R EVIEW A RTICLE Treatment of diabetic vasculopathy with rosiglitazone and ramipril: Hype or hope?

IGT population.


Introduction
Diabetes is one of the most challenging health problems in the twenty-first century.It is ranked as the fifth leading cause of death and is a major risk factor for various cardiovascular diseases (CVD). [1]Cardiovascular diseases are responsible for more than 50% and up to 80% of deaths in people with diabetes as well as for very substantial morbidity and loss of quality of life [2] [Table 1].The most important forms of CVD are coronary heart disease, cerebrovascular disease, and peripheral vascular disease.These lead to heart att acks, angina, heart failure, stroke, and gangrene or ulceration of the feet and legs requiring amputation.People with diabetes are also prone to developing CVD at a younger age and having more severe eff ects than people without diabetes.In addition, risk is increased even at the earlier stages of glucose intolerance.

Diabetic vasculopathy
Diabetes mellitus is a multifactorial disease associated with a number of microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular complications. [3,4]Diabetic macrovasculopathy is associated with structural and functional changes in large arteries that lead to increased stiff ness, abnormal pulse wave travel, and systolic hypertension. [4]Structural changes mainly result from glycation of wall components and functional changes originate in endothelial dysfunction, increased arterial stiff ness or decreased arterial distensibility [Figure 1].These changes promote the development of left ventricular hypertrophy, an independent risk factor for cardiovascular (CV) mortality. [5]part from the above-mentioned mechanisms, metabolic [advanced glycation end production (AGE), cytokines], humoral (renin-angiotensin system, endothelin, sympathetic nervous system) and hemodynamic (arterial hypertension and mechanical strain) factors contribute to the characteristic dysfunction in diabetic vasculopathy. [6]he initiators of vasculopathy that ultimately develop into long-term diabetic complications can be controlled and avoided by strict glycemic control, maintaining normal lipid proÞ les, regular physical exercise, adopting a healthy lifestyle and pharmacological interventions.

Treatment Modalities of Type 2 Diabetes
As the prevalence of type 2 diabetes continues to increase worldwide, there is an enhanced need for effective disease management.The International Diabetes Federation (IDF) has recently introduced new global guidelines for the management of diabetes. [7]Three modalities of treatment are currently available to manage diabetes: lifestyle modiÞ cation including appropriate diet and exercise programs, oral anti-diabetic agents, and insulin.Patients with diabetes are insulin resistant and oft en have metabolic syndrome, which requires a multifactorial intervention in order to reduce the incidence of CV complications [8] [Table 2].Treatment goals for patients with type 2 diabetes specify targets for glycemia and other cardiometabolic risk factors, for example, hypertension and dyslipidemia [7,9] [Table 3].
In recent years, special attention has been devoted to both thiazolidinediones (TZDs) and angiotensin converting enzyme (ACE) inhibitors when TRIPOD study [10] demonstrated that troglitazone may reduce the rate of progression to diabetes in women diagnosed with gestational diabetes and HOPE Study [11] showed that ramipril may delay the onset of diabetes.The landmark study ProActive (PROspective pioglitAzone Clinical Trial In macroVascular Events) demonstrated that pioglitazone reduces the composite of all-cause mortality, nonfatal myocardial infarction, and stroke in patients with T2DM who have a high risk of macrovascular events. [12]Recently, published landmark DREAM study demonstrated that rosiglitazone has a substantial benefit on prevention of diabetes and regression to normoglycemia and ramipril has a modest beneÞ t on regression to normoglycemia. [13,14]e TZDs are new oral antidiabetic agents providing a novel mea n s to r educ e hy p erg lyc em ia by improving insulin sensitivity.Moreover, TZDs have  [2] • Approximately 80% of people with diabetes die of CVD.
• On average, people with type 2 diabetes will die 5-10 years before people without diabetes and most of this excess mortality is due to CVD.
• People with type 2 diabetes are over twice as likely to have a heart attack or stroke as people who do not have diabetes.Indeed, people with type 2 diabetes are as likely to suffer a heart attack as people without diabetes who have already had a heart attack.
• Strokes occur twice as often in people with diabetes and hypertension as in those with hypertension alone.
• People with diabetes are 15-40 times more likely to have a lower limb amputation compared to the general population.
• People with diabetes have two to four times the risk of developing atherosclerosis compared to people without diabetes.
• The treatment of CVD accounts for a large part of the huge healthcare costs attributable to type 2 diabetes, that have been estimated to account for 10-12% of European health care expenditure.
• Part of the CV risk associated with IGT and diabetes is undoubtedly due to their association with other CV factors such as hypertension, high LDL-cholesterol and low HDL-cholesterol, and smoking.
• Lifestyle changes that improve blood glucose control, for example weight loss, dietary changes, and increased physical activity are also likely to improve these other CV risk factors.
Table 2: Control of cardiometabolic parameters in the management of type 2 diabetes as recommended by IDF [8] Cardiometabolic parameters Target values vasculoprotective properties beyond glycemic control. [15]hese drugs have potentially favorable eff ects on other components of the insulin resistance syndrome.As insulin sensitizers, they may modify CV risk factors and reduce CV mortality in T2DM and insulin resistance subjects. [16]The ACE inhibitors therapy reduces both microvascular and macrovascular complications in diabetes and appears to improve insulin sensitivity and glucose metabolism. [17]This review focuses on the potential roles of rosiglitazone, a member of TZD class of antidiabetic agents, and ramipril, an ACE inhibitor, in preventing the preclinical macrovasculopathy in diabetes and IGT population.

