JACC LogoJACC [2001] 37 (Suppl. A):299A (1302-163) [Poster Session, 50th Annual Scientific Session, American College of Cardiology, Wednesday 21 March 2001, 9:00 a.m. - 11:00 a.m., Orange County Convention Center, Hall A4, Orlando, FL]


Metformin Versus Other Oral Agents: Does the Choice of [Angiographic] Discharge Diabetic Medications Predict Mortality? Results from a Registry of 1,428 Diabetic Patients

ABSTRACT
[NDC Commentary]
[Doctors Guide Story]
[BMY Press Release]
Farangis Lavasani, Joseph
Brent Muhlestein, Benjamin D. Horne, Robert R. Pearson, Tami L. Bair, Sunni K. Kim, Chloe A. Allen Maycock, Kirti Salunkhe, Dale G. Renlund, Jeffrey L. Anderson. LDS Hospital, Salt Lake City, UT
CONTACT: Jess C. Gomez of LDS Hospital, 801-408-2182

Background: Diabetes Mellitus (DM) is a known risk factor for Coronary Artery Disease (CAD). Various oral medications that control hyperglycemia are available for the treatment of DM. It is not known, however, whether one oral medication is superior in preventing cardiovascular complications in diabetics with known CAD. The objective of this study was to evaluate the incidence of death or myocardial infarction (MI) during long-term follow-up of diabetic patients with CAD based on the type of diabetic medications (including metformin (MF), glitazones (GL), sulfonylureas (SU), and insulin) prescribed at the time of initial angiographic diagnosis.

Methods: A cohort of 1,428 patients (pts) with DM undergoing angiography at a single institution between 1994 and 2000 and documented to have severe (>=70% stenosis in a major coronary vessel) CAD were followed prospectively (mean, 2.5 1.5 years) for long-term clinical outcomes. Pt clinical, demographic, and procedural characteristics were recoreded and Cox regression controlled for these multiple covariates. Rates of death or MI in these pts were analyzed based on the type of DM medication strategy they received at hospital discharge.

Results: Patients averaged 65 11 years of age and 67% were male. The rate of mortality among those receiving MF (death=7.9%, n=215) was lower compared to GL (death=13.5%, hazard ratio [HR]=2.1, p=0.09, n=52), SU (death=15.7%, HR=1.7, p=0.049, n=681), and insulin alone (death=28.2%, HR=3.4, p<0.001, n=645). In multivariate regression, SU (HR=1.7, p<0.051) and insulin alone (HR=3.1, p<0.001) maintained independent predictive value for increased rates of death
compared to MF. The rates of MI was not different between treatment groups. In comparison to SU, sole use of insulin indicated an increased hazard of death (HR=2.0, p<0.001).

Conclusion: In this large prospective [non-randomized, uncontrolled] study, treatment of diabetic CAD patients with metformin was associated with improved survival when compared with sulfonylureas or insulin. Choosing insulin sensitization therapy as first line treatment in this population may therefore be advantageous, though this requires additional validation.


NDC comments and methodology concerns:

(1)
Baseline HbA1c and diabetes duration were NOT included in the model for regression analysis - Therefore, the treatment variables identified may represent purely surrogates for insulin secretory status [i.e., better beta-celled function in those on metformin or thiazolidinediones, worse beta-celled function in those on SFU's, and worst beta-celled function of all in those requiring exogenous insulin.] This data may only serve to confirm the already well-established association of baseline HbA1c [and/or disease duration] with macrovascular mortality.

(2) Since the incidence of MI's did not differ across treatment groups, what was the precise percentage of total mortality represented by macrovascular events and what were all of the specific modes of
exitus?

(3) Why does it appear that only insulin was analyzed as monotherapy? What were the respective data for all groups by specific monotherapy or specific combination of agents prescribed?

(4) Is there any duration of [specific or combination] drug exposure analysis
after angiography? If not, why not?

(5) How well did the diabetic prescription
after angiography correlate with that before or during angiography?

(6) Is there any specific drug-duration/exposure data available for these patients
prior to angiography?

(7) What was the prevalence of either multifocal (>1) or diffuse coronary lesions (>70% stenosed) across treatment groups at baseline?

(8) This uncontrolled, non-randomized, non-blinded, and non peer-reviewed poster may be but
hypothesis generating at best. At worst, it may be erroneous and misleading.
-Ed.
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DG DISPATCH - ACC: Metformin Outperforms Other Oral Agents In Diabetics With Severe Coronary Disease



By Jill Stein
Special to DG News


ORLANDO, FL -- March 22, 2001 -- Diabetics who have coronary artery disease (CAD) and are treated with the insulin sensitizer metformin have improved survival rates compared to those treated with sulfonylureas or insulin. This finding was reported at the 50th Annual Scientific Session of the American College of Cardiology (ACC).

Dr. Joseph B. Muhlestein and colleagues at LDS Hospital in Salt Lake City, Utah, prospectively followed 1,593
[sic! (1,428)] patients with diabetes and severe CAD who underwent angiography to determine their long-term clinical outcomes. Severe CAD was defined as a 70 percent or greater stenosis in a major coronary vessel.

The investigators recorded the patients' baseline clinical, demographic, and procedural characteristics as well as the diabetic medications administered at hospital discharge. They then analyzed the rates of death or myocardial infarction based on the anti-diabetic medication strategy they had received at the time of hospital discharge.

