As we enter the 21st century our pharmacological armamentarium is increasingly complex, offering a wide array of drugs, both as monotherapy or in combination. It is therefore frequently difficult to determine the best therapeutic option for a given patient. A common problem arises when a drug is known to give a prompt and beneficial effect in the short term, but data regarding long-term outcome are either lacking or insufficient.
This problem deserves particular attention in type 2 diabetics with coronary artery disease (CAD). Type 2 diabetes accounts for about 90% of the total diabetic population, and CAD is the most common cause of morbidity and mortality. Cardiovascular deaths are increased up to fourfold in diabetics compared with their nondiabetic counterparts.[1] Since these patients will receive antidiabetic therapy indefinitely, any undesirable cardiovascular side effects from well-known and widely used oral antidiabetic drugs should be analyzed in depth. In patients with type 2 diabetes, the University Group Diabetes Program (UGDP) reported in 1970 a higher frequency of major cardiovascular events in patients treated with sulfonylureas.[2] Awareness of this issue has increased during recent years following the detection of harmful influences of sulfonylureas on the ischemic myocardial cell.[3,4] On the other hand, cardiovascular derangement associated with the use of metformin has also been reported during both short-[5,6] and long-term follow-up.[7]
When oral antidiabetic monotherapy does not achieve the glycemic goal, combination treatment is implemented. A sulfonylurea — usually glibenclamide (known also as glyburide in the USA) — plus metformin constitute the most widely used antihyperglycemic combination in clinical practice.[8] However, the safety of this therapeutic regimen in long-term treatment is questionable.[9] The use of insulin in type 2 diabetes is also controversial. Nonetheless, after 15 or 20 years of disease, the majority of patients receive insulin.[10] The issue whether the adverse cardiovascular effects of each of these medications may be additive and detrimental for the coronary patient is of paramount importance but has not yet been addressed.
This paper aims to review briefly the cardiovascular effects of the most commonly used antidiabetic drugs, in an attempt to improve knowledge and awareness regarding their potential risks when treating patients with CAD.

Insulin
Insulin is not considered a first-line therapy in type 2 diabetes, except in particular cases such as in women with gestational diabetes (in whom all oral agents are contraindicated) or in patients with markedly elevated fasting glucose levels (>280 mg/dL).[11]
In the setting of coronary diabetes, the possible iatrogenic effects of exogenous insulin have aroused some concern, since hyperinsulinemia has been suspected to be the main culprit behind the excessive cardiovascular morbidity among diabetic patients. Hyperinsulinemia precedes the onset of diabetes and is frequently associated with dyslipidemia, obesity, and hypertension.[12] Moreover, it promotes arterial smooth muscle proliferation and synthesis of connective tissue in the arterial wall. These facts prompt a disturbing question: does insulin decrease cardiovascular complications by reducing plasma glucose, or does it facilitate atherogenesis? Most studies of insulin therapy in type 2 diabetes have been performed within an academic framework employing strict research protocols.[11] Among them, the UGDP was a randomized long-term trial comparing cardiovascular outcome in relation to variable doses of insulin therapy. Its final conclusions were that there was no proof that insulin reduced the risk of cardiovascular death, irrespective of dose. Conversely, there was no evidence that higher insulin doses were associated with increased cardiovascular risk.[13] Recent findings from the United Kingdom Diabetes Prospective Study (UKPDS) are consistent with these observations.[14]

Biguanides
Metformin is the only drug belonging to the biguanide class currently available in most parts of the world. It reduces blood glucose levels through suppression of gluconeogenesis, stimulation of peripheral glucose uptake by tissue (mainly skeletal muscles) in the presence of insulin, and decreased absorption of glucose from the gastrointestinal tract. It has no direct effects on b-cells, does not produce hypoglycemia, reduces glycohemoglobin, may reduce body weight, and improves both blood lipid profile and fibrinolytic activity. In contrast to other antidiabetic medications, metformin does not cause weight gain.
Despite these beneficial effects, metformin presents disadvantages that may influence the cardiovascular system. Gastrointestinal disturbances such as diarrhea are frequent, and the intestinal absorption of group B vitamins and folate is impaired during chronic therapy.[15] This deficiency may lead to increased plasma homocysteine levels which, in turn, accelerate the progression of vascular disease due to adverse effects on platelets, clotting factors, and endothelium.[16] The existence of a graded association between homocysteine levels and overall mortality in patients with CAD is well established.[16]
In addition, metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as heart failure or recent myocardial infarction.6 It should be remembered that another drug of the biguanide group, phenformin, was withdrawn in many countries during the 1970s due to its link with lactic acidosis. A possible association of phenformin with increased cardiovascular mortality has also been suggested.[17]
Finally, metformin undergoes renal excretion, presenting undesirable pharmacologic interactions with several widely used cardiovascular drugs. The coadministration of nifedipine or furosemide leads to increased metformin plasma levels. Furthermore, digoxin, quinidine, and triamterene — which are eliminated by renal tubular secretion — may interact with metformin by competing for proximal renal tubular transport systems.[18]
Metformin was introduced in the USA in 1995, and serious controversies regarding cardiovascular safety followed its approval for use.[5] We have found increased mortality in CAD patients receiving metformin after a 5-year follow-up.[7] However, it should be stressed that this finding be treated with caution since it arose from a nonrandomized study in which information on drug doses and severity and duration of diabetes was incomplete or unavailable.

Sulfonylureas
Today, sulfonylureas represent a mainstay of therapy in patients with type 2 diabetes; their hypoglycemic potency is directly related to baseline plasma glucose values.[19] At the cellular level, they exert their action by closing the ATP-dependent potassium channels; this feature is responsible for both the insulinotropic effect and the adverse effects on the heart.[3,4] In this context, it should be stressed that cardiac and vascular sulfonylurea receptors are structurally different from their pancreatic analog.[4] In fact, sulfonylureas have been reported to reduce resting myocardial blood flow,[20] to impair the recovery of contractile function after experimental ischemia,[21] to increase the ultimate infarct size,[22] to elicit proarrhythmic effects,[23] to abolish ischemic preconditioning in animal models,[24] and to increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction.[25] Prevention of myocardial preconditioning by glibenclamide has also been demonstrated in clinical trials.[26]
It is important to stress that not all the undesirable effects on cardiovascular outcome reported for the first-generation sulfonylureas such as tolbutamide[2] can be automatically extrapolated to the more modern second-generation compounds such as glibenclamide, which is short-acting and possesses antiarrhythmic properties.[3] In our experience, cardiovascular mortality rates in CAD patients on sulfonylureas (mainly glibenclamide) were lower than those on combined sulfonylurea-metformin therapy, and similar to the rates in patients on diet alone.[7] Another second-generation sulfonylurea, glimepiride, is more pancreas-specific and does not show interaction with cardiovascular ATP-dependent potassium channels.[3]

a-Glucosidase inhibitors
The primary mechanism of action of novel antidiabetic drugs such as acarbose and miglitol is grounded on competitive inhibition of enzymes of the a-glucosidase group (such as maltase and glucoamylase). Thus, by delaying digestion of carbohydrates, these compounds shift their absorption to more distal parts of the small intestine and colon, and defer gastrointestinal absorption of glucose. Their hypoglycemic potency is less than that of biguanides and sulfonylureas,[11] and, unlike the latter, they do not cause hypoglycemia. The effects of these agents on morbidity and mortality rates for diabetic micro- and macrovascular complications has not been studied.[27]

