7RushakoffInsulin - Continuing Medical Education - UCSF … · • OHA -- retrospective analysis: ... glulisine 0.25 0.5-1.5 3-5 Regular 0.5 2-5 6-8 Intermediate-acting NPH 1-2 4-12

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Type 2 Diabetes – Use of Insulin

Robert J. Rushakoff, MD Professor of Medicine

University of California, San Francisco

[email protected]

Today

  Quick Year in Review   Why do some patients need to take

insulin   Insulin Basics   Studies on Use of Insulin   Actual Use of Insulin

Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study

Lancet. 2010. 375:481-489 Hazard ratios for progression to first large-vessel disease event by HbA1c

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CVD Intervention Studies

 ADVANCE  ACCORD  VA

ACCORD: Action to Control Cardiovascular Risk in Diabetes

  10,251 Enrollees   60% male 40%

female   Mean age 62.2   Baseline HgA1c

8.1%   BMI - 32

  30% macrovascular dx

  Duration DM: 10 years

  Majority of intensive group on 3-5 oral agents plus insulin

  Hypoglycemia 3 times greater in intensive group

The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559

Primary and Secondary Outcomes

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ACCORD: Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups

The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559

Diabetes Care May 2010 vol. 33 no. 5 983-990

Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial

Diabetes Care May 2010 vol. 33 no. 5 983-990

Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial

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The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001286

Mean Systolic Blood-Pressure Levels at Each Study Visit

Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus


Lipid Values

Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus

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Effects of Intensive Blood-Pressure Control and Combination Lipid Therapy in Type 2 Diabetes Mellitus

Kaplan-Meier Analysis of Primary Outcome in the ACCORD Study


“The interpretation of the ACCORD BP results is

complicated by the fact that the event rate observed in the

standard-therapy group was almost 50% lower than the

expected rate.”


Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus


Hazard Ratios for the Primary Outcome in Prespecified Subgroups

Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus

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Metformin and B12 •  Decrease in vitamin

B12 levels. (decreased 4.2-47%)

•  Metformin is thought to induce malabsorption of vitamin B12 and intrinsic factor in the ileum, an effect that can be reversed by increased calcium intake.

Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomized

placebo controlled trial

BMJ 2010;340:c2181

Metformin and B12 •  Anemia may be

minimal to severe

•  may present only as a peripheral neuropathy, possibly being misdiagnosed as diabetic neuropathy.

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Incretin Drugs   GLP Agonists

  Exenatide   Liraglutide   Semaglutide   Albiglutide   Taspoglutide   Exenatide Lar   Lixsenatide

  DPP 4 Inhibitors   Vildagliptin   Sitagliptin   Saxagliptin   Alogliptin   Linagliptin   Dutogliptin   metogliptin

Liraglutide •  Administer once daily at any time of day, independently of meals

•  Inject subcutaneously in the abdomen, thigh or upper arm.

•  The injection site and timing can be changed without dose adjustment

•  Initiate at 0.6 mg per day for one week. This dose is intended to reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic control. After one week, increase the dose to 1.2 mg. If the 1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg.

•  When initiating liraglutide, consider reducing the dose of concomitantly-administered insulin secretagogues to reduce the risk of hypoglycemia

Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)

Lancet. 2009 374: 39-47

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Diabetic Patients’ Medication Underuse, Illness Outcomes, and Beliefs About Antihyperglycemic and

Antihypertensive Treatments

•  Perceived need for antihyperglycemic medication was associated with being younger, being prescribed insulin, and being prescribed multiple medications.

•  Concern about antihyperglycemic medications was associated with being younger, African American, dissatisfied with information received about medication, and of low health literacy

Diabetes Care January 2009 32 19-24

Medication Adherence •  OHA -- retrospective analysis:

–  36-93% remain on treatment for 6-24 months. –  Prospective electronic monitoring – 67-85% to as

prescribed. –  Insulin adherence in type 2 was 62-64%.

Diabetes Care 27:1218-1224, 2004

•  Patients with Type 2 DM who do not obtain at least 80% of their oral antihyperglycemic medications across 1 year are at a higher risk of hospitalization in the following year.

