Whats New in Type 2 Diabetes? Lots! C. Wayne Weart, Pharm.D. South Carolina College of Pharmacy MUSC Campus MUSC Department of Family Medicine January

What’s New in Type 2 Diabetes? Lots!

C. Wayne Weart, Pharm.D.South Carolina College of Pharmacy

MUSC CampusMUSC Department of Family Medicine

January 2012

Faculty Disclosure

• I am on the speakers bureau for Pfizer in the area of lipids and pain

• I am a consultant for Merck in the area of outcomes research

Diabetes and Obesity

• - Centers for Disease Control and Prevention survey on the prevalence of Type 2 diabetes from 1990 to 1998 in the US (Diabetes Care 2000; 23: 1278-83).

• -prevalence of diagnosed diabetes increased by 33% nationally, with a 70% increase in individuals aged 30 to 39

• -primarily related to the upsurge in obesity

BMI=body mass index.

DPP Research Group. N Engl J Med. 2002;346:393-403.

Diabetes Prevention Program: Study Design• Entry Criteria

– age 25 years

– BMI 24 kg/m2 (22 kg/m2 in Asians)

– fasting plasma glucose 95-125 mg/dL

– postglucose challenge 140-199 mg/dL

• Intervention– standard lifestyle recommendations + placebo twice daily

– standard lifestyle recommendations + metformin titrated to 850 mg twice daily

– intensive lifestyle modification (low-calorie/low-fat diet, moderate physical activity 150 min/wk)

– troglitazone (later withdrawn)

• Outcome– type 2 diabetes over average follow-up of 2.8 years

®

© 2002 Thomson Professional Postgraduate Services®

www.lipidhealth.org

Diabetes Prevention Program

• 3.2%ARR Placebo vs. Metformin NNT 32• 6.2%ARR Placebo vs. Lifestyle NNT 16• Recent analysis of DPP data found that the

lifestyle intervention group delayed the development of Type 2 diabetes by about 11 years with the metformin group delayed by about 3 years

• Cost per quality adjusted life year $1,100 and $31,300 respectively

• Annals of Intern Med 2005;142:323-332

Walking and Mortality in US Adults with DM

Arch Intern Med. 2003;163:1397-1398

• Editorial by Frank Hu from Harvard

• “So far, walking is probably the “best medicine” for both the prevention and treatment of diabetes mellitus.”

ADA: Physical Activity/Exercise Recommendations for Patients With

Type 2 Diabetes

2010 ADA Update2010 ADA Update

•• Revision of the section Revision of the section "Diagnosis of "Diagnosis of Diabetes"Diabetes" now includes the use of the now includes the use of the A1cA1c level for diabetes diagnosis, with a cutoff level for diabetes diagnosis, with a cutoff point of point of 6.5%.6.5%.

•• The section formerly named "Diagnosis of The section formerly named "Diagnosis of Pre-diabetes" is now named Pre-diabetes" is now named "Categories of "Categories of Increased Risk for Diabetes."Increased Risk for Diabetes." Categories Categories suggesting an increased risk for future suggesting an increased risk for future diabetes now include an diabetes now include an A1c range of 5.7% to A1c range of 5.7% to 6.4%,6.4%, as well as impaired fasting glucose and as well as impaired fasting glucose and impaired glucose tolerance levels.impaired glucose tolerance levels.

Diabetes Care 2010;33 Suppl. 1

ADA and ACE Glycemic Goals

American Diabetes Association. Diabetes Care. 2012;35 Suppl 1 AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13:(suppl 1)3–68.

6.5 <7<6Hemoglobin A1c (%)

140<180<140Postprandial plasmaglucose (mg/dL)

11070–130<100Fasting/preprandialplasma glucose(mg/dL)

TargetGoalNormalBiochemical Index

AACE/ACEADA 2012

Development and Progression of Type 2 Diabetes(Conceptual Representation)

RelativeActivity

Glucose

Years from Diabetes Diagnosis–10 –5 0 5 10 15 20 25 30

-10 -5 0 5 10 15 20 25 30

NGT=normal glucose tolerance; IGT=impaired glucose tolerance; IFG=impaired fasting glucose.Kendall DM, Bergenstal RM. ©2005 International Diabetes Center, Minneapolis, MN. All rights reserved. Adapted from Ferrannini E. Presentation at 65th ADA in Washington, DC, 2006.

NGT Insulin IGT/ IFG Type 2 Diabetes Resistance

Postprandial glucose

Fasting glucose

Insulin resistance —hepatic and peripheral

Insulin level

Beta-cell function

ADA/EASD Consensus Algorithm for the Initiation and Adjustment of Therapy

Diabetes Care 2009; 32:193–203

a - Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide.

Avoid Use of Glyburide?

In-hospital mortality in patients on sulfonylureas before admission (n = 459) according to the type of sulfonylureas and stratified byspecific subgroups (J Clin Endocrinol Metab, November 2010, 95(11):4993–5002)

AACE/ACE Glycemic Control Algorithm

Consensus Panel (Endocr Pract. 2009;15: 541-59)

• Management of Patients With A1C Levels of 6.5% to 7.5%• Monotherapy• For the patient with an A1C level within the range of 6.5%

to 7.5%, it is possible that a single agent might achieve the A1C goal of 6.5%. In this setting, metformin, TZDs, DPP-4 inhibitors, and a-glucosidase inhibitors (AGIs) are recommended. Because of its safety and efficacy, metformin is the cornerstone of monotherapy and is usually the most appropriate initial choice for monotherapy unless there is a contraindication, such as renal disease, hepatic disease, gastrointestinal intolerance, or risk of lactic acidosis



• Dual Therapy• As a result of its safety and efficacy, metformin should

be the cornerstone of dual therapy for most patients. When metformin is contraindicated, a TZD may be used as the foundation for this group of options. Because metformin or a TZD will serve as an insulin sensitizer, the second component of the dual therapy is usually an incretin mimetic, DPP-4 inhibitor, glinide, or sulfonylurea. These agents are recommended in the following order: incretin mimetic, DPP-4 inhibitor, or an insulin secretagogue such as a glinide and sulfonylurea



• Insulin Therapy• The considerations for insulin therapy for patients with a current

A1C of 7.6% to 9.0% are similar to those discussed previously for patients with an A1C level of 6.5% to 7.5%. When transitioning to insulin from a regimen involving triple therapy, it is customary to discontinue one or more of the orally administered agents. Use of TZDs or of sulfonylureas conjointly with insulin is associated with a risk of weight gain and fluid retention. In patients at risk, TZDs may cause or aggravate congestive heart failure, and they increase the risk of bone fractures in both women and men. Neither GLP-1 agonists nor DPP-4 inhibitors have been approved by the FDA for use with insulin. Thus, metformin is the only medication with a relatively clear indication for use in conjunction with insulin in patients with type 2 diabetes.