Glitazones
This group includes antidiabetic medications such as troglitazone, pioglitazone, and rosiglitazone, the chemical structure and mechanism of action of which are different from those of biguanides and sulfonylureas.
These recently developed drugs are insulin sensitizers, and they bind to a novel receptor called peroxisome proliferator-activated receptor (PPAR)-g, leading to increased glucose transporter expression. Sensitivity to insulin — especially in muscle — is improved, and an additional major effect is the inhibition of hepatic gluconeogenesis.[28] However, troglitazone monotherapy is only modestly effective in reducing glucose and glycohemoglobin levels. Plasma triglycerides are reduced by 10–20%, and HDL cholesterol levels increase by 5–10%, since troglitazone also stimulates the isoform PPAR-a that regulates lipid metabolism. These favorable effects are counterbalanced by a 10–15% increase in LDL cholesterol.[11] Troglitazone was recently withdrawn from clinical use in the US due to hepatotoxicity. Pioglitazone and rosiglitazone, however, do not affect PPAR-alpha. Edema has been reported in 5% of patients, and these drugs are contraindicated in diabetics with NYHA class III or IV cardiac status.[11]

Meglitinides
Meglitinides are benzoic acid derivatives that stimulate insulin secretion. The first, repaglinide, was introduced in the USA in 1998. Like sulfonylureas, it works by closing the ATP-dependent potassium channels. However, its mechanism of action seems to be more complex since possibly three repaglinide receptor binding sites have been found on the ß-cells.[29] When used as monotherapy, it reduces both fasting plasma glucose and glycohemoglobin, and has no significant effects on lipid profile. The cardiovascular safety of the drug is still uncertain. Increased morbidity, particularly acute ischemic events, was observed after 1 year compared with glibenclamide. Nevertheless, patients on repaglinide appeared to have had more severe CAD at baseline than those in the glibenclamide group, and when adjustments were made the relative risk declined.[30]

Combined antihyperglycemic treatment
Combined therapy is based on the premise that pharmacological agents acting via different mechanisms and presenting differing side effects permit the design of individualized antidiabetic regimens. This approach reflects the plausibility that monotherapy with any currently available medication is likely to fail over time in some patients, and this type of pharmacological diabetes management is widely used. Recent findings from the UKPDS showed that after 3 years, approximately 50% of patients could attain satisfactory glucose levels with monotherapy; by 9 years this had declined to only 25%.[31] Long-term problem-oriented prospective studies that focus specifically on the outcome of coronary diabetics on combined therapy are lacking. Data from an observational study performed at our laboratory indicate increased mortality over a 7.7-year follow-up in diabetics with CAD on combined treatment with metformin and glibenclamide.[32] This observation is in keeping with UKPDS reports demonstrating excess risk of all-cause mortality in the whole diabetic population receiving combined therapy, especially in patients in whom metformin was added at an early stage.[9]

Clinical implications and future directions
Comprehensive risk reduction is mandatory for diabetic patients with CAD. General measures should comprise diet, physical activity, complete cessation of smoking, and weight and lipid profile management. However, fewer than 10% of patients achieve acceptable long-term glycemic values with nonpharmacological therapy only.[33] Special emphasis should be given to blood pressure control; we have recently reported the presence of widespread undiagnosed hypertension in this population, which presented a 5-year mortality even higher than that in diabetics previously identified as hypertensives.[34] Moreover, the increased mortality associated with hypertension in mild diet-treated type 2 diabetes strongly supports the need for early onset of antihypertensive treatment in these patients.[35]
Evidence is available that long-term maintenance of normal or near-normal glucose levels using pharmacological means is protective in diabetics, improving microvascular disease (retinopathy, nephropathy, and neuropathy) and reducing both morbidity and mortality.[36] Taking into consideration that several degrees of undesirable cardiovascular effects have been reported for most antidiabetic drugs, is this also applicable to coronary diabetics? Current data indicate that the answer is yes, but alleviation of macrovascular complications remains dubious and the therapeutic criteria should not be automatically extrapolated to CAD patients, who need carefully customized treatment.
We believe that an oral antihyperglycemic agent, for example a sulfonylurea, or metformin in obese patients, should constitute first-line pharmacological therapy in type 2 diabetics with CAD; this is in keeping with recent recommendations of the American Heart Association.[37] As second-line therapy, ancillary medications such as a-glucosidase inhibitors could be added if target glucose levels are not achieved, but glibenclamide and metformin should not be used together. Finally, there is no contraindication to add insulin at a later stage as third-line therapy, provided the risk of hyperinsulinemic hypoalphalipoproteinemia — especially when associated with low HDL cholesterol levels — is monitored.[38]
What should the policy be regarding the widely used sulfonylurea-metformin combined treatment? Following approval of a given therapy for a chronic condition, large prospective, randomized, placebo-controlled trials designed to check its long-term safety and effectiveness require many years to be completed, and sometimes such studies are not performed at all. This is the case with this combined treatment in CAD patients. The data available at present indicate increased mortality in patients receiving this therapy,[9,32,39] suggesting that this combination should be used with caution in diabetics with proven CAD. The excessive mortality rate could reflect an additive expression of the adverse cardiovascular effects of each of these medications. However, we would like to stress that our own observations address specifically to the glibenclamide-metformin combined treatment,[32] and we have no information regarding combinations of metformin with other sulfonylureas, such as glimepiride or gliclazide. Furthermore, glibenclamide-metformin therapy can be safely used in noncoronary diabetic patients.
Future directions of antidiabetic pharmacological control of coronary patients should focus on both problem-oriented epidemiological studies and molecular biology research. An important area of research would be to investigate more fully the structural and functional differences between pancreatic and cardiac isoforms of ATP-dependent potassium channels. This would allow development of specific insulinotropic compounds that interact exclusively with the pancreatic channel, leaving the cardiac channel unaffected. 

REFERENCES
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2. Diabetes 1970;19:Suppl:789-830

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A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results.

Meinert CL, Knatterud GL, Prout TE, Klimt CR.

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3. Diabetologia 1995 Jan;38(1):116-21

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Cardiovascular effects of sulphonylurea derivatives. Implications for the treatment of NIDDM?

Smits P, Thien T.

Department of Medicine, University Hospital Nijmegen, The Netherlands.

Sulphonylurea derivatives are widely used in the treatment of non-insulin-dependent diabetes mellitus. The mechanism of action of the insulino-tropic effect of these agents is based on the closure of adenosine-5'-triphosphate (ATP)-sensitive potassium channels (KATP-channels) in the beta cells of the pancreas. In the last decade, these KATP-channels have been demonstrated in myocardial cells as well as in vascular smooth muscle cells. During myocardial ischaemia, the KATP-channels are thought to open by a fall in the cytosolic ATP concentration. The increase in the extracellular adenosine concentration, and the release of endothelium-derived hyperpolarizing factor (EDHF) during ischaemia may further contribute to the opening of cardiovascular KATP-channels. Independently from the mechanism of opening, sulphonylurea derivatives have been reported to block the opening of cardiovascular KATP-channels. Related to the role of KATP-channel-opening in the (patho)physiology of ischaemia, the use of sulphonylurea derivatives significantly modifies the outcome of experimental myocardial infarction. Sulphonylurea derivatives impair the recovery of the contractile function and increase the ultimate infarct size in animal models. In contrast, sulphonylurea derivatives have a beneficial effect on the incidence of ventricular fibrillation as occurs after ischaemic incidents of the myocardium. Based on these experimental observations, human studies are indicated to investigate whether the use of these drugs modifies the clinical outcome of cardiovascular events in patients with non-insulin dependent diabetes mellitus.

