Click here for the The Pathophysiology Underlying Cardiovascular Mortality Results in a Worsening of Glycemic Control SlideShow

Click here for the Sulfonylurea Dose-Responsive and Sulfonylurea-Metformin Combination Mortality SlideShow

Home Page
Reload The National Diabetes Center Site
Abstract Summary

Type 2 diabetes mellitus and cardiovascular disease share common antecedents ("insulin resistance syndrome") which include vasoactive cytokines. Poor glycemic control in Type 2 diabetes associates very strongly with macrovascular disease. Nevertheless, improving glycemia long-term does not reduce macrovascular mortality^. (Only in the setting of acute MI does tight control of hyperglycemia with insulin appear to causally impact mortality.)

Impaired glucose tolerance - which is characterized by relative normoglycemia – associates by itself significantly with macrovascular disease which in turn associates strongly with increased levels of inflammatory vasoactive cytokines. Hyperglycemia - relentlessly progressive in type 2 diabetes - further associates quite powerfullywith increased levels of inflammatory vasoactive cytokines.

Agents which have been shown to causally diminish atherosclerotic events have also been seen to favorably impact glycemic control. Ramipril, an ACE inhibitor (in HOPE) , as well as pravastatin, an HMG-CoA reductase inhibitor (in WESCOPS) may actually not only improve glycemia but also delay progression to type 2 diabetes. Coumadin – a systemic anticoagulant - may also improve glycemic control (from observational data.)

Over the long-term, therefore, it would appear much more likely that it is the macrovascular disease process itself which drives hyperglycemia by increasing vasoactive cytokines which may (1) further exacerbate insulin resistance in the face of beta-cell exhaustion and/or (2) further diminish insulin secretion.

Data from the Mayo Clinic suggests sulfonylureas are associated with enhanced cardiovascular mortality following angioplasty procedures. In settings of randomized, controlled, clinical trials, low, fixed-doses of sulfonylureas seem to improve or not change mortality measures whereas high, fixed of sulfonylureas increase cardiovascular mortality.

Initial randomization to very low-potential hypoglycemic metformin monotherapy significantly improved cardiovascular mortality in the UKPDS. Initial randomization to very high-potential hypoglycemic metformin + sulfonylurea combination therapy significantly increased cardiovascular mortality in the same UKPDS.

US clinical trials submitted to FDA for metformin initial regulatory approval showed significantly increased mortality of patients randomized to metformin on combination metformin plus sulfonylureas. [Hypoglycemia was suggested to hve played a potentially causal role].

Obervational data from Malmo show increased mortality in diabetic patients taking combination metformin plus sulfonylureas. Data from the Bezafibrate Infarction Prevention Trial show an increased cardiovascular mortality from patients on combination metformin plus sulfonylureas.

Long-term pharmacologic interventions to very tightly control Type 2 diabetes not only are ineffective in reducing mortality, but may contribute to increased morbidity and mortality [except within the context of insulin in acute MI.] Patients with established coronary artery disease should therefore probably not be on sulfonylureas and should be well-controlled on insulin. Current ADA Treatment Guidelines for Type 2 glycemic control of target A1c at 7% and action point at 8% should be maintained and not tightened. The NIH ACCORD trial -Prevention of Cardiovascular Disease in Diabetes Mellitus ("Action to Control Cardiovascular Risk in Diabetes" - currently underway to test the "extremely tight control hypothesis" should also therefore be 2-tailed and the informed consent so revised.

INTRODUCTION
Elliot Joslin, one of the better-known names in diabetes care and research, noted back in 1927 how frequently diabetes appeared to be linked with atherosclerosis²¹. More recently, Michael Stern observed that type 2 diabetes mellitus and cardiovascular disease share common antecedents ("insulin resistance syndrome".)²² Very recently, elevated inflammatory markers, especially C-Reactive Protein (CRP) and the Erythrocyte Sedimentation Rate (ESR), have been noted to be elevated in the sera of patients with both atherosclerosis and type 2 diabetes^23,24,25

As opposed to that in Type 1 Diabetes, the major cause of morbidity and mortality in Type 2 diabetes is from macrovascular [cardiovascular] disease as opposed to microvascular disease^26,27,28.


Figure 1

Several lines of evidence have pointed to a fairly strong association of mortality in Type 2 diabetes with increasing blood sugar levels [both dependent and independent of duration of disease]. ^{29,30,31,32,33,34} "Statistically valid links" were first noted in 1965-1966^35,36,37


Figure 2 (Diabetes 1994 Aug;43(8):960-7 )


In a Finnish 3.5 year study at Kuopio 1 (Figure 2), coronary heart disease deaths and events are shown to increase by tertile of hemoglobin A1c. "In NIDDM subjects, only glycated hemoglobin A1c (GHbA1c) at baseline (P < 0.01) and duration of diabetes (P < 0.05) predicted CHD death (n = 15) and all CHD events (n = 33)." Moreover the HbA1c correlation was still seen across long and short periods of disease duration. The same trend was observed in the Wisconsin Epidemiology Study of Diabetic Retinopathy reported in 1994 by Ron Klein's group where statistically significant increases in the hazard ratios for diabetes mortality, ischemic heart disease, and stroke varied as a function of the hemoglobin A1c observed at baseline (Table 1).
TABLE 1



Steve Haffner and Michael Stern's group reported similar findings from the San Antonio Heart Study in 1998 (Table 3) showing highly significant (non-adjusted) relative risk of all-cause mortality in the highest quartile 4.2-fold that of the lowest two quartiles combined (p < 0.001) and cardiovascular mortality in the highest quartile 4.9-fold that of the lowest two quartiles combined (p = 0.01.) This was confirmed by 15 year follow up data from Kuopio in 1998 showing highly significant odds ratios for cardiovascular mortality of 6.2-fold and 11.2-fold (!) in men and women respectively, as well as those for all cause mortality of 5-fold and 5.2-fold, respectively (Table 2.)

TABLE 2



TABLE 3

(Diabetes Care 1998 Jul;21(7):1167-72)

The notion that blood sugar control might influence the degree of vascular disease (instead of vice-versa) is also somewhat dampened by the high degree of cardiovascular deaths seen in "borderline diabetes"³⁸ or impaired glucose tolerance^39,40,41,42 and was even completely called into question early on^.43,44

TABLE 4

In the Bedford Mortality Study data⁴⁵ viewed above (Table 4) it can be seen that the odds ratios for both CHD and all-cause mortality trended higher in overt or "borderline" diabetic patients versus their normal glucose tolerant controls. In the Paris Prospective Study data⁴⁶ viewed below (Table 5), these values for the relative risks of all-cause mortality achieved statistical significance in (1) impaired glucose tolerant, (2) "newly diagnosed" diabetics, and (3) established diabetics compared to their normal glucose tolerant controls. The values for the relative risks of CHD mortality, however, achieved statistical significance only in "newly diagnosed" diabetics.

TABLE 5


In the Malmohus County Study⁴⁷ presented below in Table 6, however, age-sex adjusted total and cardiovascular death rates are statistically significantly higher in IGT than in normal glucose tolerance, and statistically significantly higher in diabetes than in IGT. Impaired glucose tolerant individuals have intact 2nd phase and fasting insulin responses^{48,49,50,51,52}. Were accelerated CHD to result in some factor[s] which further increased insulin resistance, this would translate into higher sugars in overt or "new-onset"diabetics, but not necessarily so in their "better beta-celled" IGT cousins⁵³.

TABLE 6

The statistically significant increased incidence of CHD mortality in an IGT population with normal glycohemoglobin A1c levels only a portion of whom will go on to develop type 2 diabetes is somewhat further evidence against the notion of specifically glycemic-driven long-term cardiovascular mortality.