• Not recommended• Regular human insulin: Humulin R and Novolin R

– Onset of action is too slow and persistence of effect is too long to mimic a normal prandial physiologic profile; the result is impaired efficacy and increased risk of delayed hypoglycemia

• NPH insulin: Humulin N and Novolin N – Does not provide a sufficiently flat “peakless” basal

insulin; highly variable absorption even within individuals; increased risk of hypoglycemia compared with the long-acting insulin analogues glargine or detemir



• “We believe that this algorithm represents the treatment preferences of most clinical endocrinologists, but in the absence of meaningful comparative data, it is not necessarily an official AACE position. Because of the insufficient number or total absence of RCTs for many combinations of therapies, the participating clinical experts used their judgment and experience.”– GOBSAT? Dr Kelly Jones

UKPDS 80. N Eng J Med 2008; 359:

UK Prospective Diabetes StudyGlucose Interventional Trial

Intensive

Conventional

Intensive

2,729 Intensive

with sulfonylurea/insulin

1,138 (411 overweight) Conventional

with diet

342 (all overweight) Intensive

with metformin

P

Trial end1997

P

5,102Newly-diagnosedtype 2 diabetes

744Diet failure

FPG >15 mmol/l

149Diet satisfactory FPG <6 mmol/l

DietaryRun-in

4209

Randomisation1977-1991

Mean age 54 years(IQR 48–60)

Any Diabetes Related Endpoint (%) at 10 years

• Diet + Metformin 28.7%

• Diet + Sulf/Insulin 36.8%

• Diet only 38.9%– RRR 26.2% with diet + metformin vs. diet

alone– ARR 10.2%– NNT 10

Death Related to Diabetes (%) at 10 years



• Diet alone 13.4%– RRR 38.8% with diet + metformin vs. diet


All Cause Mortality (%) at 10 years


• Diet + Sulf/Insulin 20%

• Diet alone 21.7%– RRR 32.7% with metformin + diet vs. diet


Myocardial Infarction (%) at 10 years



• Diet alone 17.8%– RRR 36% with diet + metformin vs, diet alone– ARR 6.4%– NNT 16

Stroke (%) at 10 years



• Diet alone 5.6%– RRR 44.4% with diet + metformin vs, diet +

sulf/insulin– ARR 2.8%– NNT 36

Microvascular Disease (%) at 10 years



• Diet alone 9.2%

• Trend but not significant with diet + metformin vs. diet alone

Long-term Effects of Metformin on Metabolismand Microvascular and Macrovascular Disease

in Patients With Type 2 Diabetes Mellitus Treated with Insulin Arch Intern Med. 2009;169(6):616-625

•390 patients treated with insulin in the outpatient clinics of 3 hospitals in a randomized, placebo-controlled trial with a follow-up period of 4.3 years. Either metformin hydrochloride, 850 mg, or placebo (1-3 times daily) was added to insulin therapy.

•The primary end point was an aggregate of microvascular and macrovascular morbidity and mortality. The secondary end points were microvascular and macrovascular morbidity and mortality independently.

“Hyperinsulinemia the Outcome of its Metabolic Effects (HOME)”

Long-term Effects of Metformin on Metabolismand Microvascular and Macrovascular Disease

in Patients With Type 2 Diabetes Mellitus Treated with Insulin Arch Intern Med. 2009;169(6):616-625

Results: • Metformin treatment prevented weight gain (mean weight gain, −3.07 kg

[range, −3.85 to −2.28 kg]; P.001), • Improved glycemic control (mean reduction in HbA1c level, 0.4%

percentage point [95% CI, 0.55-0.25]; P.001), despite the aim of similar glycemic control in both groups,

• Reduced insulin requirements (mean reduction, 19.63 IU/d [95% CI, 24.91-14.36 IU/d]; P.001).

• Metformin was not associated with an improvement in the primary end point.

• It was, however, associated with an improvement in the secondary, macrovascular end point (hazard ratio, 0.61 (95% CI, 0.40-0.94; P=.02), which was partly explained by the difference in weight.

• The number needed to treat to prevent 1 macrovascular end point was 16.1 (95% CI, 9.2-66.6).

• These sustained beneficial effects support the policy to continue metformin treatment after the introduction of insulin in any patient with DM2, unless contraindicated.

Metformin Use and Mortality Among PatientsWith Diabetes and Atherothrombosis

Arch Intern Med. 2010;170(21):1892-1899

• 19,691 patients having diabetes with established atherothrombosis participating in the Reduction of Atherothrombosis for Continued Health (REACH) Registry between December 1, 2003, and December 31, 2004, treated with or without metformin.

• Multivariable adjustment and propensity score were used to account for baseline differences.

• The main outcome measure was 2-year mortality


Arch Intern Med. 2010;170(21):1892-1899

• Results: The mortality rates were 6.3% (95% confidence interval [CI], 5.2%-7.4%) with metformin and 9.8% (8.4%-11.2%) without metformin; the adjusted hazard ratio (HR) was 0.76 (95%CI 0.65-0.89; P.001). ARR 3.5%, NNT=29

• Association with lower mortality was consistent among subgroups, noticeably in:– patients with a history of congestive heart failure (HR 0.69;

95%CI, 0.54-0.90; P=.006), – patients older than 65 years (0.77; 95%CI 0.62-0.95; P=.02), – patients with an estimated creatinine clearance of 30 to

60mL/min/1.73m2 (0.64; 95%CI, 0.48-0.86; P=.003)


Arch Intern Med. 2010;170(21):1892-1899

• Conclusions: “Metformin use may decrease mortality among patients with diabetes when used as a means of secondary prevention, including subsets of patients in whom metformin use is not now recommended.”

Metformin• Lactic acidosis is a rare but potentially fatal complication

– avoid in patients with renal dysfunction (IE males serum Cr >1.5mg/dl and females serum Cr >1.4mg/dl)

– Heart failure? • New data suggest reduced all cause mortality with

metformin vs. sulfonylurea (Diabetes Care 2005;28:2345-51)– Adjusted HR 0.66 (0.44-0.97) metformin monotherapy @ 1 yr– Adjusted HR 0.54 (0.42-0.70) combination therapy @ 1 yr

• Metformin may be used in patients with stable CHF if renal function is normal. It should be avoided in unstable or hospitalized patients with CHF. (C) ADA Standards Diabetes Care 2009; 32: suppl 1

– Liver disease– Major surgery– Alcohol abuse– Pregnancy– Radio contrast media (hold dose for 48 hrs post test)

Risk of fatal and nonfatal lactic acidosis with

metformin use in type 2 diabetes mellitus The Cochrane Library 2010, Issue 4

• Main results:– Pooled data from 347 comparative trials and cohort studies

revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group.

– There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies.

• Authors’ conclusions:– “There is no evidence from prospective comparative trials or

from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.”

Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional

contraindications.

• One trial by Rachmani and colleagues questioned the standard contraindications by studying 393 patients, all with at least one contraindication to metformin use, and found no cases of lactic acidosis over four years of the trial duration. All of the patients in this trial had renal insufficiency, with mean plasma creatinine levels of 1.5 to 2.5 mg/dl (mean level 1.8 mg/dl).– Eur J Int Med 2002;13:428–433.