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The sulfonylurea controversy: more questions from the heart.

Brady PA, Terzic A.

Department of Medicine, Mayo Clinic, Mayo Foundation, Rochester, Minnesota 55905, USA.

Myocardial ischemia and infarction are associated with substantially increased morbidity and mortality among patients with diabetes mellitus. Although many factors contribute to the increased morbidity and mortality, in patients with non-insulin-dependent (type II) diabetes mellitus, one contributor may be the use of sulfonylurea drugs, the most widely used oral hypoglycemic agents. Such a possibility, which first arose over a 25 years ago when it was observed that patients taking sulfonylurea drugs had increased cardiovascular mortality, has recently resurfaced after the discovery that sulfonylureas act by inhibiting adenosine triphosphate (ATP)-sensitive potassium channels. In the pancreas, inhibition of ATP-sensitive potassium channels induces release of insulin; but in the heart, inhibition of these channels prevents ischemic preconditioning, an endogenous cardioprotective mechanism that protects the heart from lethal injury. This review outlines the current understanding of the molecular and cellular pharmacodynamics of sulfonylurea drugs and discusses the potential clinical consequences of inhibition of ATP-sensitive potassium channels in the heart of diabetic patients with cardiac disease in whom the use of sulfonylureas may be harmful.

Publication Types:

	Review
	Review, academic

PMID: 9561992 [PubMed - indexed for MEDLINE]

 

5. N Engl J Med 1996 Jun 13;334(24):1611-2; discussion 1612-3

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Comment on:

N Engl J Med. 1995 Aug 31;333(9):541-9

Metformin-associated mortality in U.S. studies.

Innerfield RJ.

Publication Types:

	Comment
	Letter

PMID: 8628355 [PubMed - indexed for MEDLINE]

 

6. N Engl J Med 1998 Jan 22;338(4):265-6

Related Articles, Books

Lactic acidosis in patients with diabetes treated with metformin.

Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA.

Publication Types:

Letter

PMID: 9441244 [PubMed - indexed for MEDLINE]

 

7. Cardiology 1999;91(3):195-202

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Cardiology. 1999 ;91(3):203-4

Antihyperglycemic treatment in diabetics with coronary disease: increased metformin-associated mortality over a 5-year follow-up.

Fisman EZ, Tenenbaum A, Benderly M, Goldbourt U, Behar S, Motro M.

Cardiac Rehabilitation Institute, Neufeld Cardiac Research Institute, Chaim Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. zfisman@post.tau.ac.il

Mortality rates are considerably higher in chronic ischemic heart disease (IHD) patients with non-insulin-dependent diabetes mellitus (NIDDM) than in those who are nondiabetics. The relationship between different types of antihyperglycemic pharmacological therapy and mortality rate in this NIDDM population is uncertain. We aimed to examine the survival in NIDDM patients with IHD using various types of oral antidiabetic treatments over a 5-year follow-up period. 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: diet alone (n = 990), sulfonylureas (n = 1,041), metformin (n = 78) and a combination of a sulfonylurea and metformin (n = 266). 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). In the diabetic group, mortality was 18.5% for patients on diet alone, 22.5% for those on sulfonylureas, 25.6% for patients on metformin, and 31.6% for the combined sulfonylurea/metformin group (p < 0.01). When analyzing age-adjusted mortality rate and actuarial survival curves, the lowest mortality was found in patients on diet alone and the highest in patients on metformin (alone or in combination with sulfonylureas). After adjustment for variables connected with long-term prognosis, the use of metformin was associated with increased relative risk (RR) for all-cause mortality of 1.42 (95% CI 1.10-1.85), whereas the use of sulfonylureas alone was not [RR 1.11 (95% CI 0.90-1.36)]. NIDDM patients with IHD using metformin, alone or in combination with sulfonylureas, exhibited a significantly increased mortality. Until the results of problem-oriented prospective studies on oral control of NIDDM will be available, alternative therapeutic approaches should be investigated in these patients.

PMID: 10516414 [PubMed - indexed for MEDLINE]

8. Consensus statement. The pharmacological treatment of hyperglycemia in NIDDM. Diabetes Care. 1996;19(suppl I):S54–S61.

 

9. Lancet 1998 Sep 12;352(9131):832-3

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	Lancet. 1998 Sep 12;352(9131):854-65

Some answers, more controversy, from UKPDS. United Kingdom Prospective Diabetes Study.

Nathan DM.

Diabetes Center, Massachusetts General Hospital, Boston 02114, USA.

Publication Types:

Comment

PMID: 9742972 [PubMed - indexed for MEDLINE]

10. Fertig BJ, Simmons DA, Martin DB. Therapy for diabetes. In: Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiber GE, Bennett PH, eds. Diabetes in America. 2nd ed. Washington, DC: US Government Printing Office; 1995:519–539.

 

11. Ann Intern Med 2000 Jul 4;133(1):73-4

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Pharmacologic therapy for type 2 diabetes mellitus.

DeFronzo RA.

Publication Types:

Letter

PMID: 10877745 [PubMed - indexed for MEDLINE

 

12. Diabetes 1994 Jun;43(6):735-40

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Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM?

Taylor SI, Accili D, Imai Y.

Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.

Publication Types:

	Review
	Review, tutorial

PMID: 8194657 [PubMed - indexed for MEDLINE]

 

13. Diabetes 1975;24 Suppl 1:65-184

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The University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. V. Evaluation of pheniformin therapy.

Publication Types:

	Clinical trial
	Randomized controlled trial

PMID: 1090475 [PubMed - indexed for MEDLINE]

 

14. Am Heart J 1999 Nov;138(5 Pt 1):S353-9

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Hyperglycemia and hyperinsulinemia at diagnosis of diabetes and their association with subsequent cardiovascular disease in the United Kingdom prospective diabetes study (UKPDS 47).

Adler AI, Neil HA, Manley SE, Holman RR, Turner RC.

Diabetes Research Laboratory, Oxford University, Oxford, UK. amanda.adler@drl.ox.ac.uk

Publication Types:

	Clinical trial
	Multicenter study
	Randomized controlled trial

PMID: 10539797 [PubMed - indexed for MEDLINE]

 

15. Diabetologia 1983 Jan;24(1):16-8

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Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy.

Adams JF, Clark JS, Ireland JT, Kesson CM, Watson WS.

In a survey of 46 randomly selected diabetic patients on biguanide therapy, 30% had malabsorption of vitamin B12. Withdrawal of the drug resulted in normal absorption in only half of those with malabsorption. In most patients with persistent malabsorption, the results of absorption tests with exogenous intrinsic factor suggested the diagnosis of coincidental intrinsic factor deficiency. Further considerations, however, led to the concept that biguanides can induce malabsorption by two different mechanisms. One of these is temporary and unrelated to intrinsic factor secretion and the other is permanent and mediated by depression of intrinsic factor secretion.

PMID: 6825978 [PubMed - indexed for MEDLINE]

 

16. J Am Coll Cardiol 1996 Mar 1;27(3):517-27

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Homocysteine and coronary atherosclerosis.

Mayer EL, Jacobsen DW, Robinson K.

Department of Cardiology, The Research Institute, The Cleveland Clinic Foundation, Ohio 44195, USA.

Homocysteine is increasingly recognized as a risk factor for coronary artery disease. An understanding of its metabolism and of the importance of vitamins B6 and B12 and folate as well as enzyme levels in its regulation will aid the development of therapeutic strategies that, by lowering circulating concentrations, may also lower risk. Possible mechanisms by which elevated homocysteine levels lead to the development and progression of vascular disease include effects on platelets, clotting factors and endothelium. This review presents the clinical and basic scientific evidence supporting the risk and mechanisms of vascular disease associated with elevated homocysteine concentrations as well as the results of preliminary therapeutic trials.