About this linkage, Harry Keen argued back in 1968 as follows:-

If this epidemiological data that worsening glucose control portends increased cardiovascular mortality is indeed correct, then it ought to be fairly simple and straightforward to show that improving glucose control reduces cardiovascular mortality. There is good prospective data in the short-term, that tight glucose control with insulin during acute myocardial infarction does improve over-all survival^.55 Nevertheless, in the long-term this turns out not to be the case. Not just one but two^56,57 major prospective, long-term clinical trials in the latter half of the last century - both specifically designed and powered to address cardiovascular mortality - have failed to show any mortality benefit from tighter control of Type 2 diabetes. Moreover, only one of the two trials consisted of unadulterated treatment groups (UGDP.) In that trial the untreated group fared better than the groups treated with oral medications. The real question, then, is, "Given the epidemiological data, why hasn't tight control improved long-term cardiovascular mortality?" Indeed, was Dr. Keen wrong in his leap to faith?

Several possible explanations come to mind. First, it may be that diabetic cardiovascular mortality is simply dependent on baseline HbA1c and remains independent of glycemic intervention. [Clinical trials begin with similar baseline control.] Indeed, perhaps hyperglycemia in diabetes may to some extent represent the degree of atherosclerosis (rather than vice versa.) Secondly, it is possible that the medications used to treat Type 2 diabetes in these trials either were inherently unsafe or were prescribed in an unusually unsafe manner. Thirdly, might it be that total mortality increased due to malignancies induced or accelerated by the growth-enhancing effects of insulin or its secretagogues? Penultimately, it may also be possible that increases in mortality are associated with both very tight and very loose blood sugar control, i.e, a 'U-Shaped Curve' exists in Type 2 diabetes for blood sugar control. Finally, any or all of the above could be potentially operative.

Data from the UKPDS show that no matter what the therapeutic modality employed or the intensivity of the treatment arm suggested, there was relentless progression of glycemia over the course of the study (Figure 3). What could be responsible for the sustained deterioration of glycemia?


Figure 3
There is some newly emerging data that atherosclerosis, type 2 diabetes, and obesity are all characterized by increased plasma or serum levels of inflammatory vasoactive cytokines. M. Visser and colleagues have reported in JAMA⁵⁸ that, "Higher BMI is associated with higher CRP concentrations, even among young adults aged 17 to 39 years. These findings suggest a state of low-grade systemic inflammation in overweight and obese persons." Hak et al⁵⁹ reported in Arteriosclerosis, Thrombosis, and Vascular Biology in 1999 that C-Reactive Protein associates with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women. Also, John Yudkin's group has data recently published that "adipose tissue is an important determinant of a low level, chronic inflammatory state as reflected by levels of interleukin-6, tumor necrosis factor-, and C-reactive protein, and that infection with H pylori, C pneumoniae, and cytomegalovirus is not …[and] support the concept that such a low-level, chronic inflammatory state may induce insulin resistance and endothelial dysfunction and thus link the latter phenomena with obesity and cardiovascular disease."⁶⁰ Additionally, data from the Hoorn study show that not only does CRP, but also increased levels of von Willebrand's factor "are independently associated with cardiovascular and all-cause mortality in both diabetic and nondiabetic subjects….Mutual adjustment of vWf and CRP did not markedly change the results, favoring the hypothesis that vWf and CRP predict mortality through different pathways."⁶¹ Finally, recent data we have been compiling from our own clinical experience is suggesting that coumadin may improve glycemia⁶². All of the above may lend some credence to the notion that OVER THE LONG-TERM, IT MAY BE MORE LIKELY THAT MACROVASCULAR DISEASE DRIVES HYPERGLYCEMIA [BY INCREASING VASOACTIVE CYTOKINES WHICH MAY FURTHER EXACERBATE INSULIN REISTANCE IN THE FACE OF BETA-CELL EXHAUSTION.]

Type 2 diabetes accounts for 90-95% of the total number of patients with diabetes mellitus⁶³ . It is certainly less homogeneous than Type1 diabetes (insulin-dependent diabetes mellitus) although the majority (70%) of patients who comprise Type 2 diabetes manifest obesity as some basis of their pathophysiology. The evidence for this is: (1) not only are they obese at diagnosis⁶⁴, but (2) their disease dissipates with weight loss significant to the order of 5.00 to 10.00 kg/m2 of Body Mass Index (BMI) ^{65,66,67,68,69} and (3) it is more difficult for obese Type 2 diabetes patients to lose weight than their obese non-diabetic counterparts⁷⁰. Nutritional status is therefore a key pathogenic component of a majority of patients with Type 2 diabetes. Nevertheless, insufficient insulin secretion to overcome hepatic [and peripheral] insulin resistance seems to be the common pathophysiologic thread weaving its way throughout disorders currently classified as Type 2 diabetes⁷¹.

Since the genetic/concordance data are much stronger for Type 2 diabetes, than for Type1 diabetes^72,73 investigators are feverously searching for the molecular basis of the defect [or defects] in Type 2 diabetes. Obesity itself, though, has also been shown to have a very strong genetic predisposition^74,75. Given the above data relating obesity to Type 2 diabetes, perhaps a significant genetic link which has been observed in non-diabetic offspring of Type 2 diabetes patients might associate more closely with obesity [which in turn correlates with hyperinsulinemia] than with glycemia, per se⁷⁶. Several lines of evidence point to the counter-regulatory effects - both increasing insulin resistance and decreasing insulin secretion - of (1) Leptin (2) neuropeptide-Y and/or (3) TNF-beta as a likely function of adipose-cell mass^77,78,79,80.

Sulfonylureas represent a class of drugs which bind to receptors controlling the ATP-sensitive "potassium channel" - the major regulator of voltage differences across the cellular membrane. Identified previously as "SUR" [for "SulfonylUrea Receptor"] and now known as "SUR1", it is found in the insulin-producing cells of the pancreas. SUR1 is also found in the hypothalamus and is the likely physiological Leptin response element⁸¹. Leptin is a hormone released by fat cells in direct proportion to cell size (or degree of adiposity) and when Leptin binds to this receptor in the pancreas, it opens the potassium channel thereby inhibiting insulin release. This may be the major mechanism whereby obesity causes type 2 diabetes. The major pharmacological response to this abnormality has been the use of sulfonylureas, which close these same potassium channels thereby offsetting the leptin inhibition and increasing insulin release.

Unfortunately another sulfonylurea receptor ["SUR-2a") also exists in the vascular smooth muscle cells which control blood flow to the heart and other muscles based on metabolic demand. The effect of closing these SUR-2a potassium channels is to diminish blood flow to the heart. Although sulfonylurea agents differ in their affinity to bind to these SUR-2a receptors, the binding of all agents - including tolbutamide - is increased at higher concentrations⁸². This binding is also a function of ADP concentration - which has unfortunately been neglected in many studies evaluating the putative binding affinity of these hypoglycemic agents⁸³. Higher affinity SUR-2B sites are found in the cardiac smooth muscle cells where they may modulate the vasodilatory response to ischemia^84,85,86. Furthermore, another set of kATP channels exist not in the myocardial sarcolemma membrane, but in their mitochondrial membranes. These mitochondrial kATP channels appear to be extremely important in ischemic survival potential and to resemble more of the SUR-2B receptors in terms of their peculiar binding affinities⁸⁷. One question we set out to answer was, therefore, "Are higher doses of sulfonylureas associated with increased cardiovascular mortality?"


We have reviewed data from 11 major studies⁸⁸ - (1) the UGDP study in the United States (2) the UKPDS study in Great Britain (3) the metformin pivotal trials for registration with the FDA (4) the Digami study of patients with myocardial infarction in Sweden (5) the Neufeld study in Israel [6] the Melander Study in Uppsala, Sweden (7) the Garratt study of angioplasties at the Mayo Clinic (8) the Campbell studies of sulfonylurea-induced hypoglycemic mortality (9) the Malmohus County Study (10) the Bedford [Intervention ] Study and (11) the Serafimerlassarettet study in Stockholm.

Phase 1: Question: Is there substantial data that sulfonylureas cause increased cardiovascular or total mortality?
Methods: Review of prospective and retrospective studies
Trials included:
UGDP
UKPDS
Garratt/Mayo
Campbell/hypoglycemia.