Diabetes Care 27:2149-2153, 2004.

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Medication Adherence Problems Paying Out-of Pocket Medication Costs

Among Older Adults with Diabetes •  In past year:

–  19% cut back on medication for cost –  11% cut back on DM meds –  7% cut back at least once per month –  28% reported forgoing food or other essentials to pay

medication costs

Diabetes Care 27:384-391, 2004

What does this mean? Why is it occurring?

  Changing goals   Compliance

 Wrong diagnosis   Problem with oral hypoglycemic agent   Natural progression of disease

Type 2 Diabetes: What to do when the pills don’t work

Latent Autoimmune Diabetes In Adults

  Patients usually aged > 25   Clinical presentation “masquerading” as

nonobese type 2 diabetes   Initial control achieved with diet alone

or diet and oral hypoglycemic agents   Insulin dependency occurs within

months but can take 10 years

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Latent Autoimmune Diabetes In Adults

  Other features of type 1 diabetes:   Low fasting and postglucagon stimulated

C-peptide   HLA susceptibility alleles   ICA +   Anti-GAD +

Newly Diagnoses type 2 diabetics in UKPDS

ICA 6% Anti GAD 10% both 4%


  Changing goals   Compliance   Wrong diagnosis

 Problem with oral hypoglycemic agent

  Natural progression of disease


Metformin and eGFR •  186 x (Creat / 88.4)-1.154 x (Age)-0.203 x (0.742 if female) x

(1.210 if black) •  Current Guidelines call for discontinuation of Metformin

serum creatinine >150 umol/l (1.7 mg/dl). •  Estimated GFR (eGFR) being introduced as possible

better measure of renal function than serum creatinine alone

•  eGFR of 36 ml/min per 1.73m2 would be somewhat neutral to current use

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  Changing goals   Compliance   Wrong diagnosis   Problem with oral hypoglycemic agent

 Natural progression of disease


Conventional Therapies Do Not Influence β-Cell Failure: UKPDS

UKPDS 34. Lancet 1998; 352: 854-865!UKPDS 16: Diabetes 1995; 44: 1249-1258!

cohort, median values!0!6!

7!

8!

9!

10!

-1! 0! 2! 4! 6! 8! 10!Years from randomization!

Chlorpropamide!Conventional!Glibenclamide!Insulin! Metformin!

HbA

1c(%

)!

0!20!40!60!80!

100!

0! 1! 2! 3! 4! 5! 6! 7!

ß ce

ll fu

nctio

n (%

)!

0!20!40!60!80!100!

0! 1! 2! 3! 4! 5! 6! 7!

ß ce

ll fu

nctio

n (%

)!

Years from randomization!Conventional! Sulphonylurea! Metformin!

Overweight!Non-Overweight!Overweight!

Insulins Available in the US

Types and Preparations

Action profile (h) Onset Peak Duration

Rapid-acting Lispro/aspart/ glulisine 0.25 0.5-1.5 3-5 Regular 0.5 2-5 6-8

Intermediate-acting NPH 1-2 4-12 18-26 U-500 1-3 6-12 12-18

Long-acting Glargine 1.5 ---- 24 Detemir 1 ---- 23

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Insulin: Use and Adjustments

Types and Preparations

Timing Injection Glucose check

Rapid-acting Lispro/aspart/ 10 min premeal 2 hour post meal glulisine and before next meal Regular 30 min premeal before next meal

Intermediate-acting NPH Morning Pre-dinner Night Fasting

Long-acting Glargine/detemir PM Fasting

Insulin Basics   Storage

  Current vial - room temperature   Stored vials - refrigerate

  Mixing   Clear short acting insulin (regular or lispro/

aspart) added to syringe first   Glargine, detemir – not mixed at all

Insulin Basics

  Injection Sites   Classic: Upper arms, thighs, abdomen   Regular: best in abdomen - most

reproducible   Intermediate: best in abdomen and thighs   Analogues: equal throughout

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Insulin and Glucose Patterns

Polonsky, et al. N Engl J Med. 1988;318:1231-1239.