Publication Types:

	Review
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PMID: 8606260 [PubMed - indexed for MEDLINE]

 

17. JAMA 1971 Nov;218(9):1400-10

Related Articles, Books

Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. 3. Clinical implications of UGDP results.

Goldner MG, Knatterud GL, Prout TE.

Publication Types:

	Clinical trial
	Randomized controlled trial

PMID: 4941698 [PubMed - indexed for MEDLINE]

 

18. Clin Pharmacokinet 1989 Feb;16(2):100-28

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Pharmacokinetic-pharmacodynamic relationships of oral hypoglycaemic agents. An update.

Marchetti P, Navalesi R.

Cattedra Malattie del Ricambio, Istituto di Clinica Medica II, Universita di Pisa, Italy.

Oral hypoglycaemic drugs, sulphonylureas and biguanides, occupy an important place in the treatment of Type II (non-insulin-dependent) diabetic patients who fail to respond satisfactorily to diet therapy and physical exercise. Although the precise mechanisms of action of these compounds are still poorly understood, there is sufficient agreement that sulphonylureas have both pancreatic and extrapancreatic effects, whereas biguanides have predominantly extrapancreatic actions. By using labelled compounds or measuring the circulating concentrations, the main pharmacokinetic properties of oral hypoglycaemic agents have been assessed and, in some cases, their pharmacokinetic-pharmacodynamic relationships have been evaluated. A correlation between diabetes control and plasma sulphonylurea or biguanide concentrations is generally lacking at the steady-state, with the possible exception of long-acting agents; after either oral or intravenous dosing, the reduction of plasma glucose is usually related to the increased circulating drug concentrations. The toxic effects of oral hypoglycaemic drugs are more frequent in the elderly and in the presence of conditions that may lead to drug accumulation or potentiation (increased dosage, use of long-acting compounds, hepatic and renal disease, interaction with other drugs); however, a relationship between toxic effects and drug plasma levels has been reported only for biguanides.

Publication Types:

	Review
	Review, academic

PMID: 2656043 [PubMed - indexed for MEDLINE]

 

19. Diabetes Care 1996 Nov;19(11):1194-9

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Glimepiride, a new once-daily sulfonylurea. A double-blind placebo-controlled study of NIDDM patients. Glimepiride Study Group.

Rosenstock J, Samols E, Muchmore DB, Schneider J.

Dallas Diabetes and Endocrine Center, TX 75230, USA.

OBJECTIVE: To compare the efficacy and safety of two daily doses of the new sulfonylurea, glimepiride (Amaryl), each as a once-daily dose or in two divided doses, in patients with NIDDM. RESEARCH DESIGN AND METHODS: Of the previously treated NIDDM patients, 416 entered this multicenter randomized double-blind placebo-controlled fixed-dose study. After a 3-week placebo washout, patients received a 14-week course of placebo or glimepiride 8 mg q.d., 4 mg b.i.d., 16 mg q.d., or 8 mg b.i.d. RESULTS: Fasting plasma glucose (FPG) and HbA1c values were similar at baseline in all treatment groups. The placebo group's FPG value increased from 13.0 mmol/l at baseline to 14.5 mmol/l at the last evaluation endpoint (P < or = 0.001). In contrast, FPG values in the four glimepiride groups decreased from a range of 12.4-12.9 mmol/l at baseline to a range of 8.6-9.8 mmol/l at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change [vs. placebo] from baseline). Two-hour postprandial plasma glucose (PPG) findings were consistent with FPG findings. In the placebo group, the HbA1c value increased from 7.7% at baseline to 9.7% at endpoint (P < or = 0.001), whereas HbA1c values for the glimepiride groups were 7.9-8.1% at baseline and 7.4-7.6% at endpoint (P < or = 0.001, within-group change from baseline; P < or = 0.001, between-group change from baseline). There were no meaningful differences in glycemic variables between daily doses of 8 and 16 mg or between once- and twice-daily dosing. Adverse events and laboratory data demonstrate that glimepiride has a favorable safety profile. CONCLUSIONS: Glimepiride is an effective and well-tolerated oral glucose-lowering agent. The results of this study demonstrate maximum effectiveness can be achieved with 8 mg q.d. of glimepiride in NIDDM subjects.

Publication Types:

	Clinical trial
	Randomized controlled trial

PMID: 8908379 [PubMed - indexed for MEDLINE]

 

20. Circulation 1993 Sep;88(3):1245-53

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Role of K+ATP channels in coronary vasodilation during exercise.

Duncker DJ, Van Zon NS, Altman JD, Pavek TJ, Bache RJ.

Department of Medicine, University of Minnesota Medical School, Minneapolis 55455.

BACKGROUND. The mechanism of metabolic regulation of coronary vascular tone is still unclear. Therefore, we examined the role of vascular smooth muscle K+ATP channels in regulating coronary blood flow under resting conditions, during increments in myocardial metabolic demand produced by treadmill exercise, and in response to a brief ischemic stimulus. METHODS AND RESULTS. Ten chronically instrumented dogs were studied at rest and during a four-stage exercise protocol under control conditions and during intracoronary infusion of the K+ATP channel blocker glibenclamide at rates of 10 and 50 micrograms.kg-1 x min-1. Glibenclamide (50 micrograms.kg-1 x min-1) decreased coronary blood flow at rest from 51 +/- 4 to 42 +/- 6 mL/min (P < .05), decreased myocardial oxygen consumption from 5.70 +/- 0.31 to 4.11 +/- 0.56 mL O2/min (P < .05), and decreased systolic wall thickening from 21 +/- 3% to 12 +/- 3% (P < .05). The depression of systolic wall thickening produced by glibenclamide was reversed when coronary blood flow was restored to the control level with intracoronary nitroprusside, indicating a primary effect of glibenclamide on coronary flow during resting conditions. However, glibenclamide did not impair the increases of coronary blood flow, myocardial oxygen consumption, and systolic wall thickening that occurred during exercise. In eight resting awake dogs, 50 micrograms.kg-1 x min-1 glibenclamide decreased the peak reactive hyperemia blood flow rate following a 20-second coronary occlusion from 149 +/- 14 mL/min during control conditions to 111 +/- 15 mL/min (P < .05), decreased the duration of reactive hyperemia from 49 +/- 6 to 33 +/- 3 seconds (P < .05), and decreased reactive hyperemia excess flow from 33 +/- 5 to 20 +/- 4 mL (P < .05). CONCLUSIONS. These data demonstrate that K+ATP channels modulate coronary vasomotor tone under resting conditions and contribute to coronary vasodilation during ischemia. However, the coronary vasculature retains the capacity to dilate in response to increases in oxygen demand produced by exercise when K+ATP channels are blocked.

PMID: 8353886 [PubMed - indexed for MEDLINE]

 

21. Circ Res 1991 Sep;69(3):571-81

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ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage.

Cole WC, McPherson CD, Sontag D.

Department of Physiology, St. Boniface Research Centre, University of Manitoba, Winnipeg, Canada.