Results:
(1)The UGDP did show an increase in cardiovascular deaths of +806 ± 353 per 10,000 treated patients without a significant increase in total mortality (Table 8). However, it utilized a high, fixed dose of tolbutamide (4g/day.)
(2)The UKPDS data is too confounded to draw reliable conclusions - except in terms of the initial prescription. Limited to that perspective, initial prescription for sulfonylureas fared no worse than that for dietary therapy or insulin.
(3)The Garratt study was limited to diabetic patients unergoing angioplasty for acute myocardial infarction comprised of 67 patients on sulfonylureas and 118 controls. It was also retrospective and subject to selection bias - nevertheless, the inpatient mortality was 24% in the sulfonylurea group and 11% in the controls (p =0.02). The relative risk of mortality using the Cox Propotional hazards model was 2.77-fold in the sulfonylurea group. The excess risk of mortality was 1290 ±595 [95% CI 120 to 2450 deaths] per 10,000 patients.
(4)The Campbell review of "sulfonylurea-induced hypoglycemia" culled from the world literature 1940-1982 showed 670 reported cases with 56 deaths. Data from Swedish Adverse Drug Reaction Advisory Committee (SADRAC ) from 1972 to mid 1981 showed 51 cases of glyburide-induced hypoglycemia and Campbell reviewed an additional 6 cases. The median age was 75 years old and 21% were 85 years old or older. The mean daily dose of glyburide was 10 mg (perhaps the daily equivalent to 2g tolbutamide.) Twenty-four patients had protracted hypoglycemia of 12-72 hours duration and 10 died. The mortality risk for glyburide-induced hypoglycemia was calculated to be 1,754 [95% CI 875 to 2990 deaths] per 10,000 afflicted patients or 19 [95% CI 7.22 to 30.7] per 10,000 treated patients or 0.332 [95% CI 0.126 to 0.539] per 10,000 patient years.89)

Conclusion:
(1)There may be excess risk of hypoglycemic or cardiovascular deaths ranging from as low as 19 to as high as 1290 deaths per 10,000 treated patients from the use of sulfonylurea agents. The high excess mortality seen during angioplasty for acute MI should be compared to the 138/314 patients non-insulin group who died in the Digami90 study versus the 102/306 patients who died in the intensive insulin group during that trial (of diabetic patients with acute MI). That group manifested an excess mortality of 1060 ± 389 (95%CI 300 to 1820 deaths) per 10,000 patients. It may be that the risk of sulfonylurea therapy in that situation could be ascribed, at least in part, to the lack of intensive insulin treatment provided under similar background circumstances.
(2)The high excess mortality seen in the UGDP may be due to excessive doses of tolbutamide prescribed and, thereby, to the significantly increased risk of hypoglycemia [or SUR-2B/mito kATP closure]


Phase 2: Question - Is there a dose-response of sulfonylureas in terms of total or cardiovascular mortality?

Methods: meta-analysis of only randomized, controlled trials limited to fixed doses of a single sulfonylurea (tolbutamide.) Pooling was done across all studies in each strata for tolbutamide versus control groups and analyzed for excess risk using 95% confidence intervals. The observation periods for the strata had to be comparable as well. The strata were then compared for difference in excess mortality again using 95% confidence interval analysis.

Low-dose stratum trials included:
1.The Serafimerlassarettet Study - a study of secondary prevention in 178 post-MI patients with abnormal IVGTT consisting of 145 men mean aged 58 years and 33 women mean aged 68 years. The observation time ranged from 12-66 months with mean of 3 years. Randomization was based on birthdate to 83 patients on placebo and 95 patients on tolbutamide. The dose of tolbutamide was titrated up to a maximum of 1g/day "in the absence of hypoglycemic symptoms."
2.The Bedford [Intervention] Study⁹¹- consisted of 103 patients with a 2hr pc glucose of 100-200 mg/dl ("borderline diabetics") from the population previously described in Table 4. Fifty-eight patients were randomized to placebo and 55 to tolbutamide. Baseline demographics were evenly matched. Follow-up was for 8 years. Tolbutamide dosage was 500 mg po bid
3.The Malmohus County [Intervention] Study - was conducted in 147 IGT men from the population previously described in Table 6. Randomization was to 48 patients on placebo, 50 patients on "no tablet," and 49 patients on tolbutamide. Patients were followed for 20+ years. The dose of tolbutamide was 500 mg po tid
High dose stratum included the UGDP trial arms of tolbutamide versus dietary therapy (previously described)

Results:

1.Table 7-Tolbutamide showed a significant cardiovascular mortality benefit of -776 ± 314 deaths per 10,000 treated patients with 95%CI (-161 to -1390 deaths) per 10,000 treated patients in the low-dose stratum
2.Table 8 - Tolbutamide showed a significant cardiovascular mortality excess of +806 ± 353 deaths per 10,000 treated patients with 95%CI (+115 to +1500 deaths ) per 10,000 treated patients in the high-dose stratum
3.Table 7 -Tolbutamide showed a significant all-cause mortality benefit of -1310 ± 377 deaths per 10,000 treated patients with a 95%CI (-566 to -2040 deaths) per 10,000 treated patients in the low-dose stratum
4.Table 8 - Tolbutamide showed a non-significant all-cause mortality excess of +377 ± 462 deaths per 10,000 treated patients with 95%CI (-529 to +1280 deaths per 10,000 treated patients in the high dose stratum

STRATA COMPARISONS
5.The high-dose Tolbutamide stratum showed a highly significant cardiovascular mortality excess over the low-dose stratum of +1578 ± 24 deaths per 10,000 treated patients with 95%CI (+1530 to +1630 deaths) per 10,000 treated
6.The high-dose Tolbutamide stratum showed a highly significant all-cause mortality excess over the low-dose stratum of +1687 ± 3 deaths per 10,000 treated patients with 95%CI (+1630 to +1750 deaths) per 10,000 treated
.
Table 7



Table 8



Phase 3: Question: Is there some way to explore the possibility that hypoglycemia might contribute to excess total or presumed cardiovascular mortality?

Methods:

1.Meta-analysis of 2 randomized, controlled UKPDS subtrials of the same drug -metformin - under stratified conditions of [1] low-hypoglycemic potential (monotherapy) and [2] high-hypoglycemic potential (combination therapy with sulfonylurea when the fasting sugar was at least 6 mm/L or 108 mg/dl) Analysis to be done across both studies (strata) for (a) metformin versus conventional and (b) SFU monotherapy versus SFU combination with metformin groups and analyzed for excess risk using 95% confidence intervals. The strata to be then compared for any difference in excess mortality again using 95% confidence interval analysis.



Table 9

Table 10

RESULTS:

1.Table 9- Metformin showed a significant cardiovascular mortality benefit of -529 ± 219 deaths per 10,000 treated patients with 95%CI (-100 to -958 deaths) per 10,000 treated patients in the low-hypoglycemic potential stratum
2.Table 9 - Metformin + Sulfonylureas showed a significant cardiovascular mortality excess of +450 ± 221 deaths per 10,000 treated patients with 95%CI (+17 to +882 deaths ) per 10,000 treated patients in the high-hypoglycemic potential stratum
3.Table 10 -Metformin showed a significant all-cause mortality benefit of -703 ± 279 deaths per 10,000 treated patients with a 95%CI (-157 to -1250 deaths) per 10,000 treated patients in the low-hypoglycemic potential stratum
4.Table 10- Metformin + Sulfonylureas showed a significant all-cause mortality excess of +601 ± 303 deaths per 10,000 treated patients with 95%CI (+7 to +1200 deaths per 10,000 treated patients in the high-hypoglycemic potential stratum

STRATA COMPARISONS
5.The high-hypoglycemic potential Metformin + Sulfonylurea stratum showed a highly significant cardiovascular mortality excess over the low-hypoglycemic potential stratum of +979 ± 12 deaths per 10,000 treated patients with a very tight 95%CI (+955 to +1000 deaths) per 10,000 treated
6.The high-hypoglycemic potential Metformin + Sulfonylurea stratum showed a highly significant all-cause mortality excess over the low-hypoglycemic potential stratum of +1300 ± 16 deaths per 10,000 treated patients with a very tight 95%CI (+1270 to +1340 deaths) per 10,000 treated

These data appear quite robust in that the cardiovascular mortality difference in the tolbutamide studies across (different hypoglycemic potential) strata of +1578 ± 24 deaths per 10,000 treated patients [over an average of 9.73 years] compares favorably to the +979 ± 12 deaths per 10,000 treated patients [over an average of 10 years] seen across strata in the the UKPDS analyses. Likewise, the all-cause mortality difference in the tolbutamide studies across (different hypoglycemic potential) strata of +1687 ± 3 deaths per 10,000 treated patients [over an average of 9.73 years] compares favorably to the +1300 ± 16 deaths per 10,000 treated patients [over an average of 10 years] seen across strata in the the UKPDS analyses.


