Mortality from Coronary Heart Disease 
and Poor Blood Sugar Control – Cause or Effect? 
a) Why is it that Tighter Long-term Glycemic Control Does Not Reduce Cardiovascular Mortality?
b) Why is it that Very Tight Glycemic Control Might Result in Excess Morbidity and Mortality?
c) What Should be the Goals for Glycemic Control in Type 2 diabetes?

R.J. Innerfield, M.D., F.A.C.E., The National Diabetes Center, Olney, MD

Abstract Summary  
 
i.	Type 2  diabetes mellitus and cardiovascular disease share common antecedents  (“insulin resistance syndrome”) which include vasoactive cytokines
ii.	Type 2 diabetes also associates significantly with macrovascular disease
iii.	Only in the setting of acute MI does hyperglycemia appear to causally impact mortality
iv.	Improving glycemia long-term does not reduce macrovascular mortality,
v.	Impaired glucose tolerance - which is characterized by relative normoglycemia - associates significantly with macrovascular disease
vi.	Atherosclerosis per se is significantly associated with increased levels of inflammatory vasoactive cytokines
vii.	Hyperglycemia is relentlessly progressive  in Type 2 diabetes and  also associated with increased levels of inflammatory vasoactive cytokines
viii.	Coumadin – a systemic anticoagulant - may actually somewhat improve glycemia 
ix.	 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]
x.	Data from the Mayo Clinic suggests sulfonylureas are associated with enhanced cardiovascular mortality following angioplasty procedures 
xi.	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
xii.	Initial randomization to very low-potential hypoglycemic metformin monotherapy significantly improved cardiovascular mortality in the UKPDS
xiii.	Initial randomization to very high-potential hypoglycemic metformin + sulfonylurea combination therapy significantly increased cardiovascular mortality in the UKPDS
xiv.	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]
xv.	Obervational data from Malmo show increased mortality in diabetic patients taking combination metformin plus sulfonylureas
xvi.	Data from the Bezafibrate Infarction  Prevention Trial show an increased cardiovascular mortality from patients on sulfonylureas alone or on combination metformin plus sulfonylureas
xvii.	 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.]
xviii.	Patients with established coronary artery disease should probably not be on oral agents but well-controlled on insulin 
xix.	 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

 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 atherosclerosis.   More recently, Michael Stern observed that type 2  diabetes mellitus and cardiovascular disease share common antecedents  (“insulin resistance syndrome”.)   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,,

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,,.

Figure 1 – Diabetes as a risk factor for CVD in the Mr. Fit Study

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]. ,,,,,  “Statistically valid links” were first noted in 1965-1966,,

Figure 2 - CHD Deaths and Events Increase By Tertiles of HbA1c in the Kuopio 1 Study (Black -> CHD Deaths 
Pearl   -> CHD Events 
Tertile #1: <6%) 
Tertile #2: from 6 to 7%
Tertile #3: >7%)

Figure 2  (Diabetes 1994 Aug;43(8):960-7 )	Related Articles, Books, LinkOut 	
 
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
Hazard Ratios of Cause-Specific Mortality 
And Glycemia in Older-Onset Diabetes Patients
(WESDR)	

Cause of Death	Hazard Ratio for Each
1% Increase in
Baseline Glycohemoglobin*	
		
Diabetes Mortality	1.32 (1.21-1.43)	
Ischemic Heart Disease	1.10 (1.04-1.17)	
Stroke	1.17 (1.05-1.30)	
Cancer	0.99 (0.88-1.10)	
*Adjusted for other risk factors such as smoking, hypertension, etc.	Moss SE et al.	
Arch Intern Med 1994 Nov 14;154(21):2473-9	Related Articles, Books, LinkOut 	

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
Hyperglycemia as predictor of cardiovascular mortality in type 2 diabetes: a 15-year follow-up from the time of diagnosis-
The Kuopio 2 Study
	All-cause Mortality
Odds Ratio	Cardiovascular Mortality
Odds ratio	
Men	5.0, P < 0.001	6.2, P < 0.001	
Women	5.2, P < 0.001	11.2, P < 0.001	
Diabetes Care 1998 Nov;21(11):1861-9	Related Articles, Books, LinkOut 	