The role of ATP-regulated K+ channels in protecting the myocardium against ischemia/reperfusion damage was explored using glibenclamide and pinacidil to block and activate the channels, respectively. Electrical and mechanical activity of arterially perfused guinea pig right ventricular walls was recorded simultaneously via an intracellular microelectrode and a force transducer. The preparations were subjected to either 1) 20 minutes of no-flow ischemia with or without glibenclamide (1 and 10 microM) followed by reperfusion, or 2) 30 minutes of no-flow ischemia with or without pinacidil (1 and 10 microM) followed by reperfusion. No-flow ischemia for 20 minutes produced changes in electrical and mechanical activity that were completely reversed on reperfusion; resting membrane potential declined by 13 +/- 1.2 mV, action potential duration at 90% repolarization (APD90) decreased by 62%, and developed tension fell by greater than 95%, but resting tension did not change significantly. Glibenclamide (10 microM) had no effect on activity during normal perfusion, but during ischemia, resting membrane potential fell slightly further (17 +/- 1.8 mV) and APD90 declined by only 24%. Developed tension declined more slowly and to a lesser extent, but resting tension rose significantly between 10 and 20 minutes of ischemia. Reperfusion of glibenclamide-treated tissues elicited arrhythmias (extrasystoles and tachycardia), and the preparations failed to recover mechanical function. Glibenclamide at 1 microM produced qualitatively similar effects, albeit less severe. After 30 minutes of no-flow ischemia in untreated tissues, resting tension increased by approximately 130% during the no-flow period. Reperfusion caused arrhythmias (extrasystoles, tachyarrhythmias, and fibrillation) and failed to restore resting or developed tension to preischemic levels. Pinacidil at 1 microM did not affect electrical or contractile function, but at 10 microM it had a negative inotropic effect, decreasing APD90 and developed tension by 5% and 18%, respectively. Both concentrations of the drug caused a faster and greater decline in APD90 during the no-flow period. Resting tension did not change during 30 minutes of no-flow ischemia in the presence of pinacidil, and reperfusion led to 85% and complete recovery of electrical and mechanical activity at 1 and 10 microM, respectively. The data indicate that glibenclamide enhances whereas pinacidil reduces myocardial damage caused by ischemia/reperfusion. The results are consistent with the hypothesis that activation of ATP-regulated K+ channels during ischemia is an important adaptive mechanism for protecting the myocardium when blood flow to the tissue is compromised.

PMID: 1908354 [PubMed - indexed for MEDLINE]

 

22. Circulation 1992 Sep;86(3):986-94

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Myocardial protective effects of adenosine. Infarct size reduction with pretreatment and continued receptor stimulation during ischemia.

Toombs CF, McGee S, Johnston WE, Vinten-Johansen J.

Department of Cardiothoracic Surgery, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157-1096.

BACKGROUND. We hypothesized that 1) endogenous adenosine released during ischemia conferred an inherent cardioprotection, and 2) a pretreatment dose of adenosine before ischemia would provide additional protection independent of hemodynamic effects. METHODS AND RESULTS. Thirty-six anesthetized New Zealand White rabbits underwent 30 minutes of regional ischemia produced by coronary occlusion followed by 2 hours of reperfusion. The adenosine group (ADO, n = 9) received a 5-minute pretreatment infusion of 140 micrograms/kg/min of adenosine before ischemia. A control group (SAL, n = 9) received saline before ischemia. To separate the effects of adenosine used as a pretreatment versus the effects during ischemia, a third group (ADO+SPT, n = 9) received adenosine as pretreatment followed by 10 mg/kg 8-p-sulfophenyl theophylline (8-SPT), an A1/A2-receptor antagonist given before ischemia, thus allowing pretreatment with adenosine but antagonizing its effects during ischemia. To preclude any protection from endogenous adenosine released during ischemia, the fourth group (SAL+SPT, n = 9) received saline as pretreatment and 8-SPT before ischemia. Area of necrosis within the area at risk (infarct size) was determined with tetrazolium and Evans blue stains, and transmural blood flow was measured using radioactive microspheres. Collateral blood flow in the area at risk was similar in all groups, as was the size of the area at risk. Infarct size was reduced by adenosine pretreatment (ADO, 8.4 +/- 7.2%) in contrast to saline vehicle (SAL, 27.8 +/- 6.3%; p less than 0.05 versus ADO). alpha 1/alpha 2-Receptor blockade after adenosine pretreatment abolished the ischemic protection provided by pretreatment adenosine (ADO+SPT, 42.7 +/- 8.3%; p less than 0.05 versus ADO). Finally, receptor blockade of endogenously released adenosine without adenosine pretreatment increased infarct size by 24% over the nonpretreated saline group (SAL+SPT, 51.5 +/- 9.0%; p less than 0.05 versus SAL). CONCLUSIONS. We conclude that 1) endogenous adenosine building up during ischemia is cardioprotective, and 2) pretreatment with adenosine confers cardioprotection independent of hemodynamic effects. Whether pretreatment effects of adenosine subsequently modulate the effects of endogenous adenosine (through alterations in receptor population or sensitivity) or endogenous and exogenous adenosine represent additive compartments is unclear.

PMID: 1516210 [PubMed - indexed for MEDLINE]

23. Pogatsa G, Koltai ZM, Ballagi-Pordany G. Influence of hypoglycemic sulfonylurea compounds on the incidence of ventricular ectopic beats in non-insulin-dependent diabetic patients treated with digitalis. Curr Ther Res. 1993;53:329–339.

 

24. Circulation 1992 Oct;86(4):1310-6

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Role of myocardial ATP-sensitive potassium channels in mediating preconditioning in the dog heart and their possible interaction with adenosine A1-receptors.

Grover GJ, Sleph PG, Dzwonczyk S.

Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000.

BACKGROUND. A brief period of myocardial ischemia can result in an increased resistance to subsequent, more severe episodes of ischemia. Recent studies have indicated that activation of adenosine A1-receptors may mediate this preconditioning effect. It is also known that A1-activation can lead to ATP-sensitive potassium channel (KATP) opening via a G(i) protein-mediated effect. Thus, we determined whether the KATP blocker glyburide could abolish preconditioning or the protective effects of A1-receptor activation. METHODS AND RESULTS. Anesthetized dogs were subjected to 5 minutes of left circumflex coronary artery (LCx) occlusion (or sham) followed by 10 minutes of reperfusion. The hearts were then subjected to 60 minutes of LCx occlusion and 5 hours of reperfusion. Glyburide (5 micrograms/kg/min) or vehicle was given directly into the LCx 20 minutes before preconditioning or sham preconditioning. Preconditioning resulted in a significantly reduced infarct size compared with nonpreconditioned animals. Glyburide abolished the protective effect of preconditioning. To establish a link between KATP and A1-receptor activation, the effect of the A1-agonist R-PIA with or without glyburide on infarct size was determined. R-PIA (0.4 microgram/kg/min, directly into the LCx) significantly reduced infarct size, and this protective effect was abolished by glyburide. None of the treatments described above had a significant effect on peripheral hemodynamic status or myocardial blood flow. CONCLUSIONS. Preconditioning may be mediated by KATP activation, and this may be linked to A1-receptor stimulation.

PMID: 1394937 [PubMed - indexed for MEDLINE]

 

25. J Am Coll Cardiol 1999 Jan;33(1):119-24

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Comment in:

	J Am Coll Cardiol. 1999 Sep;34(3):958
	J Am Coll Cardiol. 2000 Mar 1;35(3):820-1

Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction.

Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes DR Jr.

Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota, USA.