Phase 4: Question: Is there additional data available that either hypoglycemia or sulfonylurea-metformin combination or both might contribute to excess total or cardiovascular mortality?

Methods:

I.Review of the mortality data for hypoglycemic potential of metformin plus sulfonylurea combination within the pivotal trials submitted to the FDA for initial metformin registration
II.Review of the mortality data seen in the Bezafibrate Infarct Prevention Trial in Israel for metformin plus sulfonylurea combination
III.Review of the Swedish Surveillance Study - an observational mortality data seen recently in Sweden for metformin plus sulfonylurea combination

Results:

I. Pivotal US clinical trial data for metformin⁹²

HYPOGLYCEMIA:
There was a highly significant increase in hypoglycemia manifested by patients taking combined metformin-sulfonylurea therapy in all controlled trials submitted in this NDA. Combined therapy had an 14.5% excess in hypoglycemia compared with controls for which the 99% CI was 7 to 22

Though none of these in the short-duration double blind phase appeared to be severe, there were 5 severe and 94 moderate hypoglycemic episodes seen in the US open enrollment 1C trial.
Table 11

Clinical Pharmacology data
The highly significant major toxicity, morbidity, and mortality seen in this NDA from therapy with metformin were all seen in patients with sulfonylurea-failure (p <0.01).
Glibenclamide appeared to significantly increase plasma metformin levels in clinical trials despite the lack of effect in a single dose interaction study. [There were significantly higher drug levels of metformin (p <0.05) in patients also on glibenclamide at both the 1000 (MTD 195 mcg/ml with 95% CI of 3.69 to 386 mcg/ml) and 2500mg (MTD 112 mcg/ml with 95% CI of 6.2 to 218 mcg/ml) metformin dose levels when compared to patients at the same doses on metformin monotherapy (in the 87-2D study).]
US Clinical Trial data93

The data submitted for the approval of metformin for use in the United States were from two 29-week clinical trials involving patients with non-insulin-dependent diabetes mellitus (Type 2 diabetes), reported by DeFronzo et al. (Aug. 31 issue), (1) and one 2-year, unreported, open-enrollment study. (2) One of the clinical trials was placebo-controlled, with 143 patients assigned to receive metformin and 146 to receive placebo. In the second trial, 210 patients were assigned to monotherapy with metformin, 213 to metformin plus glyburide, and 209 to glyburide alone.

Six hundred two of these patients chose to enroll in the open study to receive metformin with or without a sulfonylurea drug: 75 patients from the placebo group, 142 from the glyburide group, 217 from the metformin groups, and 168 from the metformin-plus-glyburide group. With the open study, the total duration of metformin treatment during all U.S. open and controlled studies was increased to 1136 patient-years.
There was one death in the controlled trials, and there were six additional deaths in the open study. All seven deaths occurred among the patients who had initially been assigned to metformin therapy; no deaths occurred among those initially assigned to glyburide or placebo. A comparison of the survival distributions in the treatment groups by the log-rank test revealed a significant difference from the expected distribution of 4.4 deaths in the metformin group and 2.6 deaths in the control group (P = 0.04). Moreover, all seven deaths occurred among 423 patients (1.7 percent) randomly assigned to therapy with metformin in the second study. An analysis of survival in this subgroup revealed no statistically significant difference from an expected distribution of 4.9 deaths in the metformin group and 2.1 in the control group (P = 0.09). The shortest duration of treatment resulting in a death was 97 days, and the longest was 825 days (mean [±SD], 463±242 days).

Five of the seven deaths were from cardiovascular causes (including one case of lactic acidosis and another of sudden death after newly developed glomerular dysfunction). Another death was ascribed to suicide. A 1994 review of 255 cases of metformin-associated lactic acidosis (2) revealed a significant proportion of cases due to suicidal overdose (4.7 percent; 95 percent confidence interval, 2.5 to 8.1 percent; P<0.01). The seventh death was ascribed to pulmonary fibrosis in a patient with a small-cell carcinoma of the lung.

Morbidity and mortality in patients with Type 2 diabetes are primarily from cardiovascular complications, which have not been found to be correlated with glucose control in any well- designed studies. (3) Because of the substantial morbidity and mortality from cardiovascular causes in patients with this disorder, it is difficult to discern drug-induced cardiovascular toxicity. Wishing to monitor potential metformin-associated mortality, and without the benefit of the data on excess metformin-associated mortality noted above, the Endocrinologic and Metabolic Drugs Advisory Committee of the Food and Drug Administration (FDA) recommended on March 18, 1994, that a registry be established for all patients given metformin in the United States, should the drug be approved. (4) So far, the FDA has not acted on this recommendation. A one-year study of 8000 patients receiving metformin alone or combined with a sulfonylurea drug and 2000 control patients has been requested by the FDA. This marketing study should allow the detection of differences in the rates of clinically important adverse events but will not detect small differences in overall mortality or mortality from cardiovascular causes.

It is true that (7%) more of the metformin patients elected to be followed in the open-extension than did glibenclamide patients. Nevertheless, it is of no small note that all 7 of the deaths in the US trials emanated not only from the 87-2D study, but only from the metformin arms of that trial. On an intent-to-treat basis there were 7 deaths out of 426 patients exposed to metformin in that trial versus 0 deaths in 209 patients not originally randomized to metformin but randomized rather to monotherapy with glibenclamide. The mean treatment difference of having been randomized to metformin (alone or in combination with glibenclamide) versus having been randomized to glibenclamide alone was 1.64% - 99% CI (0.0541 to 3.23%) - i.e., significant at the p < 0.01 level. Considering that 1 death was due to cancer and another to suicide, then excluding these deaths from analysis reveals a mean treatment difference of 1.17% with a 95% CI of 0.151% to 2.20% and a 99% CI of -0.173% to +2.52% - i.e., still significant at the p<0.05 level. The same levels of significance apply to consideration of ITT evaluation of deaths in all patients in the pooled Category i trials by exposure to metformin. At any rate, all six of the deaths in the open-enrollment phase were on combination therapy at the time of death. A Kaplan-Meier analysis revealed that the event rate was enriched at the end of observation to its maximum of 29.22 deaths/1000/year. [Over the entire observation period the mortality rate averaged 14.58 ±8.03 deaths/1000/year.]

Two major questions emerge from such an analysis:

1.Were patients originally randomized to metformin in the 1D study protected and, if so, by what mechanism?
2.Were patients originally randomized to glibenclamide monotherapy in the 2D study also protected and, if so, by what mechanism?

Duration of exposure may not be the answer. The smallest duration of exposure to metformin in this group was 14 days. The longest was 783 days. The mean was 498.28 ñ 209.70 days. These compare quite favorably to the statistics manifested by those patients from the other two groups in the 2D study who died.