Proposed Recommendations for Use of Metformin Based on e-GFR

Diabetes Care 2011;34:1435

eGFR (ml/min per 1.73m2) Action

>60 No renal contraindication to metformin

>45 Continue useIncrease monitoring of renal function (every 3–6 months)

<45 and >30 Prescribe metformin with cautionUse lower dose (e.g., 50%, or half-maximal dose)Closely monitor renal function (every 3-6 months) Do not start new patients on metformin

<30 Stop metformin

consistent with the National Institute for Health and Clinical Excellence guidelines in the U.K. and those endorsed by the Canadian Diabetes Association and the Australian Diabetes SocietyNOT FDA APPROVED!

Metformin-Induced Vitamin B12 Deficiency:Can it Lead to Peripheral Neuropathy?

Studies note that vitamin B12 malabsorption may occur in up to 30% of patients treated long-term with metformin

• Braza and colleagues presented information at the 2009 meeting of the American Diabetes Association of a review of the prevalence of vitamin B12 deficiency in Hispanic patients with type 2 diabetes (n=76) taking metformin. The average duration of metformin therapy was 5 years. The authors found no correlation between vitamin B12 deficiency and mean corpuscular volume. But peripheral neuropathy was noted in 7%, 23% and 77% of those who had normal, low-normal and deficient levels of vitamin B12 deficiency, respectively.

– Presented at the American Diabetes Association meeting, New Orleans, LA. June 5-9, 2009. [Abstract 569-P].

B12-intrinsic factor complex uptake by the ileal cell surface receptor is known to be calcium-dependent. and metformin may affect calcium dependent membrane action resulting the deficiency

Metformin-Induced Vitamin B12 Deficiency:Can it Lead to Peripheral Neuropathy?

Recommendations• There are no formal clinical guidelines for the management of patients with

vitamin B12 deficiency associated with metformin use. • Management is geared towards identifying patients at high risk for

deficiency– Risk factors for vitamin B12 deficiency (i.e., vegetarian diet, chronic

alcohol ingestion, prolonged use of a histamine-2-receptor antagonists or proton pump inhibitor)

• The product information for Glucophage recommends monitoring hematologic parameters (hemoglobin, hematocrit, and red blood cell indices) annually. In addition, in patients at high-risk for deficiency, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.

• In patients with vitamin B12 deficiency, treatment with oral vitamin B12 1000 mcg daily should be initiated

• While neuropathy can be related to hyperglycemia, vitamin B12 deficiency should be ruled out as a cause, especially in those patients with diabetes who are taking metformin

ACCORD Glucose Arm

• CV death, MI, or stroke: 6.9% vs. 7.2% (p = 0.16), respectively

• All-cause mortality: 5.0% vs. 4.0% (p = 0.04), respectively

• CV mortality: 2.6% vs. 1.8% (p = 0.02), respectively

Trial design: Type 2 diabetic patients were randomized to intensive therapy (glycated hemoglobin <6%, n = 5,128) versus standard therapy (glycated hemoglobin 7%-7.9%, n = 5,123). Patients were followed for 3.5 years.

Results

Conclusions

• Intensive glucose lowering (mean glycated hemoglobin 6.4%) increased all-cause and CV mortality among type 2 diabetics

• National Heart, Lung, and Blood Institute stopped the trial 17 months early

• Other studies testing intensive glycemic control are ongoing

ACCORD Study Group. N Engl J Med 2008;358:2545-59

(p = 0.16) (p = 0.04)

Intensive glucose lowering

Standard therapy

Cardiovascular death, MI, or stroke

All-cause mortality

5.0 4.0

6.9 7.2

%

Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median3.4-Year Follow-up of Glycemic Treatment

in the ACCORD Trial

• A higher average on-treatment A1C was a stronger predictor of mortality than the A1C for the last interval of follow-up or the decrease of A1C in the first year. Higher average A1C was associated with greater risk of death. The risk of death with the intensive strategy increased approximately linearly from 6–9% A1C and appeared to be greater with the intensive than with the standard strategy only when average A1C was 7%.

• CONCLUSIONS— “These analyses implicate factors associated with persisting higher A1C levels, rather than low A1C per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD.”– Diabetes Care 33:983–990, 2010

PROactive TrialLancet 2005;366:1279-89

• Pioglitazone up to 45mg or placebo added to standard recommended therapy in 5238 patients with Type 2 DM not at goal on oral agents except TZDs and +/- insulin and CV disease– Primary outcome was a composite of all cause

mortality, non-fatal MI, stroke, ACS, revascularization

– Secondary outcomes all cause mortality and non-fatal MI

– Followed for an average of 2.8 years

PROactive TrialLancet 2005;366:1279-89

• Results:– Primary composite endpoints

• 23.5% Placebo and 21% Pioglitazone • HR 0.90 (0.80-1.02) p=0.095 NS

– Secondary endpoints (death, MI, except silent MI and stroke) Not Pre-specified !!

• 14.4% Placebo and 12.3% Pioglitazone• HR 0.84 (0.72-0.98) p=0.027• RRR 16%, ARR 2.1%, NNT 48

– Heart failure (un-adjudicated)• 8% Placebo and 11% Pioglitazone p<0.0001• ARI 3%, NNH 34• Edema was also significantly greater in the pioglitazone group

MedWatch 2/20/2007• Glaxo SmithKline (GSK) notified healthcare professionals of the

results of a randomized, double-blind parallel group study [ADOPT] of 4,360 patients with recently diagnosed type 2 diabetes mellitus followed for 4-6 years to compare glycemic control with rosiglitazone relative to metformin and glyburide monotherapies. – Significantly more female patients who received rosiglitazone

experienced fractures of the upper arm, hand, or foot, than did female patients who received either metformin or glyburide.

– At GSK's request, an independent safety committee reviewed an interim analysis of fractures in another large; ongoing; controlled clinical trial and preliminary analysis was reported as being consistent with the observations from ADOPT.

• Takeda/Lilly have also gone back and the same association has been seen with pioglitazone

• Healthcare professionals should consider the risk of fracture when initiating or treating female patients with type 2 diabetes mellitus with rosiglitazone and pioglitazone.

TZD’s and Fractures

• UK-based General Practice Research Database nested case control analysis assessed the odds ratios (ORs) of having a fracture associated with the use of rosiglitazone, pioglitazone, other oral antidiabetic agents, or insulin

• ORs for users of 8 or more thiazolidinedione prescriptions (corresponding to approximately 12-18 months of therapy)rosiglitazone (OR, 2.38; 95% CI,1.39-4.09) and pioglitazone (OR 2.59; 95% CI, 0.96-7.01) were used more frequently by case patients with fracture (predominantly hip and wrist fractures) than by controls.– Arch Intern Med. 2008;168(8):820-825

TZD’s and FracturesADA Annual Meeting 6/25/2010

• A retrospective analysis conducted by the Scottish Diabetes Research Network of more than 90% of all patients with diabetes in Scotland. About 144,000 patients met the study criteria, taking at least 1 oral antidiabetic agent but not insulin, during the 2000 to 2008 study period.

• Thiazolidinediones also elevate the risk of hip fracture in women by 1.9 times (P<0.001) and in men by 2.23 times ( P=0.016) for a combined hazard ratio of 1.98 (P<0.0001). – “We calculate that up to 17% of all hip fractures in the

diabetic population can be attributed to TZDs.”

