Some Things You May Be Interested In With Regard To Therapy for Type 2 Diabetes

Oliver Z. Graham, MD

Mail-Order Endocrinologist

Department of Internal Medicine

The Agenda

Sulfonyureas, MetforminThe GLP -1 based therapies

should we use them? What about TZDs? New ADA guidelines What should target HA1c be? Target BP? New data on diet…

Glyburide…. If patient does not respond to 10

mg/day, unlikely to respond significantly to a higher dose

Maintenance doses 20 mg/day not recommended

Usually dosed once dailyNot recommended for GFR < 50 –

“Y use Glyburide?”

Glipizide…Shorter acting than glyburide – if > 15

mg/day given, divide BID prior to mealsMaximum daily dose is 40 mg/day, but

doses > 10-15 mg/day probably of little additional benefit for long term tx

Given its lower potency and shorter half life, glipizide preferable agent in elderly patients

Metformin!!Drug of choice in type 2 DMReduction HA1c about 1.5%85% of benefit seen from dose 1500

mg/day, little benefit from doses greater than 2000 mg/day

May induce modest weight lossRisk of hypoglycemia low when used as

monotherapy

How To Titrate Metformin Tell patient about the possibility of GI side

effects Begin with low dose metformin (500 mg)

taken once or twice per day with meals (before break and dinner) or 850 once daily

After 5-7 days, if GI side effects have not occurred, advance dose to 850, or two 500 mg tablets twice per day

If GI effects appear as dose advanced, decrease to previous lower dose and advance at later time

Per ADA consensus statement, 2009

Metformin and lactic acidosis Unclear exactly why metformin induces lactic

acidosis (ummm… something to do with Krebs cycle)

Occurs almost exclusively in patients with Renal, hepatic or cardiac failure Dehydration Hypoxia

Recommended to stop in hospitalized patients with “the potential to get sick” or ARF from contrast

In otherwise healthy patients, risk of LA very very low (“almost zero”)

Contraindications to Metformin Renal failure

FDA guidelines Creat > 1.4 women, >1.5 men NICE guidelines (from U.K.):

GFR 30-45: Probably safe, reduce dose by 50% GFR < 30: Not safe, stop medication

Other Contraindications (basically more RF for Lactic Acidosis) Alcoholism Heart Failure (prob safe in stable, well

compensated disease) Liver disease Decreased tissue perfusion or hemodynamic

instability

Weight Changes Associated with Anti-Hyperglycemic Therapies for Type 2 Diabetes

ADA Scientific Meeting 2005 ABS 13-or

Insulin tx 4 lb increase for every 1% A1c reduction!!

GLP-1:A novel approach to DM tx

GLP - 1: a gut hormone that is secreted in gut in response to eating food Slow gastric emptying Inhibits postprandial glucagon secretion Reduction food intake Enhance insulin secretion Very rapidly degraded in body (2 min)

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GLP –1 based therapies: Exenatide and Sitagliptin (Byetta and Januvia)

Clinical problem: GLP-1 very rapidly degraded in body

SOLUTIONS:Develop drug that mimics GLP-1 but degrades slower

(derived from gila monster saliva) Exenatide (Byetta): dosed bid or once weekly Liraglutide (Victoza): dosed once daily

Develop drug that inhibits GLP-1 degradation Sitagliptin (Januvia): Inhibits GLP -1 degradation

No weight gain!

Why use Exenatide/liraglitude (Byetta/Victoza)?

Most patients gain weight with DM tx

With Byetta WEIGHT LOSS 12 pound loss at 2 years tx

A1c reduction about 1.1%? Animal studies suggest beta cell

regeneration

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Why not use Exenatide/liraglitude (Byetta/Victoza)?

Expensive (1 year -- $2700) Long term data not available (lessons from

Avandia & Rezulin…) Possible association with necrotizing pancreatitis Black box warning: in rats associated with

malignant thyroid c cell tumors

Nausea very common (50-60%) Because slows gastric emptying

CONTRAINDICATED in GASTROPARESIS Has to given as injection

Who might get Byetta/Victoza?Obese patients not at A1C targetNow approved to given with insulin?used in severe insulin resistance

syndromes?