The answer to the first question may have to do with lack of enough power to detect a difference in that arm. The answer to the second question may not be so readily apparent. The major bug-a-boo relates to the notion that the glibenclamide-monotherapy patients had relatively similar and sufficient durations of metformin exposure to the other two groups and came from the same sulfonylurea-failure population at risk. The simplest solution would be to say that there was not enough power in that arm alone to warrant any conclusion of protection. Nevertheless, the difference between the glybenclamide lack of deaths and the seven deaths in the other two arms was statistically significant at a p < 0.01. What other possible explanations exist as to why no mortality was seen in that arm, if valid? A conceivable answer may lie in the design features of the double-blind portion of the study. The patients on metformin in the double-blind study had to be rapidly titrated up to, and, for the most part kept on, maximum doses of metformin (i.e., 2500 mg day) on top of maximum doses of glibenclamide. When glibenclamide-monotherapy patients entered the 1C study the following occurred:
1) a time lag was likely from the cessation of the 2D study
2) whatever sulfonylurea patients were taking at the time needed to be completely discontinued
3) no retitration of metformin would have been necessary
4)these patients would have been forced to discontinue sulfonylurea completely, then have metformin titrated upward in biweekly 850mg increments, and then have their previous sulfonylurea - which was not necessarily glibenclamide - retitrated upwards. This strategy is unlike the 2D combination arm in which metformin was titrated upward more gradually in weekly 500mg increments on top of maximum glybenclamide therapy (which could not be reduced.) Another intriguing lead relates to selection bias, the argument being that glybenclamide-randomized patients who elected open-enrollment were somehow more resistant to metformin toxicity than those who opted out. Here is some additional analysis:

Tables 12-15


1.The calculated total HbA1c [enrollment vs non-enrollment] selection bias (difference from the glyburide selection difference versus the metformin selection difference) was - -3.92 ± 0.0243 (95%CI -3.87 to -3.97% total Hb. This represents an average selection bias in initial blood sugars of -117 mg/dl.
2.The specific enrollment HbA1c bias difference was -2.13 ± 0.176 (95%CI -1.78 to -2.48% total Hb) implying that blood sugars were initially an average of 65 mg/dl lower in the metformin group than the glyburide group entering open enrollment combination therapy.

(a)The selective self-removal of better controlled glibenclamide patients from open enrollment (b) the decreased incidence of death in that arm followed in open enrollment combination therpay taken with (c) the the selective self-installation of better-controlled metformin patients into open enrollment and (d) the increased incidence of death in that arm followed in open enrollment combination therapy taken with the (e) highly significant increase in hypoglycemia seen with combination therapy suggests that hypoglycemia may be a significant contributing factor to the deaths seen in the other two arms.

The patients at risk of metformin-induced mortality in the US trials appear to be solely those with sulfonylurea-failure. It is difficult to sort out the precise mechanisms which may underlie this association. The University Group Diabetes Program showed significant excess mortality independently in both the sulfonylurea and biguanide arms - but no study was made of the potential additive effects of the two classes of medication taken simultaneously. The significant excess mortality displayed by the combination therapy among patients with sulfonylurea-failure in the comparatively well-underpowered US trials may, indeed, be a function of this additive phenomenon.

The sulfonylurea-failure excess risk was 1.65% with a 99% CI of 0.0545 to 3.26%. A Kaplan-Meier analysis revealed that the event rate was enriched at the end of observation to its maximum of 29.22 deaths/1000/year. [Over the entire observation period the mortality rate averaged 14.58 ± 8.03 deaths/1000/year.]


Figure 4

II. Swedish Surveillance Study⁹⁴

Against the notion of hypoglycemic predisposition is this study from 2 counties in Sweden prompted by the excess mortality found in the UKPDS early randomization study [of sulfonylurea patients to combination with metformin.] In this study the group analyzed on metformin plus sulfonylurea combination had a hemoglobin A1c of 8.3% (n=169 with 30 missing data) as opposed to the sulfonylurea group who had a hemoglobin A1c of 7.3% (n=741 with 195 missing data.) The average fasting sugars of the groups were 185 and 158 mg/dl, respectively.


This study also echoed the increased stroke mortality seen in the UKPDS combination sub-study (fatal stroke odds 5-fold increased in the combination arm.)

III.The Bezafibrate Infarction Prevention Trial⁹⁵

This study included over 3000 patients in Israel to test whether or not triglyceride reduction with bezafibrate improved mortality. Fortunately or unfortunately, this effect was not found. What was found, however, was increased mortality from patients in the screening group who were taking sulfonylurea alone or in combination with metformin. "The study sample comprised 11,440 patients with a previous myocardial infarction and/or stable anginal syndrome, aged 45-74 years, who were screened, but not included in the Bezafibrate Infarction Prevention study. Among them, 9,045 were nondiabetics and 2,395 diabetics. The diabetic patients were divided into four groups on the basis of their therapeutic regimen at screening….All NIDDM groups were similar with regard to age, gender, hypertension, smoking, heart failure, angina and prior myocardial infarction. Crude mortality rate was lower in the nondiabetic group (11.21 vs. 21.8%; p < 0.001)."
Table 17


Echoes of the UGDP. The data here again shows significantly increased mortality of sulfonylureas alone which is very significantly increased even above that when sulfonylureas are used in combination with metformin. The significance of sulfonylureas alone, but not of the combination, appears to diminish when duration of diabetes is included in multi-regression analysis. Interestingly enough, here there is no statistically significant increased mortality of the metformin monotherapy versus diet alone or of the combination versus metformin monotherapy. However, the metformin monotherapy arm is significantly underpowered.

In a secondary prevention population of diabetics [with established coronary artery disease,] the data from the Digami Study, the Jarratt Study, and the Bezafibrate Infarction prevention Study all suggest that therapy with oral agents may be detrimental. The Bezafibrate study suggests that sulfonylureas alone or in combination with metformin over the long-haul may result in excess mortality in this population. The Jarratt study suggests that any sulfonylurea therapy while undergoing angioplasty during a peri-infarct period is associated with excess mortality. Thee Digami study suggests that tight control only with insulin results in improved mortality during the peri-infarct period.



CONCLUSIONS:
1.Type 2 diabetes mellitus and cardiovascular disease share common antecedents ("insulin resistance syndrome")⁹⁶ which include vasoactive cytokines⁹⁷
2.Type 2 diabetes also associates significantly with macrovascular disease⁹⁸ and mortality in Type 2 diabetes associates with increasing blood sugar levels [both dependent and independent of duration of disease]. ^{29,30,31,32,33,34,35,36,37}
3.Only in the setting of acute MI, however, does hyperglycemia appear to causally impact mortality⁹⁹
4.Improving glycemia long-term does not reduce macrovascular mortality^100,101
5.Impaired glucose tolerance - which is characterized by relative normoglycemia - associates significantly with macrovascular disease¹⁰²
6.Atherosclerosis per se is significantly associated with increased levels of inflammatory vasoactive cytokines¹⁰³
7.Hyperglycemia is relentlessly progressive¹⁰⁴ in Type 2 diabetes and also associated with increased levels of inflammatory vasoactive cytokines¹⁰⁵
8.Coumadin - a systemic anticoagulant - may actually somewhat improve glycemia
9.OVER THE LONG-TERM, HOWEVER, IT IS MORE LIKELY THAT MACROVASCULAR DISEASE DRIVES HYPERGLYCEMIA [BY INCREASING VASOACTIVE CYTOKINES WHICH MAY FURTHER EXACERBATE INSULIN RESISTANCE IN THE FACE OF BETA-CELL EXHAUSTION]
10.Data from the Mayo Clinic suggests sulfonylureas are associated with enhanced cardiovascular mortality following angioplasty procedures¹⁰⁶
11.In settings of randomized, controlled, clinical trials, low, fixed-doses of sulfonylureas seem to improve¹⁰⁷ or not change¹⁰⁸ mortality measures whereas high, fixed of sulfonylureas increase¹⁰⁹ cardiovascular mortality
12.Initial randomization to very low-potential hypoglycemic metformin monotherapy significantly improved cardiovascular mortality in the UKPDS¹¹⁰
13.Initial randomization to very high-potential hypoglycemic metformin + sulfonylurea combination therapy significantly increased cardiovascular mortality in the UKPDS¹¹¹
14.US Clinical Trials submitted to FDA for metformin initial regulatory approval showed significantly increased mortality of patients randomized to metformin on combination metformin plus sulfonylureas¹¹² [Hypoglycemia was suggested to hve played a potentially causal role]
15.Obervational data from Malmo¹¹³ show increased mortality in diabetic patients taking combination metformin plus sulfonylureas
16.Data from the Bezafibrate Infarction Prevention Trial show an increased cardiovascular mortality from patients on sulfonylureas alone or on combination metformin plus sulfonylureas¹¹⁴
17.LONG-TERM PHARMACOLOGIC INTERVENTIONS TO VERY TIGHTLY CONTROL TYPE 2 DIABETES NOT ONLY ARE INEFFECTIVE IN REDUCING MORTALITY, BUT MAY CONTRIBUTE TO INCREASED MORBIDITY AND MORTALITY [EXCEPT WITHIN THE CONTEXT OF ACUTE MI.]
18. Patients with established coronary artery disease should probably not be on any sulfonylureas but should be tightly-controlled on insulin
19.? CURRENT ADA TREATMENT GUIDELINES FOR TYPE 2 GLYCEMIC CONTROL OF TARGET A1C AT 7% AND ACTION POINT AT 8% SHOULD BE MAINTAINED AND NOT TIGHTENED¹¹⁵