TZD’s and Macular Edema• About 170,000 persons with diabetes were identified

using the Diabetes Case Identification Database from Kaiser Permanente Southern California

• Glitazone users were more likely to develop macular edema (ME) in 2006 (odds ratio OR, 2.6; 95% confidence interval , 2.4 to 3.0)

• After excluding patients who did not have the drug benefit, did not have an eye exam, and had a HgA1c <7.0, glitazone use was still associated with an increased risk of developing ME (OR, 1.6; 95% CI, 1.4 to 1.8).

• The authors conclude: “When treating patients with DME, ophthalmologists should consider the role of the glitazones.”– Am J Ophthalmol 2009;147:583–586

TZD’s and Diabetic Macular Edema (DME)

• Using electronic health records from a database comprised of 400 general practices in the United Kingdom, data from 109,295 patients with type 2 diabetes were analyzed. Selected patients were older than 18 years of age and had been exposed to more than 6 months of TZD therapy.

• The study was designed to determine the short-term (1 year) and long-term (10 years) risks of developing DME after TZD exposure, and whether therapy with agents such as aspirin can modulate those risks.

• Results at the 1-year time point suggest a strong association between TZD use and the incidence of DME. After adjustment for the covariates of concomitant medications, weight, body mass index, blood pressure, and lipid levels, the hazard ratio at 1 year was 3.29. Furthermore, "concurrent use of TZDs and insulin was associated with a further increase in DME incidence, with a hazard of 8.44.

– American Diabetes Association (ADA) 71st Scientific Sessions: Abstract 0135-OR. Presented June 26, 2011

TZD’s and Diabetic Macular Edema• Interestingly, at 10 years, the increased risk of DME is somewhat

lower than the initial risk (hazard ratio, 2.29 for TZD alone and 3.2 for TZD plus insulin).

• "In the 10-year model, HbA1c [glycosylated hemoglobin] appears to be an important influence in modulating risk, with a reduction in HbA1c being protective against developing DME." The use of ACE inhibitors and aspirin also appears to be protective.

• Taken together, the results for the 2 time points indicate that TZD exposure leads to a 3- to 6-fold increase in risk for DME. "If such a relationship were to be firmly established, a balance of risk and benefit needs to be made when prescribing TZDs in patients with diabetes who are at high risk for DME.“

– American Diabetes Association (ADA) 71st Scientific Sessions: Abstract 0135-OR. Presented June 26, 2011

FDA Ongoing Safety Review of Actos (pioglitazone) and Potential Increased Risk of Bladder Cancer After Two

Years Exposure• In preclinical carcinogenicity studies of pioglitazone, bladder

tumors were observed in male rats receiving doses of pioglitazone that produced blood drug levels equivalent to those resulting from a clinical dose. Additionally, results from two, three-year controlled clinical studies of Actos (the PROactive study and a liver safety study) demonstrated a higher percentage of bladder cancer cases in patients receiving Actos versus comparators. These findings are currently included in the label.

• To further address the long-term risk of bladder cancer associated with Actos use the drug manufacturer, Takeda, is conducting a ten-year, observational cohort study as well as a nested case-control study in patients with diabetes who are members of Kaiser Permanente Northern California (KPNC) health plan.

– A planned five-year interim analysis was performed with data collected from January 1, 1997 through April 30, 2008. The median duration of therapy among Actos-treated patients was 2 years (range 0.2-8.5 years). The study investigators did not observe a statistically significant association between any Actos exposure and increased bladder cancer risk in the study (Hazard ratio = 1.2, 95% Confidence Interval: 0.9-1.5). However, the risk of bladder cancer increased with increasing dose and duration of Actos use, reaching statistical significance after 24 months of exposure.

• FDA Drug Safety Communication 9-17-2010

Pioglitazone and Bladder Cancer?

• Update 6-16-2011 The FDA warned that the diabetes drug Actos, known generically as pioglitazone, increases the risk of bladder cancer by at least 40% when used for more than a year or in higher cumulative doses. The agency said it will require changes in the label of the drug to reflect the new findings.

• The FDA is not taking any further action against Actos until it receives further results from an ongoing study of the drug, but France has already suspended sales and Germany has warned physicians not to prescribe the drug to new patients.

DCCT/EDIC: Incidence of Nonfatal MI, Stroke, or Death

European Assoc for the Study of Diabetes (EASD) Consensus Report 9-06

• Calls for urgent action to drastically improve the management of DM, particularly urging the increased acceptance of insulin

• All patients with Type 2 DM, if they live long enough, will need insulin

• Recent survey found that the major patient barrier to achieving optimal blood sugar control was patient resistance to insulin

• Clinical research shows that one half of patients who are not at goal on oral medications are delaying at least 4-6 years to add insulin

Glimepiride Combined with Glimepiride Combined with Morning Insulin Glargine, Morning Insulin Glargine, Bedtime Neutral Protamine Bedtime Neutral Protamine

Hagedorn Insulin, or Bedtime Hagedorn Insulin, or Bedtime Insulin Glargine in Patients with Insulin Glargine in Patients with

Type 2 DiabetesType 2 DiabetesAndreas Fritsche, Matthias Axel Schweitzer,

Hans-Ulrich Häring, and the 4001 Study Group Ann Intern Med. 2003:138:952

Insulin Titration ScheduleInsulin Titration Schedule

• Initial dose calculation: (baseline FBG [mg/dL] – 50)/10

• Insulin dose individually titrated using predefined titration regimen with fasting blood glucose (FBG) target 100 mg/dL (5.6 mmol/L)– >100 2 units

– >120 4 units

– >140 6 units

– >160 8 units

Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952

Mean A1C Levels During StudyMean A1C Levels During Study

* Decrease in A1C from baseline for Morning Glargine: P<0.001 vs Bedtime NPH and P=0.008 vs Bedtime Glargine

Time (wk)0 4 8 12 16 20 24

7.5

8.0

8.5

9.0

9.5

A1C

(%

)

7.8

8.1

8.3

*

Morning Glargine

Bedtime Glargine

Bedtime NPH

Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952

Nocturnal and SymptomaticNocturnal and Symptomatic HypoglycemiaHypoglycemia

Nocturnal Symptomatic

P<0.001

P<0.001

1723

38

0

10

20

30

40

50

60

Pa

tie

nts

(%

)

P=0.004

P=0.001

56

43

58

0

10

20

30

40

50

60

Pa

tie

nts

(%

)

MorningGlargine

BedtimeGlargine

BedtimeNPH

MorningGlargine

BedtimeGlargine

BedtimeNPH

Adapted from Fritsche A et al, and the 4001 Study Group. Ann Intern Med. 2003:138:952

57

Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on A1C Quintiles

n=58 n=58 n=58 n=58n=58

Monnier L et al. Diabetes Care. 2003;26:881–885.

0

20

40

60

80

100

<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2

Postprandial glucose Fasting glucose

A1C

Co

ntr

ibu

tio

n,

%

When do we need to add prandial insulin to basal insulin?