100

200

300

400 Glucose Insulin

0600 1000 1800 1400 0200 2200 0600

Time of Day

0600 1000 1800 1400 0200 2200 0600

Time of Day

20 40 60 80

100 120

B L S B L S

Normal

mg/

dL

µU

/mL

Relative Insulin Level

Time

Breakfast 12pm Lunch Dinner

Insulin Regimens


Time

Breakfast 12pm

AM NPH

Lunch Dinner

Insulin Regimens

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Time

Breakfast

PM NPH

Lunch Dinner

NPH

12pm

Insulin Regimens

Profiles of glucose over 24 hours both before (broken line) and after (solid line) treatment of a group of individuals with type 2 diabetes with a single injection of neutral protamine Hagedorn

insulin at bedtime titrated to control fasting glucose. The glucose curve is shifted downward, with nearly normal fasting levels

achieved but also with persistence of postprandial increments

Diabetes Care 18 (1995), pp. 843–851


Time

Breakfast

BID NPH

Lunch Dinner

NPH

12pm

Insulin Regimens

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Time

Breakfast

BID R and NPH

Lunch Dinner

NPH

regular

12pm

Insulin Regimens


Time

Breakfast

BID R and NPH

Lunch Dinner

NPH

regular

12pm

Insulin Regimens


Time

Breakfast

TID R and hs NPH

Lunch Dinner

NPH

regular

12pm

Insulin Regimens

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Time

Breakfast

BID lispro/aspart

Lunch Dinner

Long analogue

12pm

Lispro/aspart

Insulin Regimens


Time

Breakfast

TID lispro/aspart/glulisine and hs NPH

Lunch Dinner

NPH

Lispro/aspart/glulisine

12pm

Insulin Regimens

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Time

Breakfast

TID lispro/aspart/glulisine and bid NPH

Lunch Dinner

NPH


12pm

Insulin Regimens


Time

Breakfast 12pm

PM glargine

Lunch Dinner

glargine

Insulin Regimens

Correcting Fasting Hyperglycemia…

100

200

300

Normal A1C 5%–6%

PG

(m

g/

dL)

0800 1200 1800 0800

Time of Day

Uncontrolled A1C ~9%

A1C ~6%

“Controlled” A1C <7%

Adapted with permission from Cefalu WT. In: Leahy J, Cefalu W, eds. Insulin Therapy. New York: Marcel Dekker; 2002:1

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Time

Breakfast

TID lispro/aspart/glulisine and hs glargine

Lunch Dinner 12pm

glargine


Insulin Regimens


Time

Breakfast

Insulin pump

Lunch Dinner 12pm


Insulin Regimens

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Holman R et al. N Engl J Med 2009;361:1736-1747

Three-year efficacy of complex insulin regimens in type 2 diabetes.


Changes from Baseline to 3 Years in Glycated Hemoglobin,

Fasting Plasma Glucose, Postprandial Glucose, and Body

Weight and the Rate of Hypoglycemia

Three-year efficacy of

complex insulin regimens in

type 2 diabetes.

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Three-year efficacy of complex insulin regimens in type 2 diabetes.

Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30

(The 1-2-3 study)

Diabetes Obes Metab. 2006 Jan;8(1):58-66.


(The 1-2-3 study)


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(The 1-2-3 study)


Advancing Insulin Therapy in Type 2 Diabetes Previously

Treated With Glargine Plus Oral Agents

Prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/

lispro) therapy

Diabetes Care 2008 vol. 31 20-25

Daily Insulin Dose

Entry Conclusion

BBT 55 ± 28 units [0.6 ± 0.3 units/kg]

146 ± 85 units [1.4 ± 0.8 units/kg]

PPT 52 ± 24 units [0.5 ± 0.2 units/kg]

123 ± 69 units [1.2 ± 0.5 units/kg]

Insulin Therapy in Type 2 Diabetes: What is the evidence

Mariëlle J. P van Avendonk and Guy E. H. M Rutten

Diabetes, Obesity and Metabolism.