OBJECTIVES: The purpose of this study was to examine the impact of sulfonylurea drug use on outcome in diabetic patients undergoing direct coronary angioplasty for acute myocardial infarction. BACKGROUND: Sulfonylurea drugs impair ischemic preconditioning. Whether sulfonylurea drugs affect outcome adversely in diabetic patients undergoing direct angioplasty for acute myocardial infarction is unknown. METHODS: Clinical outcomes after direct balloon angioplasty for acute myocardial infarction were evaluated in 67 diabetic patients taking oral sulfonylurea drugs and 118 diabetic patients not taking these drugs. RESULTS: Hospital mortality was significantly higher among diabetics treated with sulfonylurea drugs at the time of myocardial infarction (24% vs. 11%). Univariate analysis identified sulfonylurea drug, age, ventricular function, ejection fraction less than 40%, prior bypass surgery and congestive heart failure as correlates of increased in-hospital mortality. Logistic regression found sulfonylurea drug use (odds ratio 2.77, p=0.017) to be independently associated with early mortality. Congestive heart failure, but not sulfonylurea drug use, was associated with an increased incidence of in-hospital ventricular arrhythmias. Congestive heart failure, prior bypass surgery and female gender, but not sulfonylurea drug use, were associated with late adverse events. CONCLUSIONS: Sulfonylurea drug use is associated with an increased risk of in-hospital mortality among diabetic patients undergoing coronary angioplasty for acute myocardial infarction. This early risk is not explained by an increase in ventricular arrhythmias, but may reflect deleterious effects of sulfonylurea drugs on myocardial tolerance for ischemia and reperfusion. For surviving patients sulfonylurea drug use is not associated with an increased risk of serious late adverse events.

PMID: 9935017 [PubMed - indexed for MEDLINE]

 

26. Eur Heart J 1999 Mar;20(6):439-46

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Comment in:

Eur Heart J. 1999 Mar;20(6):403-5

Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-controlled evaluation of glimepiride and glibenclamide.

Klepzig H, Kober G, Matter C, Luus H, Schneider H, Boedeker KH, Kiowski W, Amann FW, Gruber D, Harris S, Burger W.

Department of Medicine, J. W. Goethe University Frankfurt /Main, Germany.

AIMS: Glimepiride is a new sulfonylurea for diabetes treatment which is supposed to impact less on extra-pancreatic ATP-dependent K+ channels than the conventional drug glibenclamide. This study was performed to evaluate whether this results in a better maintenance of ATP-dependent K+ channel mediated ischaemic myocardial preconditioning. METHODS AND RESULTS: In a double-blind placebo-controlled study the period of total coronary occlusion during balloon angioplasty of high grade coronary artery stenoses was used as a model to compare the effects of both drugs. Quantification of myocardial ischaemia was achieved by recording the intracoronary ECG and the time to the occurrence of angina during vessel occlusion. All patients underwent three dilatations. The first dilatation (dilatation 1) served to determine the severity of ischaemia during vessel occlusion. During dilatation 2, baseline values were recorded. Thereafter, glimepiride (15 patients: 1.162 mg), glibenclamide (15 patients: 2.54 mg) or placebo (15 patients) were intravenously administered over 12 min. Dilatation 3 started 10 min after the beginning of the drug administration. Mean ST segment shifts in the placebo group decreased by 35% (dilatation 2: 0.23; dilatation 3:0.15 mV; CI -0.55 to 0.00 mV; P=0.049). A similar reduction also occurred in the glimepiride group, in which repetitive balloon occlusion led to a 34% reduction (dilatation 2: 0.35; dilatation 3: 0.23 mV; CI -0.21 to -0.02 mV; P=0.01). There was little influence however, on mean ST segment shifts in the glibenclamide group (dilatation 2 and dilatation 3: 0.24 mV; CI -0.10 to 0.25 mV; P=0.34). Accordingly, time to angina during balloon occlusion slightly increased (by 30%) in the placebo group (dilatation 2: 37 s; dilatation 3: 48 s; CI 0.0 to 15.0 s; P=0.16); increased by 13% in the glimepiride group (dilatation 2: 40 s; dilatation 3: 45 s; CI 0.0 to 14.0 s; P=0023); and remained unchanged in the glibenclamide group (dilatation 2 and dilatation 3: 30 s; CI -7.5 to 7.5 s; P=0.67). CONCLUSION: These results show that glimepiride maintains myocardial preconditioning, while glibenclamide might be able to prevent it.

Publication Types:

	Clinical trial
	Multicenter study
	Randomized controlled trial

PMID: 10213347 [PubMed - indexed for MEDLINE]

 

27. Am Heart J 1999 Nov;138(5 Pt 1):S334-7

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Treatment of diabetes mellitus: implications of the use of oral agents.

Rao SV, Bethel MA, Feinglos MN.

Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USA.

Publication Types:

	Review
	Review, tutorial

PMID: 10539794 [PubMed - indexed for MEDLINE]

 

28. Diabetes 1996 Dec;45(12):1661-9

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Thiazolidinediones in the treatment of insulin resistance and type II diabetes.

Saltiel AR, Olefsky JM.

Department of Signal Transduction, Parke-Davis Pharmaceutical Research Division, Warner Lambert, Ann Arbor, Michigan, USA.

Insulin resistance, characterized by reduced responsiveness to normal circulating concentrations of insulin, is a common feature of almost all patients with type II diabetes. The presumed central roles of both peripheral and hepatic insulin resistance suggest that the enhancement of insulin action might be an effective pharmacological approach to diabetes. Thiazolidinediones are a new class of orally active drugs that are designed to enhance the actions of insulin. These agents reduce insulin resistance by increasing insulin-dependent glucose disposal and reducing hepatic glucose output. Clinical studies in patients with type II diabetes, as well as other syndromes characterized by insulin resistance, have demonstrated that thiazolidinediones may represent a safe and effective new treatment. Although the precise mechanism of action of these drugs remains unknown, transcriptional changes are observed in tissue culture cells that produce enhanced insulin action. This regulation of gene expression appears to be mediated by the interactions of thiazolidinediones with a family of nuclear receptors known as the peroxisome proliferator-activated receptors (PPARs). The further elucidation of the molecular actions of these drugs may reveal much about the underlying mechanisms of insulin resistance.

Publication Types:

	Review
	Review, tutorial

PMID: 8922349 [PubMed - indexed for MEDLINE]

 

29. Diabetes 1998 Mar;47(3):345-51

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Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes.

Fuhlendorff J, Rorsman P, Kofod H, Brand CL, Rolin B, MacKay P, Shymko R, Carr RD.

Diabetes Discovery, Novo Nordisk A/S, Bagsvaerd, Denmark. jfu@novo.dk

The action of repaglinide, a novel insulin secretagogue, was compared with the sulfonylurea glibenclamide with regard to the hypoglycemic action in vivo, binding to betaTC-3 cells, insulin secretion from perifused mouse islets, and capacity to stimulate exocytosis by direct interaction with the secretory machinery in single voltage-clamped mouse beta-cells. Two binding sites were identified: a high-affinity repaglinide (KD = 3.6 nmol/l) site having lower affinity for glibenclamide (14.4 nmol/l) and one high-affinity glibenclamide (25 nmol/l) site having lower affinity for repaglinide (550 nmol/l). In contrast to glibenclamide, repaglinide (in concentrations as high as 5 micromol/l) lacked the ability to enhance exocytosis in voltage-clamped beta-cells. Repaglinide was more potent than glibenclamide in stimulating insulin release from perifused mouse islets (EC50 29 vs. 80 nmol/l). The greater potency of repaglinide in vitro was paralleled by similar actions in vivo. The ED50 values for the hypoglycemic action were determined to be 10.4 and 15.6 microg/kg after intravenous and oral administration, respectively. The corresponding values for glibenclamide were 70.3 microg/kg (intravenous) and 203.2 microg/kg (oral). Further, repaglinide (1 mg/kg p.o.) was effective (P < 0.001) as an insulin-releasing agent in a rat model (low-dose streptozotocin) of type 2 diabetes. These observations suggest that the insulinotropic actions of repaglinide and glibenclamide in vitro and in vivo are secondary to their binding to the high-affinity repaglinide site and that the insulinotropic action of repaglinide involves both distinct and common cellular mechanisms.