Zisman hypothesized that basal insulin therapy should parallel hepatic glucose production, which would in turn maintain a narrow blood glucose range, specifically at night. Once the difference in bedtime and morning values increases, this suggests maximum titration of basal insulin has been reached and prandial doses may be needed to further improve glycemic control. He termed this the BeAM (difference between Bedtime and AM glucose) factor. A BeAM factor of 55 mg/dl or greater was established as the point at which patients may benefit from the addition of prandial insulin to the regimen. (71st ADA Scientific Sessions, San Diego, CA 6-27-2011)

59

Time, min

IR In

sulin

, mU

/L nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

The Incretin Effect in Subjects Without and With Type 2 Diabetes

Control Subjects (n=8)

Patients With Type 2 Diabetes (n=14)

Time, min

IR In

sulin

, mU

/L nm

ol / L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 120 0

Oral glucose load

Intravenous (IV) glucose infusion

Incretin Effect

The incretin effect is diminished

in type 2 diabetes.

Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.Permission pending.

60

Role of Incretins in Glucose Homeostasis

DPP-4 = dipeptidyl-peptidase 41. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913.2. Ahrén B. Curr Diab Rep. 2003;2:365–372.3. Drucker DJ. Diabetes Care. 2003;26:2929–2940.4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.

Ingestion of food

Beta cellsAlpha cells

Release of gut hormones —

Incretins1,2

Pancreas2,3

Glucose-dependent Insulin from beta cells

(GLP-1 and GIP)Glucose uptake

by muscles2,4

Glucose production

by liver

Blood glucose

Glucose dependent Glucagon from

alpha cells(GLP-1)

GI tract

ActiveGLP-1 & GIP

DPP-4 enzyme

InactiveGIP

InactiveGLP-1

Exenatide - Byetta

• Synthetic injectable GLP-1 that binds to and activates human GLP-1 receptors

• Increases glucose dependent insulin synthesis and secretion in beta cells

• Inhibits glucagon secretion from the alpha cells and thus hepatic glucose production

• Slows gastric motility• Promotes early satiety and potential weight

loss

Exenatide – ByettaNovember 2, 2009 FDA Alert – Renal Failure

• From April 2005 through October 2008, FDA received 78 cases of altered kidney function (62 cases of acute renal failure and 16 cases of renal insufficiency), in patients using Byetta. Some cases occurred in patients with pre-existing kidney disease or in patients with one or more risk factors for developing kidney problems including severe nausea and vomiting leading to dehydration. Labeling changes include:

• Information regarding post-market reports of acute renal failure and insufficiency, highlighting that Byetta should not be used in patients with severe renal impairment (creatinine clearance <30 ml/min) or end-stage renal disease.

• Recommendations to healthcare professionals that caution should be applied when initiating or increasing doses of Byetta from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 ml/min).

• Recommendations that healthcare professionals monitor patients carefully for the development of kidney dysfunction, and evaluate the continued need for Byetta if kidney dysfunction is suspected while using the product.

Liraglutide – Victoza by Novo-Nordisk

• A human analog of the glucagon-like peptide-1 (GLP-1) with 97% amino acid sequence homology to endogenous human GLP-1. – T1/2 ~11-15 hrs– 1.2 mg dose (2 pens/mo)

– $312.07 AWP

– 1.8 mg dose (3 pens/mo) – $468.11 AWP

– Adjunct to diet and exercise for Type 2 DM but not first line and no data in combo with insulin

Liraglutide – Victoza by Novo-NordiskLiraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

Risk of Thyroid C-cell Tumors BOX WARNING• Liraglutide causes dose-dependent and treatment-duration-dependent

thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether liraglutide will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness)

• In clinical trials of liraglutide, there were 6 reported cases of papillary thyroid carcinoma in patients treated with liraglutide and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years).

Liraglutide – Victoza by Novo-NordiskPancreatitis• In five clinical trials including more than 3,900 people,

there were seven cases of pancreatitis in patients using liraglutide and one case in a patient using another diabetes medicine. This constituted a 4:1 imbalance of pancreatitis cases, when considering the number of patient exposures (2.2 vs. 0.6 cases per 1000 patient-years). Five cases were reported as acute pancreatitis and two cases with were reported as chronic pancreatitis.

• Patients taking liraglutide should be aware of the symptoms of pancreatitis, such as severe abdominal pain that may also radiate into the back, possibly with nausea, and vomiting. If patients experience these symptoms, they should immediately talk to their healthcare professional.

June 13, 2011 FDA MedWatch Reminder Victoza (liraglutide [rDNA origin]) Injection: REMS - Risk of Thyroid C-cell Tumors, Acute Pancreatitis

Liraglutide with or without oralantidiabetic drug therapy in type 2 diabetes: an

overview of the LEAD 1–5 studies Diabetes, Obesity and Metabolism, 11 (Suppl. 3), 2009, 26–34

Liraglutide once a day versus exenatide twice a day for type 2diabetes: a 26-week randomised, parallel-group,

multinational, open-label trial (LEAD-6)

• Mean baseline HbA1c for the study population was 8.2%. Liraglutide reduced mean HbA1c significantly more than did exenatide (–1.12%; estimated treatment difference –0.33; p<0.0001) and more patients achieved a HbA1c value of less than 7% (54% vs 43%, respectively; odds ratio 2.02; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (–24 mg/dl vs –9 mg/dl; estimated treatment difference –16.5 mg/dl;p<0.0001) but postprandial glucose control was less effective after breakfast (-20 mg/dl vs – 27.9 mg/dl; p<0.0001) and dinner (-15 mg/dl vs -23.5 mg/dl; p<0.005).

• Both drugs promoted similar weight losses (liraglutide –3.24 kg vs exenatide –2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; p=0.0131; 25.5% vs 33.6% had minor hypoglycemia).

Lancet 2009; 374: 39–47

Daily Liraglutide vs. Exenatide Weekly

• 9-16-2011 from EASD Meeting• In a "head-to-head study, the mean reduction in

HbA1c for patients on the more convenient dosing schedule of exenatide weekly was 1.26%, compared with a 1.48% reduction with liraglutide (P<0.05)." However, "patients taking liraglutide experienced more gastrointestinal adverse effects than those taking exenatide."

National Institute for Health and Clinical Excellence (NICE) 10/2010 . • Liraglutide 1.2 mg daily in dual therapy regimens (in

combination with metformin or a sulphonylurea) is recommended as an option for the treatment of people with type 2 diabetes, only if:– The person is intolerant of either metformin or a sulphonylurea, or

treatment with metformin or a sulphonylurea is contraindicated, and The person is intolerant of thiazolidinediones and dipeptidyl peptidase-4 (DPP-4) inhibitors, or treatment with thiazolidinediones

and DPP-4 inhibitors is contraindicated. – Treatment with liraglutide 1.2 mg daily in a dual therapy regimen

should only be continued if a beneficial metabolic response has been shown (defined as a reduction of at least 1 percentage point in HbA1c at 6 months).

• Liraglutide 1.8 mg daily is not recommended for the treatment of people with type 2 diabetes.