2009. epub.

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Insulin Therapy in Type 2 Diabetes: Bottom Line

 Basal Insulin  Premixed Insulin  Basal Bolus


  Basal Insulin   Continuing metformin and/or sulphonylurea after start

of therapy with basal long-acting insulin results in better glycemic control with less insulin requirements, less weight gain and less hypoglycemic events.

  Long-acting insulin analogues in combination with oral medication are associated with similar glycemic control but fewer hypoglycemic episodes compared with NPH insulin.


  Premixed Insulin   Most of the trials demonstrated better glycemic

control with premix insulin therapy than with a long-acting insulin once daily, but premix insulin causes more hypoglycemic episodes.

  Analogue premix provides similar HbA1c, but lower postprandial glucose levels compared with human premix, without increase in hypoglycemic events or weight gain.

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  Basal Bolus   Drawing conclusions from the limited

number of studies concerning basal-bolus regimen seems not possible. Some studies showed that rapid-acting insulin analogues frequently result in a better HbA1c or postprandial glucose without increase of hypoglycemia than regular human insulin.


  A once-daily basal insulin regimen added to oral medication is an ideal starting point. All next steps, from one to two or even more injections per day should be taken very carefully and in thorough deliberation with the patient, who has to comply with such a regimen for many years

Starting Insulin–Patient Barriers

  Using insulin as a threat   Fear of injections   Weight gain   Insulin meaning they have bad diabetes

and now will get complications or die   Worsening of atherosclerosis   Patient leaves and does not come back

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Starting Insulin

  Home glucose Monitoring   Reinforce basic diet   Discuss reasons that the oral agents are

no longer adequate to control their diabetes

  Teach insulin techniques

Starting Insulin Not at goal on Sulfonylurea, Metformin,

Thiazolidinedione, DPP 4 inhib, and/or GLP angonist

  Option 1: Start am or hs glargine or hs detemir   Start at about 10 Units   Titrate up by 2-8 units every 5-7 days

based on fasting glucose level.   ? Which other drugs to continue

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When to go to > 1 shot per day   HgA1c >7 or your goal

  Morning or evening glucose remains > 140 mg/dl

Options

 Split the glargine or detemir   Glucose in AM at goal; Glucose before dinner >140 (pm shot)

  Glucose in PM at goal; Glucose in AM >140 (am shot)

  Add premeal lispro/aspart/glulisine

  Change to bid premixed insulin – 70/30, 75/25

Questions

  DC sulfonylurea

  Continue metformin

 ? Thiazolidinedione

Insulin Name First Component

Second Component

Component Ratio

First:Second

Humulin 70/30 Human NPH Human Regular 70:30

Humalog 50/50 lispro protamine lispro 50:50

Humalog 75/25 lispro protamine lispro 75:25

Novolin 70/30 Human NPH Human Regular 70:30

Novolog 70/30 aspart protamine aspart 70:30

Premixed Insulins

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Starting Insulin Patient on Sulfonylurea, Metformin and

Thiazolidinedione

  Option 2: Start bid insulin – pre mixed   Start at about 20 U am, 10 U pm   Titrate up by 2-8 units every 5-7 days based on

fasting and pre dinner glucose levels.   DC of sulfonylurea. Continue metformin, ??

Thiazolidinedione

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A1c Control in a Primary Care Setting: Self-titrating an Insulin Analog Pre-mix (INITIATEplus Trial)

Am J Med 2009 11;122(11):1043-9

A1c Control in a Primary Care Setting: Self-titrating an Insulin Analog Pre-mix (INITIATEplus Trial)

Am J Med 2009 11;122(11):1043-9

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Adjust to Target in Type

2 Diabetes: Comparison of

a simple algorithm with carbohydrate counting for

adjustment of mealtime

insulin glulisine

Diabetes Care 2008. 31.1305-1310 Diabetes Care 2008. 31.1305-1310

Diabetes Care 2008. 31.1305-1310

Adjust to Target in Type 2 Diabetes: Comparison of a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine

