Some Things You May Be Interested In With Regard To Therapy for Type 2 Diabetes Oliver Z. Graham, MD...
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Transcript of Some Things You May Be Interested In With Regard To Therapy for Type 2 Diabetes Oliver Z. Graham, MD...
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
1414
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
26
When goal is to avoid hypoglycemia
27
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
52
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