Sitagliptin - Januvia & Saxagliptin - Onglyza Indications and Usage

• Monotherapy– Adjunct to diet and exercise to improve glycemic control in patients

with type 2 diabetes mellitus• Combination therapy

– To improve glycemic control in combination with metformin or a PPAR (peroxisome proliferator-activated receptor gamma) agonist (eg, thiazolidinediones) when the single agent alone with diet and exercise does not provide adequate glycemic control

– When used in combination with a sulfonylurea, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia

• Important limitations of use– Should not be used in patients with type 1 diabetes or for the

treatment of diabetic ketoacidosis

Sitagliptin and Insulin Now FDA Approved

• Add-on Combination Therapy with Insulin (with or without Metformin)– Sitagliptin provided significant improvements in A1C (-0.6%),

FPG (-15 mg/dl), and 2-hour PPG (-36 mg/dl) compared to placebo. Both treatment groups had an adjusted mean increase in body weight of 0.1 kg from baseline to Week 24.

– There was an increased rate of hypoglycemia in patients treated with sitagliptin. (15.5% vs 7.8%)

• Sitagliptin was associated with an incremental cost-effectiveness ratio of $169,572 per QALY saved– Diabetes Care 33:695–700, 2010

Dosage and Administration Saxagliptin - Onglyza

• Usual dose for Onglyza as monotherapy or in combination with metformin or a TZD is 2.5 or 5 mg once a day without regard to meals (a fixed dose combo with QD metformin has been submitted to the FDA)

• The recommended dose for patients with moderate to severe renal disease (IE CrCl<50 ml/min) is 2.5 mg once daily

• Patients taking significant CYP 3A4 inhibitors (ketoconazole, itraconazole, protease inhibitors, clarithromycin, etc) should receive no more than 2.5 mg per day

• Saxagliptin 5-10 mg has produced a dose related reduction in lymphocytes of about 100-120 cells/microl but no clinically relevant adverse reactions have been seen to date

Linagliptin - Tradjenta

• May 2, 2011 The FDA approved linagliptin – Tradjenta the newest of the DPP-4 inhibitors by Boehringer Ingelheim and Lilly for the treatment of Type 2 diabetes– FDA approved either as monotherapy or in

combination with metformin, glimepiride or pioglitazone

– Linagliptin is primary eliminated by non-renal excretion and does not accumulate with mild to moderate renal dysfunction

Linagliptin - Tradjenta• Monotherapy - placebo-adjusted change in HbA1c compared to

placebo of - 0.69 % (p<0.0001).• Metformin - placebo-adjusted change

in HbA1c compared to placebo of - 0.64 % (p<0.0001).• Metformin + Glimipiride - placebo-adjusted change in HbA1c

compared to placebo of

- 0.62 %• Pioglitazone - placebo-adjusted change in a HbA1c change

compared to placebo of

- 0.51 (p<0.0001).


ADA Scientific Sessions Late Breaking Abstract Sunday, June 26, 2011 Abstract No: 0030-LB

ADA Scientific Sessions Late Breaking Abstract Sunday, June 26, 2011 Abstract No: 0030-LB


• One potential advantage of linagliptin over sitagliptin and saxagliptin is that only a small amount (less than 7%) is eliminated by the kidneys. – No dosage adjustment is needed for patients

with impaired renal or hepatic function

• The recommended dose of linagliptin is 5 mg once daily, without regards to meals.

• US Food and Drug Administration’s database of reported adverse events for those associated with the dipeptidyl peptidase4 inhibitor sitagliptin and the glucagon-like peptide-1 mimetic exenatide, from 2004-2009; data on adverse events associated with 4 other medications were compared as controls.(rosiglitazone, nateglinide, repaglinide and glipizide)

• The primary outcomes measures were rates of reported pancreatitis, pancreatic and thyroid cancer, and all cancers associated with sitagliptin or exenatide, compared with other therapies.

Pancreatitis, Pancreatic, and Thyroid Cancer With Glucagon-

LikePeptide-1–Based Therapies

GASTROENTEROLOGY 2011;141:150–156

Pancreatitis, Pancreatic, and Thyroid Cancer With Glucagon-Like Peptide-1–Based Therapies

GASTROENTEROLOGY 2011;141:150–156

Pancreatitis, Pancreatic, and Thyroid Cancer With Glucagon-Like Peptide-1–

Based TherapiesGASTROENTEROLOGY 2011;141:150–156

• “For now this analysis of the FDA data base does not establish that pancreatitis, pancreatic and thyroid cancer are caused by GLP-1based therapy. It simply raises the level of concern that they may be and that the appropriate prospective studies are required to rule them out.”

ADA Clinical Practice Recommendations - 2012

• Blood Pressure Treatment/GoalsA goal SBP < 130 mmHg is appropriatefor most patients with diabetes. (C)Patients with diabetes should be treatedto a DBP < 80 mmHg. (B)

• Pharmacologic therapy for patients with diabetes and hypertension should be with a regimen that includes either an ACE inhibitor or an ARB. If one class is not tolerated, the other should be substituted.


ADA 2012 Clinical Practice Recommendations (Diabetes Care 2012;35: S11-S63)

• “Growing evidence suggests that there is an association between increase in sleep-time blood pressure and incidence of CVD events. A recent RCT of 448 participants with type 2 diabetes and hypertension demonstrated reduced cardiovascular events and mortality with median follow-up of 5.4 years if at least one antihypertensive medication was given at bedtime.”

• “Administer one or more antihypertensive medications at bedtime. (A)”

Influence of Time of Day of Blood Pressure–Lowering Treatment on

Cardiovascular Risk in Hypertensive Patients with Type 2 DiabetesDiabetes Care 2011; 34:1270-76

• A prospective, randomized, single study center in Spain, open-label, blinded end point trial on 448 hypertensive patients with type 2 diabetes, 255 men/193 women, mean age 62.5 years, randomized to ingest all their prescribed hypertension medications upon awakening or 1 or more of them at bedtime.

• Ambulatory blood pressure was measured for 48 hrs at baseline and again annually or even more frequently (quarterly) after adjustments in treatment.

• The mean follow-up was 5.4 years.• This was a subset of the original MAPEC Trial in 2156

hypertensive subjects from Spain (Chronobiology International 2010; 27(8): 1629–1651)

Influence of Time of Day of Blood Pressure–Lowering Treatment onCardiovascular Risk in Hypertensive Patients with Type 2 Diabetes

(Diabetes Care 2011; 34:1270-76)

• Results: patients ingesting one or more hypertension medications at bedtime showed a significantly lower cardiovascular risk (adjusted by age and sex) than subjects ingesting all medications upon awakening (hazard ratio 0.33 [95% CI 0.21–0.54]; P , 0.001).

• The difference between groups in the adjusted risk of major events (cardiovascular death, myocardial infarction, and stroke) was also statistically significant (0.25 [0.10–0.61]; P = 0.003).

• There was a significant 12% cardiovascular risk reduction per each 5 mmHg decrease in asleep systolic blood pressure during follow-up (P , 0.001).

CV Risk Reduction Even Greater in Patients With Diabetes

The HOPE Study Investigators. N Engl J Med. 2000;342:145-153.The HOPE Study Investigators. Lancet. 2000;355:253-259.