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Amylin

37-amino acid β-cell hormone that is co-secreted with insulin in response to meals

Acts as a neuroendocrine hormone that binds to specific receptors in the hindbrain, including area postrema

Has both glucoregulatory and anorexigenic actions •  decreases the rate of gastric emptying •  suppresses hepatic glucose output by inhibiting glucagon secretion

Anti-obesity effects in diet-induced obese (DIO) rodents: •  Reductions in food intake •  Reductions in body fat, with preservation of lean mass

Pramlintide: Soluble Analog of Human Amylin

Adapted from Weyer C, et al. Curr Pharm Des 2001; 7:1353-73. Mack C, et al. Diabetes 2003; 52: A389. Schmitz O, et al. Diabetes 2004; 53:S233-S2381.

Human amylin

Amide S S A Y

T N S

G V N

T

T T T

N

A A A

L I

K S

S C

C Q R

L N

N N F

G

F L

V H

Pramlintide or Mealtime Insulin Added to Basal Insulin Treatment for Patients With Type 2

Diabetes

Diabetes Care 2009 32:1577-1582

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DIGAMI2 (European Heart J. Prepublication Feb 2005)

 Group 1 – IV insulin then long term SQ insulin  Group 2 – IV insulin then standard treatment  Group 3 – Standard treatment

Mortality

Effect of different updated glucose lowering treatments on mortality and morbidity

Mellbin, L. G. et al. Eur Heart J 2008 29:166-176

Insulin Treatment and Risk of Cancer 1. Hemkens LG, Grouven U, Bender R et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009;52:1732-44. 2. Jonasson JM, Ljung R, Talbäck M, Haglund B, Gudbjörnsdòttir S, Steineck G. Insulin glargine use and short-term incidence of alignancies—a population based follow-up study in Sweden. Diabetologia 2009;52:1745- 4. 3. Currie CJ, Poole CD, Gale EAM. The influence of glucose lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009;52:1766–77. 4. Colhoun HM, SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009;52:1755-65.

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Insulin Treatment and Risk of Cancer

  Four studies   Studies involve convoluted statistical

manipulation of epidemiologic data   There are fundamental internal

disagreements and multiple inconsistencies.

Does Diabetes Therapy Influence the Risk of Cancer?

● German study1: N=127,031 –  Glargine vs human insulin - a decrease in all cancers with

Glargine

–  After adjusting for dose, a dose-dependent increase in cancer risk was found for treatment with glargine compared with human insulin (P<.0001): the adjusted HR was 1.09 for a daily dose of 10 IU, 1.19 for 30 IU, and 1.31 for 50 IU

–  No increased risk was found for aspart or lispro compared with human insulin

–  did not take into account body mass index and the duration of time that the patients were on insulin.

–  time on insulin was very short, only about 1.6 years, 1.  Hemkens LG, et al. Diabetologia. 2009. doi:10.1007/s00125-009-1418-4.


●  Swedish study1: N=114,841

– No statistically significant difference in cancer incidence between patients on insulins other than glargine, and those on glargine plus other insulins

– Women on glargine alone, however, had a higher risk of breast cancer than those on insulins other than glargine, with an RR of 1.99

4 Large Observational Studies

1.  Jonasson JM, et al. Diabetologia. 2009. doi:10.1007/s00125-009-1444-2.

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●  Swedish study1: N=114,841

• In Sweden, an increased risk of breast cancer was reported only in women who used glargine insulin alone, but not in those women who used glargine insulin plus other types of insulin


1.  Jonasson JM, et al. Diabetologia. 2009. doi:10.1007/s00125-009-1444-2.

Does Diabetes Therapy Influence the Risk of Cancer? (cont)

●  Scottish study1: N=49,197

–  Glargine with rapid-acting insulin had a slightly lower rate of cancer progression than did human insulin (HR 0.8, P<.26), but glargine alone had a higher overall rate (HR 1.55, P=.045)

–  The number of site-specific cancers was small, but more cases of breast cancer were noted with glargine alone, compared with nonglargine insulins (HR 3.39, P=.004)