Sitagliptin (Januvia) Reduction HA1c 0.5-0.8 Weight neutral, well tolerated Long term safety not established Relatively expensive No hypoglycemia when used as monotherapy Think about using it in:

Patients with contraind to SU/Metformin (eg Januvia safe in renal failure)

Patients who in whom hypoglycemia bad (elderly) Add on therapy in which you need marginal HA1c

reduction

What about Thiazolidinediones? (TZD) 0.5 – 1.4 reduction in HA1c Weight gain 5-12 lbs at 1 year Edema 4-30% 2 fold increase in CHF Increase fracture rate, decrease BMD in women (per

scottish study accounts for 17% all hip fx) Trioglitazone (Rezulin) – taken off market because of

risk of life threatening hepatotoxicity Rosigliazone (Avandia) – taken off market given

possible 30-40% increased risk MI per meta-analysis Pioglitazone (Actos) – only agent left in US

Consider use as “add on drug” to avoid Insulin in selected cases

Drug Cost Comparison (per month)

Drug and Dose Cost/mo

Glucose Strips (2 per day) $60

Sulfonylurea Generic $4-14Brand $50

Rapaglinide 2 mg tid $175Acarbose 100 mg tid $88Metformin 1000 bid Generic $ 4-32

Brand $132Rosiglitazone 8 mg qd $223Pioglitazone 45 mg/d $222Sitagliptin $181Exenatide 5mcg $230

10mcg $255Glargine, 45 U/d $150

24 hour fitness center $44YMCA $60

When to continue oral therapy when on insulin – a general recommendation (but not set in stone)

Start basal insulin stop TZD, but consider continue the SU, continue Metformin Better glycemic control with less insulin

requirements, weight gain, hypoglycemiaStart premeal insulin stop SU,

JanuviaContinue Metformin forever until pt

develops contraindications

Generic Oral Hypoglycemic Slide

HgA1c

Time

Change from Drug A to B, C, or D

Add Drug A to B, or B to A

Add Drug C

Add Drug D

Diabetes Care. Published online Oct 22, 2008

2009 ADA Type 2 Consensus Statement Diabetes Treatment Algorithm

An American Diabetes Association consensus statement represents the authors’ collective analysis, evaluation, and opinion at the time of publication and does not represent official association opinion.

Antihyperglycemic therapy in type 2 diabetes: general recommendations.

Inzucchi S E et al. Dia Care 2012;35:1364-1379

Copyright © 2011 American Diabetes Association, Inc.

When Goal is to Avoid Weight Gain

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When goal is to avoid hypoglycemia

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When goal is to minimize costs

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Sequential insulin strategies in type 2 diabetes.

Inzucchi S E et al. Dia Care 2012;35:1364-1379

Copyright © 2011 American Diabetes Association, Inc.

A case study A 64 YO man with Type 2 DM comes in to see

you for his first visit. Meds: Nifedipine, ASA, lovastatin, metoprolol,

70/30 insulin BID PMH: DM 2 dx 15 years ago

+ Diabetic Retinopathy Creatinine 2.3, 1.4 g/dl protein/day

PE BP 167/94, BMI 36 HA1C 8.3 LDL 145

What is your target HA1c?What is your target BP and LDL?

Some big DM studies you may be familiar withRecent trials that evaluated HA1c with

focus on cardiovascular mortality ACCORD, ADVANCE, VA Diabetes

Prior trials that evaluated HA1c with less stringent HA1c goals mostly that demonstrated improvement in microvascular complications DCCT (Type 1 DM), UKPDS (Type 2)

The ACCORD Trial (2008)10,251 patients x 3.5 years (terminated

early) Inclusion criteria: H/O CVD event or

significant CVD riskAverage 62 years oldBaseline HA1c 8.1Achieved Median HA1c 6.4 (intensive)

vs 7.5 (control)

ACCORD TRIALOutcomes

Primary outcome (MI, stroke, CV Death) reduced in intensive Glycemic group (not statisticallySignificant)BUT:Significant increase in all cause death and CVD disease!(1.41 vs 1.14% per year257 vs. 203 deaths over 3.5 yrsHR 1.22)

Why did more people die in with intensive glucose control in ACCORD?

No one really knows ? Severe hypoglycemia increased risk of

CV death ? Weight gain ? Med interactions ? Rapid reduction of HA1c by 2%

ADVANCE Trial (2008) 11,140 Patients x 5 years History of major or microvascular disease or

at least one other RF for vascular disease Average age 66, baseline HA1c 7.2 Median HA1c 6.3 (intensive) vs 7.0 (control) No difference in overall mortality or

macrovascular events Most significant finding: reduced

development of macroalbuminuria

VADT - Veterans Administration Diabetes Trial

•1742 Enrollees•97% male•Mean age 60.4

•BMI 31.3•Majority had multiple CV risk factors

•72% HTN•40% macrovascular dx•62% retinopathy•43% neuropathy

VADT - Veterans Administration Diabetes Trial

Primary Endpoint: NO DIFFERENCE IN CARDIOVASCULAR DISEASE OUTCOMES, but overall LESS PATIENTS DIED THAN PREDICTED Standard: 29.3% (predicted – 40%) Intensive: 27.4% (predicted – 31.6%)

Why was mortality better than expected?