-30

-35

-40

-25

-20

-15

-10

-5

0

NonfatalMI Stroke CV Death

All-CauseMortality*

HOPE MICRO-HOPE

20%22%

32%33%

26%

37%

16%

24%

% R

elat

ive

Ris

k R

educ

tion

Effects Beyond Baseline Therapy• Aspirin and other antiplatelets• Beta-blockers• Lipid-lowering agents

• Diuretics• Calcium channel blockers

P=0.01

P=0.0001

P=0.0074

P=0.004

P=0.0003P=0.005

P=0.0002

P=0.0002

*Secondary end point

76.279.9

0

20

40

60

80 76.279.9

0

20

40

60

80

Results• Primary endpoints of composite CV morbidity and mortality were significantly reduced by 21% in the CCB/ACEI group RR=1.21[CI 95%, (1.06-1.37)]• Secondary endpoint of Systolic blood pressure was reduced significantly over time (42 months) with both treatments.•BP control rates (SBP/DBP <140/90mm/Hg) significantly increased for both groups between baseline and 36 months (Figure).

Conclusions• The study demonstrated the effectiveness of a single pill fixed dose combination therapy of amlodipine/benzapril compared to HCTZ/benzapril on CV morbidity and mortlaity.• Future initial hypertension pharmacotherapy could be impacted by these findings.

37.2 37.9

0

20

40

60

80

37.2 37.9

0

20

40

60

80

ACCOMPLISHACCOMPLISH

%

Trial Design: ACCOMPLISH was a randomized, multinational double-blind trial (n=11,508). The aim was to determine the most effective therapeutic pharmacotherapy for controlling systolic hypertension and preventing CVD events in high risk patients. Participants were included if they were ≥ 60 Years with 1 risk factor and ≥ 55 years with 2 risk factors. One group received a single pill combination fixed dose of an ACE inhibitor (benzapril) and a calcium channel blocker (CCB). The other group received a single pill fixed dose combination of an ACE inhibitor and a diuretic (HCTZ). The primary endpoint was CV morbidity and mortality.

HCTZ+ACEIn=5723

CCB+ACEIn=5700

Blood Pressure % control Rates(SBP/DBP < 140/90 mmHg)

Jamerson et al., Presented at ACC, 2008 © 2008, American Heart Association. All rights reserved.

Baseline 36 months

% c

ontr

olle

d

% c

ontr

olle

d

ACCOMPLISH Results: ACEI/CCB vs. ACEI/Diuretic

• Men RRR 20% ARR 2.5% NNT 40• Women RRR 17% ARR 1.6% NNT 63• >/= 65y/o RRR 19% ARR 2.3% NNT 44• >/= 70y/o RRR 21% ARR 2.8% NNT 36• Diabetes RRR 21% ARR 2.2% NNT 46• No Diabetes RRR 18% ARR 2.1% NNT 48

NEJM 2008;359:2417-28


Nephropathy – Treatment• In the treatment of the nonpregnant patient

with micro- or macroalbuminuria, either ACE inhibitors or ARBs should be used. (A)

• If one class is not tolerated, the other should be substituted. (E)


Captopril in Patients with Type 1 DM and Nephropathy (NEJM 1993;329:1456-62)

Outcome Placebo Captopril RRR ARR NNT

Death 6.93% 3.86% 44% 3.07% 32

Dialysis/

Transplant

15.34% 9.66% 37% 5.68% 18

Death/Dialysis/Transplant

20.79% 9.66% 47% 9.68% 10

Doubling Serum Creatinine

21.28% 12.08% 43% 9.20% 11

Angiotensin Receptor Blockers in Patients with Type 2 DM and

Nephropathy• RENAAL – losartan 50-100mg vs. placebo for

3.4yrs, 28% reduction in ESRD, 25% reduction in doubling serum Cr, and no reduction in death. (NEJM 2001;345:861-9)

• IDNT – irbesartan 300mg vs. amlodipine 10mg vs. placebo for 2.6 yrs, 33% reduction in doubling serum Cr vs. placebo and 37% reduction vs. amlodipine (NEJM 2001;345:851-60)

COOPERATE Trial(Lancet 2003; 361:117-24)

• 263 patients with non-diabetic renal disease from Japan randomized to losartan 100mg, trandolapril 3mg or the combination 100mg plus 3mg daily

• Primary endpoint was doubling of serum Cr plus ESRD at 3 years

• Results 23% of patients on losartan and 23% of patients on trandolapril vs. 11% of patients on the combination reached the primary endpoint and BP control was similar in all groups NNT 9

• Dual Blockade of the RAS in Patients with Type 2 DM? Recent letter Lancet 2008 suggests data is flawed

• CAUTION AVOID COMBO ACEI +ARB?

Mann JFE et al. Lancet 2008; 372:547-553.

ONTARGET: Incidence of primary and secondary renal outcomes

Outcome R, n (%)

T, n (%)

R + T, n (%)

T vs R HR

p R + T vs R HR

p

All dialysis, doubling of creatinine, death

1150 (13.4)

1147 (13.4)

1233 (14.5)

1.00 0.968 1.09 0.037

All dialysis and doubling of creatinine

174 (2.03)

189 (2.21)

212 (2.49)

1.09 0.420 1.24 0.038

R=ramiprilT=telmisartan

ONTARGET Renal Outcomes

• “These findings of ONTARGET support previous guidelines that propose use of drugs to block the renin-angiotensin system as part of an antihypertensive regimen to lower blood pressure and urinary protein in chronic kidney disease. These data should not lead to guideline modifications. However, the admonishment against use of combination therapy to block the renin-angiotensin system in people at low risk of chronic kidney disease is clear. Combined with previous studies, ONTARGET supports the notion that use of single agents to block the renin-angiotensin system is well tolerated.”

Pantelis A Sarafidis, George L Bakris– Lancet 2008;372:511-12

Aliskiren (Tekturna) Safety Update• December 20, 2011 - Novartis announced that following

the seventh interim review of data from the ALTITUDE study with Tekturna® (aliskiren), a decision to terminate the trial has been taken on the recommendation of the independent Data Monitoring Committee (DMC) overseeing the trial. The trial involved 8606 patients with type 2 diabetes and renal impairment who are at high risk of cardiovascular and renal events

• The DMC concluded that patients were unlikely to benefit from treatment added on top of standard anti-hypertensives (ACEI or ARB), and identified higher adverse events in patients receiving Tekturna in addition to standard of care in the trial. Specifically, in the trial arm in which Tekturna was added to the standard of care there was an increased incidence after 18-24 months of non-fatal stroke, renal complications, hyperkalemia and hypotension in this high-risk study population.


Lipid Management• Statin therapy should be added to lifestyle therapy, regardless of baseline

lipid levels, for diabetic patients:– with overt CVD (A)– without CVD who are over the age of 40 years and have one or more other

CVD risk factors (A)• For patients at lower risk than above (e.g. without overt CVD and under

the age of 40 years), statin therapy should be considered in addition to lifestyle therapy if LDL cholesterol remains 100 mg/dl or in those with multiple CVD risk factors. (E)

• In individuals without overt CVD, the primary goal is an LDL cholesterol 100 mg/dl (2.6 mmol/l). (A)

• In individuals with overt CVD, a lower LDL cholesterol goal of 70 mg/dl (1.8 mmol/l), using a high dose of a statin, is an option. (B)

• If drug-treated patients do not reach the above targets on maximal tolerated statin therapy, a reduction in LDL cholesterol of 30–40% from baseline is an alternative therapeutic goal. (A)

Diabetes Care 2012;35 Suppl 1

Heart Protection Trial in Patients with DM (Lancet 2003;361:2005-16)

• 5963 adults (age 40-80) with DM (90% Type 2) and TC of 135mg% or greater randomized to simvastatin 40mg/d or placebo for 5 yrs.

