Hypotensive

Precautions:

• If treating diabetes, use

much lower doses than

used for other reasons

• Start with 0.8 mg first

thing in the morning


9/23/2014

15

Dopamine agonist works here

Diabetes 58:4 (2009):773-795.

Amylin analog

Actions:

• Slows gastric emptying

• Therefore feeling of early satiety

• Decreases post-prandial glucagon secretion

Option:

• pramlintide (Symlin)

Amylin analog

Advantages:

• Contributes to weight

loss

Disadvantages:

• Injected prior to meals

• Hypoglycemia

• May cause nausea

Amylin analong

Contraindications:

• Hypoglycemia unawareness

• Gastroparesis

Precautions:

• if also taking insulin, reduce mealtime insulin dose by 50% to reduce risk of hypoglycemia

• Needs to be taken separated from oral meds or may impair their absorption


Amylin analog works here

Diabetes 58:4 (2009):773-795.

thursday gs 6 majewski - c.ymcdn.com€¦ · the ominous octet of type 2 diabetes per ralph a....

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