BIBLIOGRAPHY
1 Stern M.P. Do non-insulin-dependent diabetes mellitus and cardiovascular disease share common antecedents? Ann Intern Med (1996) 93:1780-1783.
2 Yudkin, John S., Stehouwer, C. D. A., Emeis, J. J., Coppack, S. W., C-Reactive Protein in Healthy Subjects: Associations With Obesity, Insulin Resistance, and Endothelial Dysfunction : A Potential Role for Cytokines Originating From Adipose Tissue? Arteriosclerosis, Thrombosis, and Vascular Biology (1999) 19: 972-978
3 Multiple Risk Factor Intervention Trial Research Group, Stamler J., Vaccaro O., Neaton J.D. and Wentworth D. Diabetes, other risk factors and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care (1993) 16:434-444
4 Malmberg K. Prospective randomized study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. Br. Med.J. (1997) 314:1512-1515
5 UK Prospective Diabetes Study (UKPDS) Group, Lancet Loc. Cit
6 Klimt C.R., Knatterud G.L., Meinert C.L. and Prout T.E. A study of the effects of hypoglycemic agents in vascular complications in patients with adult-onset diabetes. Diabetes (1970), 19:747-830.
7 Fuller JF, Shipley MJ, Rose G, Jarrett RJ, Keen H; Coronary Heart Disease Risk and Impaired Glucose Tolerance. The Whitehall Study. Lancet (1980);i, 1373-1376
8 Hak AE, Stehouwer CDA, Bots ML, Polderman KH, Schalkwijk CG, Westendorp CD, Hofman A, Witteman JCM; Associations of C-Reactive Protein With Measures of Obesity, Insulin Resistance, and Subclinical Atherosclerosis in Healthy, Middle-Aged Women, Arteriosclerosis, Thrombosis, and Vascular Biology. (1999) 19:1986-1991
9 UK Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet (1998) 352:837-853.
10 Jager, A, van Hinsbergh, VW.M., Kostense, PJ., Emeis, JJ., Yudkin, JS., Nijpels, G, Dekker, JM., Heine, RJ., Bouter, LM., Stehouwer, CDA., von Willebrand Factor, C-Reactive Protein, and 5-Year Mortality in Diabetic and Nondiabetic Subjects : The Hoorn Study Arteriosclerosis, Thrombosis, and Vascular Biology (1999) 19: 3071-3078
11 Garratt KN, Brady PA, Hassinger NL, D Grill DE, Terzic A and Holmes DR Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol (1999) 33:119-124
12 Knowler WC, Sartor G, Melander A, Schersten B , Glucose tolerance and mortality, including a substudy of tolbutamide treatment. Diabetologia. (1997) Jun;40(6):680-6.
13 Jarrett RJ, McCartney P, Keen H; The Bedford Survey:Ten year Mortality rates in Newly Diagnosed Diabetics, Borderline Diabetics and Normoglycemic controls and Risk Indices for Coronary Heart disease in Borderline Diabetics Diabetologia (1982) 22:79-84
14 Klimt C.R., Knatterud G.L., Meinert C.L. and Prout T.E. , Diabetes, Loc. Cit.
15 UK Prospective Diabetes Study (UKPDS) Group, Effect of Intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) Lancet (1998) 352:854-865
16 Ibid
17 Innerfield R.J. Metformin-Associated Mortality in U.S. Studies. New Eng J Med (1996) 334:1611-1613
18 Olsson J., Lindberg G., Gottsäter M., Lindwall K., Sjöstrand Å., Tisell A., .Melander A. Increased mortality in Type II diabetic patients using sulphonylurea and metformin in combination: a population-based observational study Diabetologia (2000) 43:558-560
19 Fisman EZ, Tenenbaum A, Benderly M, Goldbourt U, Behar S, Motro Mn . Antihyperglycemic treatment in diabetics with coronary disease: increased metformin-associated mortality over a 5-year follow-up. Cardiology (1999) 91(3):195-202
20 Krolewski AS, Laffel LM, Krolewski M, Quinn M, Warram JH Glycosylated hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus. N Engl J Med. (1995) May 11;332(19):1251-1255.
21 Joslin, EP, Arteriosclerosis and diabetes, Ann. Clin. Med. (1927) 5:1061.
22 Stern M.P. Ann Intern Med (1996), loc.cit.
23 Yudkin, John S., Stehouwer, C. D. A., Emeis, J. J., Coppack, S. W.,Arteriosclerosis, Thrombosis, and Vascular Biology(1999) loc. Cit.
24 Hak AE, Stehouwer CDA, Bots ML, Polderman KH, Schalkwijk CG, Westendorp CD, Hofman A, Witteman JCM; Associations of C-Reactive Protein With Measures of Obesity, Insulin Resistance, and Subclinical Atherosclerosis in Healthy, Middle-Aged Women, Arteriosclerosis, Thrombosis, and Vascular Biology. (1999) 19:1986-1991
25 Jager, Agnes, van Hinsbergh, Victor W. M., Kostense, Piet J., Emeis, Jef J., Yudkin, John S., Nijpels, Giel, Dekker, Jacqueline M., Heine, Robert J., Bouter, Lex M., Stehouwer, Coen D. A., von Willebrand Factor, C-Reactive Protein, and 5-Year Mortality in Diabetic and Nondiabetic Subjects : The Hoorn Study Arteriosclerosis, Thrombosis, and Vascular Biology (1999) 19: 3071-3078
26 Harris MI, in National Diabetes Data Group, eds. Diabetes in America:diabetes data compiled in 1984. Bethesda, .:National Institutes of Health, Chapter VI, 1985: publication no. 85-1468
27 Multiple Risk Factor Intervention Trial Research Group, Stamler J., Vaccaro O., Neaton J.D. and Wentworth D. Diabetes Care, Loc. Cit
28 Koskinen P, Manttari M, Manninen V, Huttunen JK, Heinonen OP, Frick, MH; Coronary Heart Disease Incidence in NIDDM Patients in the Helsinki Heart Study, Diabetes Care (1992) ;15(7), 820-825
29 Kuusisto J, Mykkanen L, Pyorala K, Laakso M ; NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes. (1994):43:960-967
30 Moss SE, Klein R, Klein BE, Meuer SM; The association of glycemia and cause-specific mortality in a diabetic population. Arch Intern Med. (1994 )154:2473-2479
31 Wei M, Gaskill SP, Haffner SM, Stern MP ;Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality. The San Antonio Heart Study. Diabetes Care (1998) Jul;21(7):1167-72
32 Lehto S, Ronnemaa T, Haffner SM, Pyorala K, Kallio V, Laakso M Dyslipidemia and hyperglycemia predict coronary heart disease events in middle-aged patients with NIDDM Diabetes (1997) Aug;46(8):1354-9
33 Niskanen L, Turpeinen A, Penttila I, Uusitupa MI ;Hyperglycemia and compositional lipoprotein abnormalities as predictors of cardiovascular mortality in type 2 diabetes: a 15-year follow-up from the time of diagnosis. Diabetes Care (1998) Nov;21(11):1861-9
34 Jarrett RJ, McCartney P, Keen H; Diabetologia ,Loc. Cit.
35 Keen H, Rose G, Pyke DA,, Boyns DR, Chlouverakis C, Mistry S, Blood Sugar and arterial disease Lancet (1965) 2:505
36 Ostrander LD, Francis T, Hayner NS, Kjelsberg MO, Epstein FH, Relationship of cardiovascular disease to hyperglycemia. Ann. Int. Med. (1965) 62:1188