• Patients with LDL of 116mg% or more, major vascular events 27.9% placebo vs. 23.3% simvastatin. (ARR 4.6%, NNT 22)

• Patients with LDL of less than 116mg%, major vascular events 20.9% placebo vs, 15.7% simvastatin. (ARR 5.2%, NNT 20)

FDA Safety Update Simvastatin6-8-2011 FDA Safety Update

•Based upon data from the SEARCH Trial the FDA is recommending limiting the use of the highest approved dose of the cholesterol-lowering medication, simvastatin (80 mg) because of increased risk of muscle damage.

•Simvastatin 80 mg should be used only in patients who have been taking this dose for 12 months or more without evidence of muscle injury (myopathy).

•Simvastatin 80 mg should not be started in new patients, Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drugincluding patients already taking lower doses of the drug.

FDA Safety Update Simvastatin• Fifty-two patients (0.9%) in the 80-mg group versus one

patient (0.02%) in the 20-mg group developed myopathy (defined as unexplained muscle weakness or pain with a serum CK >10 times the upper limit of normal [ULN]). This was higher than the labeled risk (based on clinical trial data) of 0.53%.

• Twenty-two patients (0.4%) in the 80-mg group versus no patient in the 20-mg group developed rhabdomyolysis (defined as unexplained muscle weakness or pain with serum CK >40 times ULN).

• The risks for myopathy and rhabdomyolysis with simvastatin 80 mg were highest in the first 12 months of treatment, 5 per 1000 person-years and 2 per 1000 person-years, respectively, and decreased to 1 per 1000 person-years and 0.4 per 1000 person-years after that.

FDA Safety Update SimvastatinFDA is requiring changes to the simvastatin label to add new contraindications (should not be used with certain medications) and dose limitations for using simvastatin with certain medicines.

•Contraindicated with : Itraconazole, Ketoconazole, Posaconazole (New), Erythromycin, Clarithromycin, Telithromycin, HIV/HCV protease inhibitors, Nefazodone, Gemfibrozil (old 10mg), Cyclosporine (old 10 mg), and Danazol (old 10mg).

•Maximum 10 mg simvastatin dose with:, Verapamil (old 20mg) and Diltiazem (old 40 mg).•Maximum 20 mg simvastatin dose with: Amiodarone (old 10mg), Amlodipine (New) and Ranolazine (New)

CARDSLancet 2004,364:685-96

• 2838 patients (age 40-75) from the UK and Ireland with Type 2 DM and no history of CVD or PVD

• LDL < 160mg/dl but with a history of HBP, smoking, retinopathy or micro/macroalbuminuria randomized to atorvastatin 10mg or placebo

• Trial stopped early after 3.9 years

CARDS Lancet 2004,364:685-96

• Primary endpoint 9.0% vs 5.8% – 37% RRR, 3.2% ARR%, NNT 32

• Acute coronary events 5.5% vs 3.6%– 36% RRR, 1.9% ARR, NNT 53

• Stroke 2.8% vs 1.5%– 48% RRR, 1.3% ARR, NNT 77Benefits were similar regardless of baseline

lipids, age or gender

Henry C. Ginsberg, MDCollege of Physicians & Surgeons , Columbia University, New York

For The ACCORD Study Group

N Engl J Med 2010; 362:1563-1574

All participants on open-labeled simvastatin, 20 to 40 mg/day◦ Simvastatin dose complied with lipid guidelines

Patients randomized to double-blind placebo or fenofibrate, 54 to 160mg/day◦ Dosing based upon eGFR level

Only blinded ACCORD trial

Observed Follow-up: 4 to 8 years (mean 4.7 years)

◦ N Engl J Med 2010; 362:1563-1574

Primary Outcome By Treatment Group and Baseline Subgroups

N Engl J Med 2010; 362:1563-1574

FDA Drug Safety CommunicationTrilipix (fenofibric acid)

11/9/2011 Trilipix (fenofibric acid) may not lower a patient's risk of having a heart attack or stroke. •RECOMMENDATION: Fenofibrate at a dose equivalent to 135 mg of Trilipix was not shown to reduce coronary heart disease morbidity and mortality in patients in two large randomized controlled trials of patients with type 2 diabetes mellitus (FIELD and ACCORD); healthcare professionals should consider the benefits and risks of Trilipix when deciding to prescribe the drug to patients, and counsel patients about those benefits and risks.


Antiplatelet Therapy● Consider aspirin therapy (75–162 mg/ day) as a primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk >10%). This includes most men 50 years of age or women 60 years of age who have at least one additional major risk factor (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria). (C)● Aspirin should not be recommended for CVD prevention for adults with diabetes at low CVD risk (10-year CVD risk <5%, such as in men 50 years of age and women 60 years of age with no major additional CVD risk factors), since the potential adverse effects from bleeding likely offset the potential benefits. (C)● Use aspirin therapy (75–162 mg/day) as a secondary prevention strategy in those with diabetes with a history of CVD. (A)● For patients with CVD and documented aspirin allergy, clopidogrel (75 mg/day) should be used. (B)● Combination therapy with ASA (75– 162 mg/day) and clopidogrel (75 mg/day) is reasonable for up to a year after an acute coronary syndrome. (B) AVOID using more than 81 mg ASA if on ticagrelor - Brilinta


Caution when using Aspirin!

• According to JNC-7 do not recommend even low dose aspirin (IE 81mg) until blood pressure is controlled first as the risk of hemorrhagic stroke is increased.

• Data from the UK MRC Research Group in 5499 men age 45-69 with CV risk factors randomized to placebo or 75mg aspirin/day

Caution when using Aspirin!

• The risk of CV events was reduced by 45% in those with SBP <130mmHg and only 6% with SBP >145mmHg.

• The risk of stroke was reduced by 59% in those with SBP <130mmHg but hemorrhagic stroke increased by 42% with SBP >145mmHg.

• (BMJ 2000;321:13-17)

STENO Type 2 DM Trial (Lancet 1999;353:617-22/NEJM 2003;348;383-93)

• 160 patients (mean age 55, 74% men) with type 2 DM and urinary albumin excretion rate between 30 and 300mg/24hrs.

• Intensive treatment to control BP, glucose, & lipids, in addition to diet, exercise, and aspirin vs. standard care.

• All diabetic outcomes at 4 and 8 years (death, CV events, nephropathy, neuropathy and retinopathy).

STENO Type 2 DM Trial (Lancet 1999;353:617-22/NEJM 2003;348;383-93)

Outcomes Intensive Standard RRR NNT

Nephropathy 11% 25% 56% 7

Retinopathy progression 26% 43% 49% 6

Blindness in 1 eye 1% 9% 85% 13

Progression of autonomic neuropathy

11% 29% 62% 6

Combined death and macrovascular events

34% 54% 37% 5

Documents

Whats New in Type 2 Diabetes? Lots! C. Wayne Weart, Pharm.D. South Carolina College of Pharmacy MUSC Campus MUSC Department of Family Medicine January