CONTROVERSIES IN ORAL HYPOGLYCEMIC

DRUGS

MARYAM ALSHEHHIPGY3 INTERNAL MEDICINEMCMASTER UNIVERSITY29 SEP 2010

Oral Hypoglycemic Drugs

Mechanism of Lactic Acidosis

O2

Glycolysis

Mechanism of Lactic Acidosis

O2

Glycolysis

✕

Biguanide

Such agents include metformin, phenformin, and buformin.

phenformin was discontinued in the US in 1976 because of probable association with lactic acidosis.

However, metformin is currently in common use in many parts of the world.

Metformin1995 metformin was introduced in US

1996 (FDA) received reports of lactic acidosis in 66 pts treated with metformin.

In 47 pts, diagnosis was confirmed with lactate >5 mmol/L .

N Engl J Med 1998; 338:265-266

Based on the estimate that 1 million Americans are taking metformin, the reported rate of confirmed lactic acidosis is about 5 cases per 100,000 or higher.

In an analysis of prescription and hospitalization data in Saskatchewan, Canada, Stang et al. reported 9 cases per 100,000.

N Engl J Med 1998; 338:265-266

The FDA indicated that

Metformin should be held in

1.Acute CHF

2.Sepsis

Not to be started in pt over 80 yrs old unless Crcl normal.

These restrictions significantly reduce the number of patients who could benefit from metformin treatment.

Cochrane Syst review 2010

To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies.

Cochrane Database of Systematic Reviews 2010, Issue 4.

Selection criteria

1.Prospective and observational cohort studies

2.Type 2 diabetes >1 month duration

3.Whom evaluated for metformin, alone or in combination compared to placebo or any other glucose-lowering therapy.

Interventions:

Metformin ( 1 -3 gm/day)

Comparison with

placebo, diet, insulin, glyburide (glibenclamide), gliclazide, glipizide, glimepiride, chlorpropamide, tolbutamide, acarbose, nateglinide, repaglinide, miglitol, troglitazone, rosiglitazone, pioglitazone, vildagliptin, sitagliptin, saxagliptin, dapagliflozin, and guar gum.

Effects of interventions

1-Incidence of lactic acidosis

-No cases of fatal or nonfatal lactic acidosis reported in the metformin group( 70,490 pt-yrs)

-No cases in the non-metformin (55,451 pt-yrs)

-Poisson statistics used

With 95% confidence, the upper limit for the true incidence of metformin-associated lactic acidosis was 4.3 cases per 100,000 pt-yrs, and 5.4 cases per 100,000 pt-yrs.

When combining data from metformin and non-metformin groups the upper limit for the true incidence of lactic acidosis in all patients with type 2 diabetes was 2.4 cases per 100,000 pt-yrs.

Blood lactate levels

Baseline (1.13 ± 0.25 mmol/L).

No difference in the net change of lactate levels from baseline for metformin compared to placebo or non-biguanide therapies, with a weighted mean difference (WMD) of 0.12 mmol/L (95% CI -0.01 to 0.25).

The mean lactate level during metformin treatment was 1.24 ± 0.31 mmol/L, which was not significantly different from non-biguanide

Results 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.

ConclusionThere 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.

The only evidence that metformin associated with lactic acidosis comes from reports of approximately 330 cases that have occurred in patients while on metformin treatment.

The incidence of lactic acidosis occurring in patients on metformin has been estimated from population studies to be 2 to 9 cases per 100,000 patient-years (Bodmer 2008; Misbin 1998; Stang 1999; Wilholm 1993).

Essentially all of the cases reported were in patients with severe underlying conditions that in themselves could have caused the lactic acidosis.

Table 1: Reports submitted to Health Canada of suspected adverse reactions (ARs) associated with thiazolidinediones from date marketed in Canada to Mar. 1, 2002*

Variable Rosiglitazone (Avandia)

Pioglitazone (Actos)

Date marketed in Canada

Mar 2000 Aug 2000

Total no. of AR reports 282 29

No. of serious reports 134 24

No. of reports with CV 60 8

No. of reports with liver and biliary disorders†

16 1

No. of reports with fatal outcome

10 1

Canadian Adverse Reaction Newsletter Volume 12 · Issue 3 · July 2002

TZD

Mechanism

Rosiglitazone

July 2010, 33 members of the joint advisory committee met and they agreed that the drug posed significant cardiovascular risk.

Doctor Guide Sep 23 AlertFDA Restricts Use of Rosiglitazone, EMEA Recommends Suspension

ROCKVILLE, Md -- September 23, 2010

The US Food and Drug Administration (FDA) announced that it will significantly restrict the use of the diabetes drug rosiglitazone (Avandia) to patients with type 2 diabetes who cannot control their diabetes on other medications.These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with rosiglitazone.On July 14, 2010, the FDA Advisory Panel voted to keep rosiglitazone on the market despite concerns over associated heart risks -- 20 members voted in favour, while 12 members voted to recommend that the FDA withdraw the drug.Today, the European Medicines Agency (EMEA) recommended the suspension of the marketing authorisations for rosiglitazone-containing anti-diabetes medications in Europe (Avandia, Avandamet, and Avaglim). These medicines will stop being available in Europe within the next few months. Physicians should stop prescribing rosiglitazone-containing medicines.