37 Kingsbury KJ, Relationship between glucose tolerance and atherosclerotic vascular disease, Lancet (1966) 2:1374
38 Jarrett, RJ, loc. lit.
39 Fuller JF, Shipley MJ, Rose G, Jarrett RJ, Keen H, Loc. Cit
40 Pyolara K, Relationship of Glucose Tolerance and Plasma Insulin to the Incidence of Coronary Heart Disease: Results from two population studies in Finland, Diabetes Care (1979) 2(2):131-141
41 Ducimetiere P, Eschwege E, Richard JL, Thibult N, et al, Coronary heart disease mortality in relation with diabetes, blood glucose and plasma insulin levels. The Paris Prospective Study ten years later. Hormone Metabol Res Suppl Series (1985)15:41-56
42 Welborne TA and Wearne K, Coronary heart Disease incidence and cardiovascular mortality in Brusselton with reference to glucose and insulin concentrations. Diabetes Care (1979) 2:154-160
43 Vigorita VJ, Moore GW, Hutchins GM, Absence of correlation between coronary arterial atherosclerosis and severity or duration of diabetes mellitus of adult onset. Am J Cardiol (1980)46:535-542
44 Jarrett RJ, Shipley MJ, Type 2 (non-insulin-dependent) diabetes mellitus and cardiovascular disease - putative association via common antecedents: further evidence from the Whitehall Study. Diabetologia (1988) 19:205-210
45 Jarrett, RJ, McCartney P, Keen H, Diabetologia (1982). Loc. Cit.
46 Balkau B, Eschwege E, Papoz L, Richard J-L, Clause J-R, Warnet J-M, Ducimetiere P;Risk factors for early death in non-insulin dependent diabetes and men with known glucose tolerance status. BMJ (1993) 307:295-299
47 Knowler WC, Sartor G, Melander A, Schersten B, Glucose tolerance and mortality, including a substudy of tolbutamide treatment. Diabetologia (1997) 40:680-686
48 Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Bennett PH: The natural history of impaired glucose tolerance in the Pima Indians. NEJM (1988) 319,1500-1509
49 Sicree RA, Zimmet PZ, King HOM, Coventry JS: Plasma insulin response among Naruans: prediction of deterioration in glucose tolerance over 6 years. Diabetes (1987) 36:179-186
50 Haffner SM, Stern MP, Mitchell BD, Hazuda HP, Patterson JK: Incidence of Type II diabetes in Mexican Americans predicted by fasting insulin and glucose levels, obesity, and body-fat distribution. Diabetes (1990) 39:283-288
51 Kadowaki T, Miyaka Y, Hagura R, Akunama Y, Kajinuma H, Kuraya N, Takaku F, Kosaka K: Risk factors for worsening to diabetes in subjects with impaired glucose tolerance. Diabetologia (1984) 26:44-49
52 Lundgren H, Bengtsson C, Biohme G, Lapidus L, Waldenstrom J: fasting serum insulin concentration and early response as risk determinant for developing diabetes. Diabetic Med (1990) 7:407-413
53 Fontbonne A, Eschwege E, Cambien F, Richard JL, Ducimetiere P, Thibult N, Warnet JM, Claude JR, Rosselin GE: Hypertriglyceridaemia as a risk factor of coronary heart mortality in subjects with impaired glucose tolerance or diabetes. Results from the 11-year follow-up of the Paris prospective Study. Diabetologia (1989) 32:300-304
54 Keen H, Jarrett, RJ, Chlouverakis C, Boyns DR, The effect of treatment of moderate hyperglycemia on the incidence of arterial disease. Postgrad. Med.J. (1968) 44:960
55 Malmberg K. Br. Med.J. (1997) loc. Cit.
56 University Group Diabetes Program, A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes Diabetes (1975) 24 (Suppl 1):65-184
57Turner R. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet (1998) Loc. Cit.[LancetOnline]
58Visser M, Bouter LM, McQuillan GM, Wener MH, Harris, TB, Elevated C-Reactive Protein Levels in Overweight and Obese Adults JAMA. (1999) 282:2131-2135
59 Hak AE, Stehouwer CDA, Bots ML, Polderman KH, Schalkwijk CG, Westendorp CD, Hofman A, Witteman JCM; Arteriosclerosis, Thrombosis, and Vascular Biology. (1999) loc. Cit.
60 Yudkin JS, Stehouwer, C. D. A., Emeis, J. J., Coppack, S. W., Arteriosclerosis, Thrombosis, and Vascular Biology (1999) loc.cit.
61 Jager, A, van Hinsbergh, VW.M., Kostense, PJ., Emeis, JJ., Yudkin, JS., Nijpels, G, Dekker, JM., Heine, RJ., Bouter, LM., Stehouwer, CDA Arteriosclerosis, Thrombosis, and Vascular Biology (1999) loc.cit.
62 The National Diabetes Center, Coumadin Therapy Appears to Improve Glycemic Control, data on file, (2000)
63 Harris MI, loc. Cit.
64 Everhart J, Knowler WC, and Bennett PH, in National Diabetes Data Group, eds. Diabetes in America: Chapter IV, loc.cit.
65 Bistrian BR, Blackburn GL, Flatt JP, Sizer J, Scrimshaw NS, and Sherman M, Diabetes (1976) 25:494
66 Genuth SL, Am. J. Clin. Nutr (1979) 32:2579
67 Hughes TA, Gwynne JT, Switzer BR, Herbst C, and White G, Am J Med (1984) 77:7
68 Hadden DR, Montgomery DAD, Skelley RJ, Tremble RR, Weaver SA,
Wilson FA, and Buchanan KD, Br Med J (1975) 3:276, 1975
69 Bogardus C, Ravusin E, Robbins DC, Wolfe RR, Horton ES, and Sims EAH, Diabetes (1984) 33:311
70 Henry RR, Wiest-Kent TA, Scheaffer L, Kolterman OG, and Olefsky JM, Diabetes (1986) 35:155
71 Haffner SM, Stern MP, Hazuda HP, Mitchell BD, and Patterson JK, NEJM (1988) 319:1297
72 Newman B, Selby JV, King MC, Slemenda C, Fabsitz R, and Friedman GD,
Diabetologia (1987) 30:763
73 Barnett AH, Eff C, Leslie RD, and Pyke DA, Diabetologia (1981) 20:87,
74 Bouchard C, Tremblay A, Despres JP, Nadeau A, Lupien PJ, Theriault G, Dussault J, Moorjani S, Pinault A, and Fournier G, NEJM (1990) 322:1477
75 Stunkard AJ, Harris JR, Pedersen NL, and McClearn GE, NEJM (1990) 322:1483
76 Haffner et al, loc. Cit.
77 Emilsson V, Liu YL, Cawthorne MA, Morton NM, Davenport M, Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes (1997) Feb;46(2):313-6
78 Mizuno TM, Mobbs CV,Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology (1999) Feb;140(2):814-7
79 Ebihara K, Ogawa Y, Katsuura G, Numata Y, Masuzaki H, Satoh N, Tamaki M, Yoshioka T, Hayase M, Matsuoka N, Aizawa-Abe M, Yoshimasa Y, Nakao K , Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action. Diabetes (1999) Oct;48(10):2028-33
80 Nisoli E, Carruba MO, Tonello C, Macor C, Federspil G, Vetto R; Induction of Fatty Acid Translocase/CD36, Peroxisome Proliferator-Activated Receptor-gamma-2, Leptin, Uncoupling Proteins 2 and 3, and Tumor Necrosis Factor-alpha Gene Expression in Human Subcutaneous Fat by Lipid Infusion. Diabetes (2000) 49(3):319