PMID: 9519738 [PubMed - indexed for MEDLINE]

 

30. Am Heart J 1999 Nov;138(5 Pt 1):S338-45

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FDA approach to the regulation of drugs for diabetes.

Fleming A.

Worldwide Clinical Trials, Inc, Division of Endocrine and Metabolic Drug Products, Food and Drug Administration, Chevy Chase, MD 20815, USA.

Publication Types:

	Review
	Review, tutorial

PMID: 10539795 [PubMed - indexed for MEDLINE]

 

31. JAMA 1999 Jun 2;281(21):2005-12

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Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group.

Turner RC, Cull CA, Frighi V, Holman RR.

Radcliffe Infirmary, Oxford, England. robert.turner@drl.ox.ac.uk

CONTEXT: Treatment with diet alone, insulin, sulfonylurea, or metformin is known to improve glycemia in patients with type 2 diabetes mellitus, but which treatment most frequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A1c (HbA1c) below 7% is unknown. OBJECTIVE: To assess how often each therapy can achieve the glycemic control target levels set by the American Diabetes Association. DESIGN: Randomized controlled trial conducted between 1977 and 1997. Patients were recruited between 1977 and 1991 and were followed up every 3 months for 3, 6, and 9 years after enrollment. SETTING: Outpatient diabetes clinics in 15 UK hospitals. PATIENTS: A total of 4075 patients newly diagnosed as having type 2 diabetes ranged in age between 25 and 65 years and had a median (interquartile range) FPG concentration of 11.5 (9.0-14.4) mmol/L [207 (162-259) mg/dL], HbA1c levels of 9.1% (7.5%-10.7%), and a mean (SD) body mass index of 29 (6) kg/m2. INTERVENTIONS: After 3 months on a low-fat, high-carbohydrate, high-fiber diet, patients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin. MAIN OUTCOME MEASURES: Fasting plasma glucose and HbA1c levels, and the proportion of patients who achieved target levels below 7% HbA1c or less than 7.8 mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis. RESULTS: The proportion of patients who maintained target glycemic levels declined markedly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA1c levels below 7%. In obese patients randomized to metformin, 18% attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA1c levels below 7%. Patients less likely to achieve target levels were younger, more obese, or more hyperglycemic than other patients. CONCLUSIONS: Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA1c below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years approximately 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need multiple therapies to attain these glycemic target levels in the longer term.

Publication Types:

	Clinical trial
	Randomized controlled trial

PMID: 10359389 [PubMed - indexed for MEDLINE]

 

32. Clin Cardiol 2001 Feb;24(2):151-8

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Oral antidiabetic treatment in patients with coronary disease: time-related increased mortality on combined glyburide/metformin therapy over a 7.7-year follow-up.

Fisman EZ, Tenenbaum A, Boyko V, Benderly M, Adler Y, Friedensohn A, Kohanovski M, Rotzak R, Schneider H, Behar S, Motro M.

Cardiac Rehabilitation Institute, the Chaim Sheba Medical Center, Tel-Hashomer, Israel.

BACKGROUND: A sulfonylurea--usually glyburide--plus metformin constitute the most widely used oral antihyperglycemic combination in clinical practice. Both medications present undesirable cardiovascular effects. The issue whether the adverse effects of each of these pharmacologic agents may be additive and detrimental to the prognosis for coronary patients has not yet been specifically addressed. HYPOTHESIS: This study was designed to examine the survival in type 2 diabetics with proven coronary artery disease (CAD) receiving a combined glyburide/metformin antihyperglycemic treatment over a long-term follow-up period. METHODS: The study sample comprised 2,275 diabetic patients, aged 45-74 years, with proven CAD, who were screened but not included in the bezafibrate infarction prevention study. In addition, 9,047 nondiabetic patients with CAD represented a reference group. Diabetics were divided into four groups on the basis of their therapeutic regimen: diet alone (n = 990), glyburide (n = 953), metformin (n = 79), and a combination of the latter two (n = 253). RESULTS: The diabetic groups presented similar clinical characteristics upon recruitment. Crude mortality rate after a 7.7-year follow-up was lower in nondiabetics (14 vs. 31.6%, p<0.001). Among diabetics, 720 patients died: 260 on diet (mortality 26.3%), 324 on glyburide (34%), 25 on metformin alone (31.6%), and 111 patients (43.9%) on combined treatment (p<0.000001). Time-related mortality was almost equal for patients on metformin and on combined therapy over an intermediate follow-up period of 4 years (survival rates 0.80 and 0.79, respectively). The group on combined treatment presented the worst prognosis over the long-term follow-up, with a time-related survival rate of 0.59 after 7 years, versus 0.68 and 0.70 for glyburide and metformin, respectively. After adjustment to variables for prognosis, the use of the combined treatment was associated with an increased hazard ratio (HR) for all-cause mortality of 1.53 (95% confidence interval [CI] 1.20-1.96), whereas glyburide and metformin alone yielded HR 1.22 (95% CI 1.02-1.45) and HR 1.26 (95% CI 0.81-1.96), respectively. Conclusions: We conclude that after a 7.7-year follow-up, monotherapy with either glyburide or metformin in diabetic patients with CAD yielded a similar outcome and was associated with a modest increase in mortality. However, time-related mortality was markedly increased when a combined glyburide/metformin treatment was used.

PMID: 11460818 [PubMed - indexed for MEDLINE]

 

33. Curr Opin Lipidol 1996 Aug;7(4):227-33

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Does treatment of noninsulin-dependent diabetes mellitus reduce the risk of coronary heart disease?

Giugliano D.

Department of Geniatrics and Metabolic Diseases, Second University of Naples, Italy.

Diabetes is an independent risk factor for the development of coronary heart disease and has a tremendous impact on mortality. In patients with noninsulin-dependent diabetes mellitus, coronary heart disease is the leading cause of death. Both hyperinsulinemia and hyperglycemia have been suggested as risk factors for accelerated atherogenesis in diabetes. Whichever mechanism is implicated, a beneficial effect of therapy in preventing cardiovascular disease is a major requirement. Until now, it is not clear whether stringent control of blood glucose levels reduces the risk of development of coronary heart disease in patients with noninsulin-dependent diabetes mellitus. This review emphasizes the relative roles of insulin and glucose on coronary heart disease development in noninsulin-dependent diabetes mellitus. The different therapeutic options of pharmacological treatment in hyperglycemia in noninsulin-dependent diabetes mellitus are discussed, as well as their impact on coronary heart disease risk.

Publication Types:

	Review
	Review, tutorial

PMID: 8883498 [PubMed - indexed for MEDLINE]

 

34. Am J Cardiol 1999 Aug 1;84(3):294-8

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Prevalence and prognostic significance of unrecognized systemic hypertension in patients with diabetes mellitus and healed myocardial infarction and/or stable angina pectoris.

Tenenbaum A, Fisman EZ, Boyko V, Goldbourt U, Auerbach I, Shemesh J, Shotan A, Reicher-Reiss H, Behar S, Motro M.