Diabetic medications administered upon discharge were categorized as follows: insulin only, a sulfonylurea (with or without insulin), glitazone (with or without insulin or a sulfonylurea) and metformin (with or without insulin, a sulfonylurea, or glitazone).

The mean age of the study population was 65 years, about two-thirds of the patients were men.

Results showed that only 17 (8 percent) of 215 metformin-treated patients died compared with seven (14 percent) of 52 patients who received glitazone, 109 (16 percent) of 681 patients who received a sulfonylurea, and 181 (28 percent) of 645 patients who received insulin alone.

Further analysis revealed that the use of a sulfonylurea and insulin alone predicted increased rates of death compared to metformin. The rate of myocardial infarction did not differ between treatment groups.

"Although observational in nature, the results suggest that selecting an insulin-sensitizing agent as first-line therapy in type 2 diabetics with CAD may be beneficial," Dr. Muhlestein suggested. He emphasized, however, that this hypothesis needs to be verified in further studies.

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Bristol Meyers' metformin increases type 2 diabetes survival



$$$$$

New York--March 22 (BridgeNews)--Bristol-Myers Squibb's Glucophage provided a better rate of long-term survival for patients with type 2 diabetes and coronary artery disease, according to a recent controlled study that compared the effect of Glucophage to other oral diabetes pills.

--Stephen Adler, BridgeNews



*                 *                    *

The following is the text of today's announcement with emphasis added by BridgeNews. BridgeStation links to company data have been inserted at the end:

Patients With Type 2 Diabetes and Coronary Artery Disease Have Improved


Long-Term Survival if Treated With Metformin

Study Results Show that Patients Treated with Metformin Have Improved Survival Rates vs. Patients Treated with Another Type of Oral Diabetes Pill or Insulin

Findings Presented During American College of Cardiology Annual Meeting

SALT LAKE CITY, MARCH 22 -- IT IS ESTIMATED THAT UP TO 20 PERCENT OF THE MORE THAN 15 MILLION AMERICANS WITH TYPE 2 DIABETES ALSO SUFFER FROM CORONARY ARTERY DISEASE, AND THIS NUMBER INCREASES WITH AGE. NOW, THE RESULTS OF A NEW STUDY MAY HELP PHYSICIANS TO MORE APPROPRIATELY TREAT THESE PATIENTS IN ORDER TO IMPROVE THEIR CHANCES OF LONG-TERM SURVIVAL.

ACCORDING TO THE RESULTS OF THE STUDY OF PATIENTS AT LDS HOSPITAL IN SALT LAKE CITY, PATIENTS WITH TYPE 2 DIABETES AND CORONARY ARTERY DISEASE (CAD) WHO WERE PLACED ON THERAPY WITH GLUCOPHAGE(r)(METFORMIN HYDROCHLORIDE TABLETS) AT THE TIME OF DISCHARGE FROM THE HOSPITAL HAD AN IMPROVED RATE OF LONG-TERM SURVIVAL VS., PATIENTS WHO WERE PLACED ON OTHER ORAL DIABETES PILLS, CALLED SULFONYLUREAS, OR INSULIN.

The results of the study, titled "Metformin versus Other Oral Agents: Does the Choice of Discharge Diabetic Medications Predict Mortality," were presented this week during the 50th Annual Scientific Sessions of the American College of Cardiology in Orlando, Florida.

"It has been well established that patients with type 2 diabetes are at increased risk of developing coronary artery disease," said Joseph B. Muhlestein, M.D., Director of Cardiac Research at LDS Hospital in Salt Lake City, Utah, and principal investigator of the study.

"While there are various medications available to help patients with type 2 diabetes to manage their condition, until now, there has not been data to indicate which of these medications has an advantage in helping to improve long-term survival in patients who also have CAD. The results of our large prospective study indicate that metformin may offer an advantage when used in treating this patient population," he says.

In order to evaluate the effects of metformin, investigators followed 1,428 patients with type 2 diabetes and documented severe CAD prospectively for an average of 2.5 years in order to evaluate long-term outcomes. The results of the study demonstrated that patients with type 2 diabetes and CAD who were prescribed metformin at the time of hospital discharge had a 13.5% [sic! (7.9%)] death rate vs. patients who were placed on sulfonylureas (15.7 percent death rate) or insulin (28.2 percent death rate). There was no difference in the rate of heart attacks experienced in all three patient groups.

"The results of this study point to the need for further clinical trials," said Dr. Muhlestein.

"In addition to CAD, type 2 diabetes can also lead to other serious complications such as kidney failure, blindness, amputations and stroke. The key to helping patients to avoid these serious complications is to provide

them with medications like metformin that not only allow them to manage their blood sugar, but also help them to avoid the additional medical conditions that are associated with this disease."

Metformin is sold under the tradename Glucophage(r) and Glucophage XR(r), a new extended-release version of Glucophage, which allows for once-a-day dosing. These drugs are marketed by Bristol-Myers Squibb (NYSE: BMY).

LDS Hospital is the flagship hospital of Intermountain Health Care's 22 hospital-network and serves as a major cardiac referral center for seven states and more than 100 regional health institutions throughout the Intermountain West.

SOURCE LDS Hospital

/CONTACT: Jess C. Gomez of LDS Hospital, 801-408-2182/


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