ADOPT TrialThe efficacy of TZD (Rosiglitazone) as compared

with other OHD (Metformin and Glyburide) in maintaining long term glycemic control in type 2 DM

Double–blind,RCT

4360 Type 2 DM,who had not received previous treatment for recently (diagnosed in 3 yrs) diagnosed DM

488 Centers in US, Canada and 12 European countries.

4 years

Included (Age:30-75, FBS:7-10mmol/L, on lifestyle modification only)

Excluded (significant hepatic disease, renal impairment, UA, H/O lactic acidosis, CHF and uncontrolled HTN)

Primary outcome :the time to monotherapy failure (FBS>10 mmol/L)

Secondary outcome: HbA1c,insulin sensitivity and beta cell function (using homeostasis model assessment)

4360 pts

Results

Results Higher rate of fractures.

Rosiglitazone

Metformin

Glyburide

Men 32 (3.95) 29 (3.36) 28 (3.35)

Women 60 (9.30) 30 (5.08) 21 (3.47)

Lower limb 36 (5.58) 18 (3.05) 8 (1.32)

Upper limb 22 (3.41) 10 (1.69) 9 (1.49)

spinal 1 (0.16) 1 (0.17) 1 (0.17)Incidence allowing for the period of exposure was 2.74 per 100 pt-yr with rosiglitazone, 1.54 per 100 pt-yr with metformin and 1.29 with glyburide

In addition in a large population-based study using the UK-based General Practice Research Database both pioglitazone and rosiglitazone associated with low trauma risk in men and women.

Pioglitazone (OR 2.59, 95% CI 0.96-7.01)

Rosiglitazone (OR 2,38,9, 95% CI 1.39-4.09)

What about Pioglitazone?

Proactive studyPROspective pioglitAzone Clinical Trial In

macroVascular Events

5238 pts from 19 countries,> 3yrs

RCT, in type 2 DM,age 35-75, HbA1c >6.5%

Pt on diet alone or OHD ,but not TZDs

Pt are at increased risk of macrovascular disease

(MI,stroke in the, PCI,CABG last 6 months,ACS……..)

Diabetes Care, Volume 27, number 7, July 2004

-Primary endpoint: composite all cause mortality

Nonfatal MI, ACS, cardiac intervention, stroke, major leg amputation or bypass

-Secondary end point:

Individual components of the primary outcome and

CV mortality

Diabetes Care, Volume 27, number 7, July 2004

ResultsPrimary outcome ,HR=0.90 (CI 95% 0.80-1.02)

Secondary outcome composite of all causes of mortality, MI or stroke

HR= 0.84 (CI 95% 0.72-0.98)

Current Cardiology Review,2009,Vol 5,No.3

Current Cardiology Review,2009,Vol 5,No.3

Sep,2.2010Pioglitazone poses same risk as rosiglitazone in

insurer’s study

Puplished by Circulation:Cardiovascular Quality and Outcomes.

36,000 pt

602 (4.16%) of rosiglitazone suffered MI, AHF or death compared with 599 (4.14%) of pioglitazone.

Sulfonylureas &cvsIn the recent past attention had been given to

SU and CV safety.

Potential impact on myocardial ischemic preconditioning.

Glibenclamide (Glyburide) bind to pancreatic ATP-sensetive channel (KATP) also bind on myocardial able to block myocardial preconditioning mechanism.

Other SU are pancreatic beta-cells specific.

The myocardium in a protective fashion, allowing greater tolerance of subsequent ischemia

Preconditioning will limit anginal pain ,minimize irreversible tissue injury and protect the myocardial function

ATP dependent potassium channels in myocardial cells play a role in this process.

Pharmacological agents that open KATP channels have protective effect ,while a gents closing it oppose preconditioning by ischemia.

KATP channels present also in the pancreatic beta-cell.

SU bind to a subunit of beta-cell KATPchannel complex (SU receptor) causing closure of the channel and stimulation of insulin secretion

SU bind to CV KATP channel causing closure of the channels and opposing preconditioning

A Systematic Review and Meta-Analysis of Hypoglycemia and Cardiovascular Events. A comparison of glyburide with other secretagogues and with insulin.

RCTs on Type 2 diabetes

Compared glyburide monotherapy with monotherapy using other sulfonylureas, meglitinides, or insulin

21 trials

Diabetes Care February 2007 vol. 30 no. 2 389-394

Outcomes: hypoglycemia (major, minor, or all), weight changes, Cardiovascular events included incident MI , stroke, amputation, CHF and cardiovascular death.

Comparator

Pts hypoglycemic episode [RR (95% CI)

All hypoglycemic episodes per pt-yr [rate ratio (95% CI)

CV events [RR (95% CI)

Death [RR (95% CI)

Weight gain (kg) [WMD (95% CI)

All secretagogues

1.52 (1.21–1.92) 42.1%

1.80 (1.06–3.09) 76.8%

0.84 (0.56–1.26) 12.6%

0.87 (0.70–1.07) 0%

1.69 (–0.41 to 3.80) 31.4%

Sulfonylureas

1.83 (1.35–2.49) 43.4%

1.44 (1.13–1.85) 17.6%

0.92 (0.71–1.19) 0%

0.79 (0.47–1.32) 33.7%

2.49 (–0.48 to 5.47) 4.9%

Insulin 0.88 (0.25–3.06) 92.5%

0.089 (0.019–0.408) 83.1%

0.89 (0.70–1.14) NA

0.97 (0.79–1.20) NA

–2.28 (–2.42 to –2.14) 0%

Glyburide caused more hypoglycemia than other secretagogues and other sulfonylureas.

Glyburide was not associated with an increased risk of cardiovascular events, death, or weight gain.

Conclusion

????Is SU (Glyburide) safe in type 2 DM ?

What about Metformin??

Avandia???

Actos???

Based on all that I think am the winner (Insulin)

Thank you