Cardiac Rehabilitation Institute, Chaim Sheba Medical Center, Tel-Hashomer, Israel. zfisman@post.tau.ac.il

Few data are available regarding the prevalence and prognostic significance of the triple coexistence of undiagnosed systemic hypertension, diabetes mellitus, and coronary heart disease. This study aimed to evaluate the prevalence and prognostic significance of unrecognized hypertension in cardiac diabetic patients previously defined as "normotensives" over a 5-year follow-up period. The study sample comprised 11,515 patients aged 45 to 74 years with a previous myocardial infarction and/or anginal syndrome who were screened but not included in the Bezafibrate Infarction Prevention study. Among them, 9,033 were nondiabetics and 2,482, diabetics. The diabetics were divided into 3 groups: (1) 1,272 normotensives, (2) 152 patients without history of hypertension but with elevated blood pressure ("unrecognized hypertensives"), and (3) 1,058 hypertensives with established diagnosis. The prevalence of both diagnosed and unrecognized hypertension in diabetics pooled together increased from 49% to 69% when World Health Organization and new Joint National Committee-VI criteria were compared. Crude all-cause mortality was lower in nondiabetics than in diabetics (11.2% vs 22.0%; p <0.001). Among diabetics the lowest all-cause mortality was documented for normotensives (19.3%), whereas the highest mortality was observed in unrecognized hypertensives (26.3%, p = 0.003). Both unrecognized and established hypertensives demonstrated a significant stroke-related mortality excess: about four- and threefold increases in cerebrovascular accident-related death, respectively, were observed (p = 0.002). On multivariate analysis, both unrecognized and diagnosed hypertension were consistent predictors of increased all-cause mortality, with a hazard ratio of 1.28 (95% confidence interval 0.90 to 1.82) and 1.24 (95% confidence interval 1.03 to 1.49), respectively. Our findings demonstrate widespread undiagnosed hypertension in diabetic coronary patients; their 5-year mortality was significantly increased compared with normotensives, and tended to be even higher than in diabetics previously identified as hypertensives.

PMID: 10496438 [PubMed - indexed for MEDLINE]

 

35. Hypertension 1999 Apr;33(4):1002-7

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Hypertension in diet versus pharmacologically treated diabetics: mortality over a 5-year follow-up.

Tenenbaum A, Fisman EZ, Boyko V, Goldbourt U, Graff E, Shemesh J, Shotan A, Reicher-Reiss H, Behar S, Motro M.

Cardiac Rehabilitation Institute and the Bezafibrate Infarction Prevention Coordinating Center, Neufeld Cardiac Research Institute, the Chaim Sheba Medical Center, Tel-Hashomer, Israel.

The natural history of non-insulin-dependent diabetes mellitus (NIDDM) differs markedly between patients with diet treated and pharmacologically treated disease. However, the interrelationship between hypertension and these common diabetes types has not been specifically addressed in previous studies. This study was designed to evaluate the prognostic significance and prevalence of hypertension in coronary patients with diet versus pharmacologically treated NIDDM over a 5-year follow-up period. The study sample comprised 11 515 patients aged 45 to 74 years with a previous myocardial infarction and/or anginal syndrome who had been screened but were not included in the Bezafibrate Infarction Prevention study. Among them, 9033 were nondiabetics and 2482, diabetics (987 diet treated and 1495 pharmacologically treated). The prevalence of hypertension among nondiabetics, diet-treated diabetics, and pharmacologically treated diabetics was 31%, 42%, and 43%, respectively. Crude all-cause mortality (CM) was lower in the nondiabetic patients (11.2% versus 22.0%; P<0.001). Among diabetics, 548 patients died: 81 diet treated normotensives (CM 14%); 100 diet-treated hypertensives (CM 24.4%); 205 pharmacologically treated normotensives (CM 24.2%); and 162 pharmacologically treated hypertensive patients (CM 25.0%). Age-adjusted mortality was lowest for the normotensive patients in the diet-treated group and highest for the hypertensive pharmacologically treated patients. Multivariate analysis shows that hypertension is a strong and independent predictor of increased CM in diet-treated but not in pharmacologically treated NIDDM: hazard ratio (HR) was 1.68 (95% confidence interval [CI] 1.24 to 2.29) for the diet-treated versus 1. 01 (95% CI 0.82 to 1.26) for the pharmacologically treated diabetics. The contribution of hypertension to stroke mortality was substantial for both diet treated and pharmacologically treated NIDDM: hazard ratios were 3.17 (95% CI 1.12 to 8.98) and 2.21 (95% CI 0.72 to 6.77), respectively. The increased risk of mortality associated with hypertension in relatively mild diet-treated NIDDM strongly supports the clinical benefit of early blood pressure control among diabetic patients with ischemic heart disease.

PMID: 10205238 [PubMed - indexed for MEDLINE]

 

36. Endocr Pract 2000 Jan-Feb;6(1):43-84

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The American Association of Clinical Endocrinologists Medical Guidelines for the Management of Diabetes Mellitus: the AACE system of intensive diabetes self-management--2000 update.

American Association of Clinical Endocrinologists.

Publication Types:

	Guideline
	Practice guideline

PMID: 11428359 [PubMed - indexed for MEDLINE]

 

37. Circulation 1999 Sep 7;100(10):1134-46

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Erratum in:

Circulation 2000 Apr 4;101(13):1629-31

Comment in:

Circulation. 1999 Sep 7;100(10):1132-3

Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association.

Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, Mitch W, Smith SC Jr, Sowers JR.

Publication Types:

	Review
	Review, tutorial

PMID: 10477542 [PubMed - indexed for MEDLINE]

 

38. J Am Coll Cardiol 1999 Nov 1;34(5):1443-51

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Hyperinsulinemic hypoalphalipoproteinemia as a new indicator for coronary heart disease.

Saku K, Zhang B, Shirai K, Jimi S, Yoshinaga K, Arakawa K.

Department of Internal Medicine, Fukuoka University School of Medicine, Japan. hh035399@msat.fukuoka-u.ac.jp

OBJECTIVES: The purpose of this study was to investigate the association among insulin resistance, high density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD), and to test the hypothesis that HDL-C may ameliorate the adverse effects of insulin. BACKGROUND: Serum low HDL-C (hypoalphalipoproteinemia) and hyperinsulinemia are independent predictors for CHD, but a strong negative correlation exists between them, as in patients with syndrome X. METHODS: Fifty-four pairs of cases (M/F: 49/5), defined as patients with angiographically proved CHD, and control subjects (M/F: 49/5) matched with cases with regard to gender and age were included. Insulin resistance was assessed by the homeostasis model assessment (HOMA). RESULTS: Cases had increased HOMA insulin resistance and lower serum levels of HDL-C than controls. A receiver operating characteristic (ROC) curve analysis indicated that HDL-C and insulin resistance were significant discriminators of CHD (area under ROC curve: 0.72 and 0.69, respectively). The interaction between HDL-C and the association of insulin resistance with CHD was significant: subjects with hyperinsulinemia and high HDL-C had no increased risk of CHD. Multivariate conditional logistic regression analysis showed that hyperinsulinemic hypoalphalipoproteinemia was a stronger indicator for CHD than either HDL-C or insulin resistance alone (-2 log likelihood: 19.0 vs. 12.6 or 15.7). CONCLUSIONS: Hyperinsulinemic hypoalphalipoproteinemia was a more potent indicator for CHD than either insulin resistance or low serum HDL-C levels alone, and the adverse effects of hyperinsulinemia seem to be ameliorated by high HDL-C levels.

PMID: 10551691 [PubMed - indexed for MEDLINE]

39. UK Diabetes Prospective Study (UKPDS) Group. Effect of intensive blood-glucose control on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–865.