Probable answer: Statin, ASA, really good BP control

So what does this all mean? Based on ACCORD, ADVANCE, VA trial no

clear evidence aggressive reduction HA1c results in improvement mortality or macrovascular complications at 3-5 years

BUT --- Recent data from UKPDS (10 years followup) suggest long term reduction in MI with improved glycemic control

Very clear correlation between reducing microvascular events and improved glycemic control DCCT trial: Getting HA1c from 9% to 7% resulted

in 60% reduction in retinopathy, nephropathy and neuropathy at 6.5 years

Suggested Goals for Glycemic Treatment in Patients with Type 2 Diabetes.

Ismail-Beigi F. N Engl J Med 2012;366:1319-1327.

So just tell me what to do! Target HA1c < 7% for the majority Consider a lower HA1c (< 6.5) in younger,

healthier, newly diagnosed patients Higher target HA1c if life expectancy < 5

years, severe hypoglycemia, advanced microvascular or macrovascular complications, other significant co-morbid conditions

Aggressive tx with ASA, statin, and BP control

ADA consensus statement, 2009

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Feel proud of any HgA1c reduction

From “horrible control” to “poor control” – pat yourself on the back!!

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To really make a difference, go beyond the HA1cDon’t forget about BP control, Statin

use and ASA!

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But what BP to target? Trials clearly show improvement mortality/morbidity with SBP <

140 Trials to eval SBP < 120-130:

Normotensive ABCD: No improvement mortality, but modest improvement

retinopathy, albuminuria SANDS trial:

No improvement mortality, but modest regression LVH ACCORD BP trial:

Reduction CVA (absolute benefit 1 in 89 pts at 5 yrs) No change in mortality or composite end point More adverse effects (increase creat, hypotension,

syncope etc) in lower bp group

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ADA Guideline 2013, BP ControlAll DM patients Target BP < 140/80 In select groups, consider SBP < 130

Highly motivated patients, if can be done without significant side effects

Significant protienuria (> 500 mg - 1 g protien excretion/day)*

High risk for cardiovascular events or established vascular disease*

*(not really ADA recs, but recs of other authors/societies)

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(except ACE/ARB in proteinuria)

Primary Prevention of Cardiovascular Disease with a Mediterranean DietInclusion Criteria:

either type 2 diabetes mellitus or at least three of the following major risk factors: smoking, hypertension, elevated low-density lipoprotein cholesterol levels, low high-density lipoprotein cholesterol levels, overweight or obesity, or a family history of premature coronary heart disease

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Summary of Dietary Recommendations to Participants in the Mediterranean-Diet Groups and the Control-Diet Group.

Estruch R et al. N Engl J Med 2013;368:1279-1290.

Kaplan–Meier Estimates of the Incidence of Outcome Events in the Total Study Population.

Estruch R et al. N Engl J Med 2013;368:1279-1290.

30% reductionIn majorCardiovascularEvents!

Pharmacologic Agents for Glycemic Control in Patients with Type 2 Diabetes.

Ismail-Beigi F. N Engl J Med 2012;366:1319-1327.

Start onsulfonylurea or

insulin

TYPE 2 DIABETES

SYMPTOMATICAnd very highNO YES

Referral for:•Diet•HGM•Exercise•Foot Care

Goal Met

Start Metformin

Referral for:•Diet•HGM•Sick Day Rules•Exercise (+/- EST)•Foot Care

NO

Continue Current TreatmentAdd

Medication

YESConsidertransitionto metformin

Robert Rushakoff’s approach, UCSF

TYPE 2 DIABETES

Metformin

OBESE THIN

Exenatide Sulfonylurea

Add Sulfonylurea

(consider TZD)

•Start insulin – use pens•Add detemir, glargine or PM NPH (isolated fasting hyperglycemia or insurance)•? of which existing meds to continue, generally all •Change to bid premixed insulin •? of which existing meds to continue, generally just metformin•Change to basal and with premeal insulin•? of which existing meds to continue, generally just metformin

Goal Not Met

Sitagliptin

Thin or no injection

Sitagliptin(consider TZD)

Goal Not Met

Add Sulfonylurea(consider TZD)

Goal Not Met

Goal Not Met

Robert Rushakoff’s approach, UCSF