Table 3
Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality. The San Antonio Heart Study
	
Sex 	Relative Risk of All-cause Mortality (Compared to  Non-Diabetics)	Relative Risk of Cardiovascular Mortality 
(Compared to  Non-Diabetics)	
Men	2.1x (1.3-3.5)	3.2x (1.4-7.1)	
Women	3.2x (1.9-5.4)	8.5x (2.8-25.2)	
By Quartiles of Glycemia within the Diabetic population			
Adjustments 	Relative Risk of  All-cause Mortality (Highest Quartile Compared to  Quartiles 1&2 Combined)	Relative Risk of Cardiovascular Mortality (Highest Quartile Compared to  Quartiles 1&2 Combined)	
Non-adjusted  	4.2x (p < 0.001)	4.9x (p = 0.01) 	
Adjusted 	4.7x	4.9x	
Diabetes Care 1998 Jul;21(7):1167-72 Related Articles, Books, LinkOut

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”  or impaired glucose tolerance,,, and was even completely called into question early on., 

Table  4 Bedford Mortality Study: Odds Ratio of Dying	Event	Odds Ratio “Borderline Diabetics” vs Controls	Odds Ratio
 Diabetics vs “Borderline Diabetics”	
Males	All Deaths	1.10  ns	1.66 ns	
	CHD Deaths	1.42 ns	1.31 ns	
Females	All Deaths	2.76 (p<0.05)	1.38 ns	
	CHD Deaths	5.16 ns	2.12 ns	
Diabetologia 1982 22:79-84	Related Articles, Books, LinkOut 	

 In the Bedford Mortality Study data 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 data 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. These values for the relative risks of  CHD mortality achieved statistical significance only in “newly diagnosed” diabetics. 

Table 5
CHD Mortality in the Paris Prospective Study	Normal Glucose
Tolerance	Impaired Glucose
Tolerance	Newly-diagnosed
Diabetes	Established
Diabetes	
N	6161	697	180	128	
Total Deaths	757	132	56	30	
All-cause
Mortality Relative Risk
(95%CI)	1
()	1.6
(1.3 to 2.0)	2.7
(2.0 to 3.6)	2.0
(1.4 to 3.0)	
CHD Relative Risk
(95%CI)	1
()	1.6
(1.0 to 2.6)	2.2
(1.1 to  4.6)	2.3
(1.0 to 5.3)	

In the Malmohus County Study 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,,,,.  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 cousins.

Table 6 The Malmohus County Study	Normal Glucose Tolerance	Impaired Glucose Tolerance	Diabetes	
N	1564	253	683	
Total Deaths	579	173	571	
Age-Sex Adjusted
Total Death rate per 1000 person-years	37.9 ±  1.9
(37.8 to 38.0)	53.6 ±  4.2
(53.1 to 54.1)	70.1 ±  3.6
(69.8 to 70.4)	
Age-Sex Adjusted
CV Death rate per 1000 person-years	14.3 ±  1.1
(14.2 to 14.4)	16.3 ±  2.4
(16.0 to 16.6)	25.8 ±  2.0
(25.6 to 26.0)	

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:-

It is, of course, possible to formulate three standard hypotheses
to explain the relationship – that A causes B, that B causes A,
or that both A and B are caused by C.  We have chosen to examine
what is perhaps the most likely and potentially the most useful
of these explanations – that hyperglycemia contributes causally
to the development of the arterial lesions.  It is a useful	
explanation because there is long experience and knowledge of

methods aimed at lowering the blood sugar: the possibility of 
intervening in the progress of a disease process is one which 
stimulates both the interest of the doctor and the co-operation of 
the patient.	

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. Nevertheless, in the long-term this turns out not to be the case. Not just one but two, 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 
Progression of A1c with time over the course of the UKPDS

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 JAMA 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 al 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.”  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.”  Finally, recent data we have been compiling from our own clinical experience is suggesting that coumadin may improve glycemia.    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 mellitus . 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 diagnosis, 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) ,,,, and (3) it is more difficult for obese Type 2 diabetes patients to lose weight than their obese non-diabetic counterparts.  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 diabetes.