81 Lee K, Dixon AK, Richardson PJ, Pinnock RD; Glucose-receptive neurones in the rat ventromedial hypothalamus express KATP channels composed of Kir6.1 and SUR1 subunits. J Physiol (1999) Mar 1;515 ( Pt 2):439-52
82 Zunkler BJ, Henning B, Ott T, Hildebrandt AG, Fleck E Effects of tolbutamide on ATP-sensitive K+ channels from human right atrial cardiac myocytes. Pharmacol Toxicol (1997) Feb;80(2):69-75
83 D'hahan N, Moreau C, Prost AL, Jacquet H, Alekseev AE, Terzic A, Vivaudou M, Pharmacological plasticity of cardiac ATP-sensitive potassium channels toward diazoxide revealed by ADP. Proc Natl Acad Sci U S A (1999) Oct 12;96(21):12162-7
84 Schnitzler MM, Derst C, Daut J, Preisig-Muller R ATP-sensitive potassium channels in capillaries isolated from guinea-pig heart. J Physiol (2000) Jun 1;525 Pt 2:307-17
85 Daut J Maier-Rudolph W von Beckerath N Mehrke G G:unther K
Goedel-Meinen L Hypoxic dilation of coronary arteries is mediated by
ATP-sensitive potassium channels. [Physiologisches Institut der Technischen Universit:at M:unchen, Biedersteiner, Federal Republic of Germany] Science (1990) 247(4948):1341-4,
86 Grover GJ McCullough JR Henry DE Conder ML Sleph PG Anti-ischemic
effects of the potassium channel activators pinacidil and cromakalim and the
reversal of these effects with the potassium channel blocker glyburide.
Department of Pharmacology, Squibb Institute for Medical Research, Princeton,
New Jersey. (1989) J Pharmacol Exp Ther 251(1):98-104,
87 Miura T, Liu Y, Kita H, Ogawa T and Shimamoto K, Roles of mitochondrial ATP-sensitive K channels and PKC in anti-infarct tolerance afforded by adenosine A1 receptor activation J.Amer. Coll. Cardiology (2000)35:1238-245
88 Innerfield, RJ, Significant Excess Mortality in "High-hypoglycemic Potential" Therapy for Type 2 Diabetes - a metanalysis. (2000) [in submission]
89 Campbell IW. Metformin and the sulfonylureas: the comparative risk. Horm Metab Res (1985) Suppl 15:105-11,
90Malmberg K., Norhammar A., Wedel H. and Ryden L. Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction. Long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) Study. Circulation (1999) 99:2626-2632
91 Keen H, Jarrett RJ, Ward JD, Fuller JH, Borderline diabetics and their response to tolbutamide. Adv. Metab Disord (1973) 2:Suppl 2; 521-531
92 .Innerfield RJ. Medical officer safety review of an NDA submission. Metformin. (NDA 20-357.) (On file at FDA, Bethesda, Md., May 1994 [FOI].)
93 Innerfield R.J, New Eng J Med (1996) loc.cit.
94 Olsson J., Lindberg G., Gottsäter M., Lindwall K., Sjöstrand Å., Tisell A., .Melander A. Diabetologia (2000) loc.cit.
95 Fisman EZ, Tenenbaum A, Benderly M, Goldbourt U, Behar S, Motro M.. Cardiology loc.cit.
96 Stern M.P. Do non-insulin-dependent diabetes mellitus and cardiovascular disease share common antecedents? Ann Intern Med (1996) 93:1780-1783.
97 Yudkin, John S., Stehouwer, C. D. A., Emeis, J. J., Coppack, S. W., C-Reactive Protein in Healthy Subjects: Associations With Obesity, Insulin Resistance, and Endothelial Dysfunction : A Potential Role for Cytokines Originating From Adipose Tissue? Arteriosclerosis, Thrombosis, and Vascular Biology (1999) 19: 972-978
98 Multiple Risk Factor Intervention Trial Research Group, Stamler J., Vaccaro O., Neaton J.D. and Wentworth D. Diabetes, other risk factors and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care (1993) 16:434-444
99 Malmberg K. Prospective randomized study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. Br. Med.J. (1997) 314:1512-1515
100 UK Prospective Diabetes Study (UKPDS) Group, Lancet Loc. Cit
101 Klimt C.R., Knatterud G.L., Meinert C.L. and Prout T.E. A study of the effects of hypoglycemic agents in vascular complications in patients with adult-onset diabetes. Diabetes (1970), 19:747-830.
102 Fuller JF, Shipley MJ, Rose G, Jarrett RJ, Keen H; Coronary Heart Disease Risk and Impaired Glucose Tolerance. The Whitehall Study. Lancet (1980);i, 1373-1376
103 Hak AE, Stehouwer CDA, Bots ML, Polderman KH, Schalkwijk CG, Westendorp CD, Hofman A, Witteman JCM; Associations of C-Reactive Protein With Measures of Obesity, Insulin Resistance, and Subclinical Atherosclerosis in Healthy, Middle-Aged Women, Arteriosclerosis, Thrombosis, and Vascular Biology. (1999) 19:1986-1991
104 UK Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet (1998) 352:837-853.
105 Jager, A, van Hinsbergh, VW.M., Kostense, PJ., Emeis, JJ., Yudkin, JS., Nijpels, G, Dekker, JM., Heine, RJ., Bouter, LM., Stehouwer, CDA., von Willebrand Factor, C-Reactive Protein, and 5-Year Mortality in Diabetic and Nondiabetic Subjects : The Hoorn Study Arteriosclerosis, Thrombosis, and Vascular Biology (1999) 19: 3071-3078
106 Garratt KN, Brady PA, Hassinger NL, D Grill DE, Terzic A and Holmes DR Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol (1999) 33:119-124
107 Knowler WC, Sartor G, Melander A, Schersten B , Glucose tolerance and mortality, including a substudy of tolbutamide treatment. Diabetologia. (1997) Jun;40(6):680-6.
108 Jarrett RJ, McCartney P, Keen H; The Bedford Survey:Ten year Mortality rates in Newly Diagnosed Diabetics, Borderline Diabetics and Normoglycemic controls and Risk Indices for Coronary Heart disease in Borderline Diabetics Diabetologia (1982) 22:79-84
109 Klimt C.R., Knatterud G.L., Meinert C.L. and Prout T.E. , Diabetes, Loc. Cit.
110 UK Prospective Diabetes Study (UKPDS) Group, Effect of Intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) Lancet (1998) 352:854-865
111 Ibid
112 Innerfield R.J. Metformin-Associated Mortality in U.S. Studies. New Eng J Med (1996) 334:1611-1613
113 Olsson J., Lindberg G., Gottsäter M., Lindwall K., Sjöstrand Å., Tisell A., .Melander A. Increased mortality in Type II diabetic patients using sulphonylurea and metformin in combination: a population-based observational study Diabetologia (2000) 43:558-560
114 Fisman EZ, Tenenbaum A, Benderly M, Goldbourt U, Behar S, Motro Mn . Antihyperglycemic treatment in diabetics with coronary disease: increased metformin-associated mortality over a 5-year follow-up. Cardiology (1999) 91(3):195-202
115 Krolewski AS, Laffel LM, Krolewski M, Quinn M, Warram JH Glycosylated hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus. N Engl J Med. (1995) May 11;332(19):1251-1255.

Home Page
Reload The National Diabetes Center Site