1.  Colhoun HM; for the SDRN Epidemiology Group. Diabetologia. 2009. doi:10.1007/s00125-009-1453-1.


●  Scottish study1: N=49,197

– Glargine – overall, no increase in cancer

– Breast Cancer – no increase for all glargine users

– Breast Cancer - Increase for glargine only - only 6 cases


1.  Colhoun HM; for the SDRN Epidemiology Group. Diabetologia. 2009. doi:10.1007/s00125-009-1453-1.

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●  UK study1: N=62,809

–  Metformin monotherapy carried the lowest risk of cancer; adjusted HR was 1.08 for metformin + sulfonylurea, 1.36 for sulfonylurea monotherapy, and 1.42 for insulin-based regimens; adding metformin to insulin reduced progression to cancer (HR 0.54); risk for patients on basal human insulin alone vs glargine was 1.24

–  Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69) or pancreatic cancer (HR 4.63) but did not influence the risk of breast or prostate cancer; sulfonylureas were associated with a similar pattern of risk as insulin


1.  Currie CJ, et al. Diabetologia. 2009. doi:10.1007/s00125-009-1440-6.

Insulin Treatment and Risk of Cancer

  Many types of cancer are increased in diabetic patients

  Recent retrospective observational studies suggest that long-acting insulin analog glargine may increase and that biguanide metformin may decrease cancer risk

  The evidence provided by these studies is weak and disputable because of many experiment and analysis limitations. Therefore it is possible neither to confirm nor to exclude the effect of these drugs on cancer in diabetic patients.

  While waiting for more careful studies we have no evidence-based rationale for changing treatment approach to diabetic patients

Drug Cost Comparison Drug and Dose Cost/month

Glucose Strips (2 per day) $66

Sulfonylurea Generic $4-14 Brand $50

Rapaglinide 2 mg tid/nateglinide 120 tid $193/164 Acarbose 100 mg tid $88 Metformin 1000 bid Generic $ 4-32

Brand $161 Rosiglitazone 8 mg qd $266 Pioglitazone 45 mg/d $245 Sitagliptin/Saxagliptin $207/190 Exenatide 10mcg /Liraglutide 1.2mg $271/280 Colesevelam 3750 mg/d $224 Bromocriptine 2.5-5mg $62-130 Glargine, 45 U/d /(pen) $150/182 Salsalate 4g/d $50

24 hour fitness center $35 YMCA $65

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Drug Cost Comparison Drug and Dose Cost/month

Glucose Strips (2 per day) $66

Sulfonylurea Generic $4-14 Brand $50

Rapaglinide 2 mg tid/nateglinide 120 tid $193/164 Acarbose 100 mg tid $88 Metformin 1000 bid Generic $ 4-32

Brand $161 Rosiglitazone 8 mg qd $266 Pioglitazone 45 mg/d $245 Sitagliptin/Saxagliptin $207/190 Exenatide 10mcg /Liraglutide 1.2mg $271/280 Colesevelam 3750 mg/d $224 Bromocriptine 2.5-5mg $62-130 Glargine, 45 U/d /(pen) $150/182 Salsalate 4g/d $50

24 hour fitness center $35 YMCA $65

Glargine (45 units/d), metformin, glimepiride 1-2 checks per day $226

Glargine (45 units/d), metformin, glimepiride Exenatide (10 bid) 1-2 checks per day $497

Glargine (45 units/d), metformin, glimepiride symlin 1-2 checks per day $537

Novolog 70/30 (80 Units/d), metformin 2 checks per day $423

Glargine (45 units/d), Lispro 50 units/d, Metformin 4 checks per day $507

Metformin, glimepiride, pioglitazone Sitagliptin 1-2 checks per day $526

Documents

7RushakoffInsulin - Continuing Medical Education - UCSF … · • OHA -- retrospective analysis: ... glulisine 0.25 0.5-1.5 3-5 Regular 0.5 2-5 6-8 Intermediate-acting NPH 1-2 4-12