Since the genetic/concordance data are much stronger for Type 2 diabetes, than for Type1 diabetes, 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,. 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 se.  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,,,.  

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 element. 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 concentrations.  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 agents.  Higher affinity SUR-2B sites are found in the cardiac smooth muscle cells where they may modulate the vasodilatory response to ischemia,,.  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 affinities.  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 studies - (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.)

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 Digami 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 ] Study – 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  very tight 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  very tight 95%CI (+1630 to +1750 deaths) per 10,000 treated
.

Table 7
Low Hypo-
Glycemic
Potential Low-Dose
Tolbutamide
<=1.5g/day 	Controls	Treated	
		
Average Observation Period 10.48 years	
n	
CV Deaths	
Total Deaths	
n	
CV Deaths	
Total Deaths	
							
   Bedford	125	19	27	123	16	25	
  Serafinerlasarettet	
83	
16	
16	
95	
13	
13	

Malmohus	
98	
30	
68	
49	
7	
24	
							
Totals	306	65	111	267	36	62	

CV mortality difference = -776 ± 314/10,000 patients
95%CI (-161 to –1390) /10,000 patients
TM difference = -1310 ± 377/10,000 patients
95%CI (-566 to -2040) /10,000 patients

Table 8
High Hypo-
Glycemic
Potential High-Dose
Tolbutamide
>=4g/day	Controls	Treated	
		
Study duration
Average 8.1 years	
N	
CV Deaths	
Total Deaths	
n	
CV Deaths	
Total Deaths	
							
   UGDP	64	3	7	204	26	30	

CV mortality difference = +806 ± 353/10,000 patients
95%CI (+115 to +1500) /10,000 patients
TM difference = +377 ± 462/10,000 patients
95%CI (-529 to +1280) /10,000 patients

Conclusion:  There does appear to be a dose-responsive increase in cardiovascular and all-cause mortality which could, again, represent either significantly increased risk of hypoglycemia or increased cardiotoxicity due to SUR-2B/mito kATP closure 

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
Low Hypo-
Glycemic
Potential
Metformin vs
Conventional Rx	Conventional Rx	Metformin	

N	
CV Deaths	
Total Deaths	
n	
CV Deaths	
Total Deaths	
							
   UKPDS34	411	53	89	342	26	50	

CV mortality difference = -529 ± 219/10,000 patients
95%CI (-100 to –958) /10,000 patients
TM difference = -703 ± 279/10,000 patients
95%CI (-157 to -1250) /10,000 patients

Table 10
High Hypo-
Glycemic
Potential 
SFU vs Combination
SFU + metformin	SFU 	SFU + metformin
Combination Rx	

n	
CV Deaths	
Total Deaths	
n	
CV Deaths	
Total Deaths	
							
   UKPDS34	269	13	31	268	25	47	

CV mortality difference = +450 ± 221/10,000 patients
95%CI (+17 to +882) /10,000 patients
TM difference = +601 ± 303/10,000 patients
95%CI (+7  to +1200) /10,000 patients

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

Methods:

1.	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
2.	Review of the mortality data seen in the Bezafibrate Infarct prevention Trial in Israel for metformin plus sulfonylurea combination
3.	Review of the observational mortality data seen recently in Sweden for metformin plus sulfonylurea combination

Results: 

Pivotal US clinical trial data for metformin

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
AE/IME	total	mild	moderate	severe	
Diaphoresis	15	6	8	1	
Glucose_blood_decreased	6	4	2	0	
Hunger_abnormal	1	0	0	1	
Hypoglycemia	124	80	42	2	
Hypoglycemic_reaction	24	14	0	0	
Irritability	1	0	1	0	
Jitteriness	1	0	1	0	
Night_sweat	4	3	1	0	
Shakiness	10	8	2	0	
Sweating_increased	17	10	7	0	
Tension_nervous	14	3	10	1	
Tingling	7	6	1	0	
Tremor	25	17	8	0	
Tremulousness	3	2	1	0	
TOTAL	252	153	94	5	

Patients over age 65 (n=69) vs those under age 65 (n=495) reported more:
AE’s/IME’s (52% vs 43%)
asthenia (22% vs 11%)
hypoglycemia (12% vs 7%)

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 data

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:

Table 12
Did Glyburide
Randomized
Patient Enter Open
Enrollment?	n	HbA1c
	
No	68	7.10 	
Yes	142	9.47 	
P	-	P<0.01	
Difference (95%CI)	74	+2.37±0.45 (+1.47 to +3.27)	
Table 13
Did Metfomin
(Monotherapy)
Randomized
Patient Enter Open
Enrollment?	n	HbA1c
	
No	78	9.50	
Yes	132	7.90	
P	-	P<0.01	
Difference (95%CI)	54	-1.60±0.443 (-.707 to –2.45)	
Table 14
Did Metfomin
& SFU therapy
Patient Enter Open
Enrollment?

	N	HbA1c
	
No	45	7.84	
Yes	168	6.90	
P	-	P<0.01	
Difference (95%CI)	123	-0.94±0.302 (-0.334 to –1.54) 	

Table 15
Did any Metfomin
Randomized
Patient Enter Open
Enrollment?

	N	HbA1c
	
No	123	8.89 	
Yes	300	7.34 	
P	-	P<0.01	
Difference (95%CI)	177	-1.55±0.155 (-1.25 to –1.85) 	

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

3.	Swedish Surveillance Study 

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.

Odds Ratios for Mortality of Combination Rx versus SFU Monotherapy
Cause of mortality	Multiple causes
OR (95% CI)	Underlying cause
OR (95% CI)	
Ischemic Heart Disease	1.82 (1.31 to 2.53)	1.73 (1.17 to 2.55)	
Stroke	2.06 (1.23 to 3.45)	2.33 (1.17 to 4.63)	
Other causes		1.39 (0.95 to 2.02)	
Non IHD, non-stroke	1.17 (0.73 to 1.89)		
Overall	1.63 (1.27 to 2.09)	1.63 (1.27 to 2.09)	
Table 16
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.) 

4.	The Bezafibrate Infarction Prevention Trial 

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
	diet alone  	sulfonylureas  	metformin 	sulfonylurea and
metformin	
n	990	1,041	78	266	
All-cause
Mortality	18.5%	22.5%	25.6%	31.6%	
Excess (all-cause) mortality 	0	+4.0±1.79%
0
-	+7.16±5.10%
-
0	+13.1±3.11%
+9.10±3.13%
+5.94±5.71%	
(95%CI)	 -	(+0.49 to +7.5%)
-
-	(-2.83 to +17.81%)
-
-	(+7.01 to +19.2%)
(+2.97 to +15.2%)
(-5.25 to +17.1%)	

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.  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”) which include vasoactive cytokines
2.	Type 2 diabetes also associates significantly with macrovascular disease
3.	Only in the setting of acute MI does hyperglycemia appear to causally impact mortality
4.	Improving glycemia long-term does not reduce macrovascular mortality,
5.	Impaired glucose tolerance - which is characterized by relative normoglycemia - associates significantly with macrovascular disease
6.	Atherosclerosis per se is significantly associated with increased levels of inflammatory vasoactive cytokines
7.	Hyperglycemia is relentlessly progressive  in Type 2 diabetes and  also associated with increased levels of inflammatory vasoactive cytokines
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 procedures 
11.	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
12.	Initial randomization to very low-potential hypoglycemic metformin monotherapy significantly improved cardiovascular mortality in the UKPDS
13.	Initial randomization to very high-potential hypoglycemic metformin + sulfonylurea combination therapy significantly increased cardiovascular mortality in the UKPDS
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 sulfonylureas [Hypoglycemia was suggested to hve played a potentially causal role]
15.	Obervational data from Malmo 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 sulfonylureas
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 oral agents but well-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 Tightened