Glycemia
Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptorgamma (PPARγ).These proliferator-activated receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver.Activation of PPARγ nuclear receptors regulates the transcription of insulin responsive genes involved in the control of glucose production, transport, and utilization.In addition, PPARγ-responsive genes also participate in the regulation of fatt y acid metabolism.Ramipril has direct eff ects on the renin-angiotensin-kallikrein system and may prevent diabetes through eff ects on the beta cell and by vascular and metabolic effects on muscle that may amplify the eff ects of insulin. [18]he ACE inhibitors increase islet blood flow and pancreatic beta-cell perfusion by reducing angiotensin II-mediated vasoconstriction in the pancreas, [19] which may potentially slow down or reverse the decline in beta-cell function.The ACE inhibitors may also increase the insulin-mediated glucose disposal, thereby decreasing the need for pancreatic insulin secretion and may reduce insulin resistance in skeletal muscle. [20]his may be due to increased bradykinin-mediated nitric oxide production. [21]The ACE inhibitors may also reduce insulin resistance at the liver and fat cell, which reduce hepatic glucose production and lower free fatt y acid level. [22] 4].[25] In two 26-week placebocontrolled studies, [26,27] signiÞ cant reductions in FPG and HbA1c were seen with rosiglitazone.A 52-week randomized, double-blind trials showed that FPG and HbA1c levels fell signiÞ cantly with rosiglitazone in comparison to glibenclamide. [28]A recently published study demonstrated that rosiglitazone therapy reduced plasma insulin, proinsulin, split proinsulin, and free fatt y acid level compared with glibenclamide therapy. [29]recent publication of a meta-analysis of data from 42 clinical trials suggesting an increased risk of myocardial infarction (MI) and cardiovascular death with rosiglitazone led to a media furor and widespread patient panic. [30]The pooled data showed a 43% increase in relative risk of MI among T2DM treated with rosiglitazone.However, interim findings from ongoing RECORD (rosiglitazone evaluated for cardiac outcomes and regulation of glycemia in diabetes) study were inconclusive regarding the eff ect of rosiglitazone on the overall risk of hospitalization or death from cardiovascular causes. [31]The study found no evidence of any increased mortality, either from any cause or from cardiovascular causes.Further research is needed to determine the long-term cardiovascular eff ects of rosiglitazone.

Researchers Study population Methodology Results/Comment
Trevisan and Tiengo [37] T2DM; n=122 Ramipril 1.25 mg/day; Low-dose ACE inhibition with ramipril could arrest the duration: 6 months progressive rise in albuminuria in T2DM patients with persistent microalbuminuria.
Nielsen et al. [38] T2DM, n= 16 Ramipril (5mg)/day; Benefi cial impact of ramipril on left ventricular hypertrophy in duration: 6 month normotensive nonalbuminuric T2DM patients MICROHOPE Substudy [39] T2DM; n=3577 Ramipril 10 mg/day vs. Lowered the risk of the combined primary outcome by 25%, placebo and Vitamin E; myocardial infarction by 22%, stroke by 33%, CV death by duration: 4.5 years 37%, total mortality by 24%, revascularization by 17%, and overt nephropathy by 24%.Ramipril was benefi cial for CV events and overt nephropathy in T2DM patients Þ rst to explore that ACE inhibitor ramipril prevents the development of diabetes. [11][34][35][36] As monotherapy, two trials have evaluated the use of ramipril in diabetic patients [Table 5].Trevisan and Tiengo [37] showed that low dose ACE inhibition with ramipril could arrest the progressive rise in albuminuria in diabetic patients with persistent microalbuminuria.The beneÞ cial eff ects of this therapy were accompanied by relatively few adverse events and none of them was directly related to treatment.Another study conducted by Nielsen et al, [38] demonstrated that ramipril induces regression of left ventricular hypertrophy in normotensive, nonalbuminuric NIDDM patients, independent of reduction in systemic blood pressure.

Rosiglitazone and Preclinical Vasculopathy
[49] The clinical studies on vasculopathy with rosiglitazone are summarized in Table 6.
A study by Kim et al. [47] evaluated the eff ect of rosiglitazone in subjects with prediabetes or nondiabetic metabolic syndrome and demonstrated signiÞ cant decrease in arterial stiff ness (PWV) in the rosiglitazone group in comparison to untreated control group.The observed PWV change might have resulted from additional eff ects of rosiglitazone beyond metabolic control.Other studies also showed that rosiglitazone in healthy subjects [50] and in T2DM patients [49] signiÞ cantly improved vascular endothelial function without changes in blood glucose level.A possible explanation of reduced arterial stiff ness might be that rosiglitazone directly aff ects PPAR-γ activation in the vascular wall. [47]Another study by Shargorodsky et al. [48] demonstrated signiÞ cant improvement of the small artery elasticity with rosiglitazone; however, no signiÞ cant change was found in the large artery elasticity.The authors explained that large arteries have a major component of Þ xed Þ brotic tissue that probably needs more time for repair.Pistroch et al. [49] compared the glycemic control by rosiglitazone with nateglinide and demonstrated that rosiglitazone had therapeutic eff ects on endothelial dysfunction in diabetic patients.
Until now, no research has been published to examine the eff ect of rosiglitazone on arterial stiff ness in IGT patients.
The DREAM trial examined the eff ect of rosiglitazone on atherosclerosis on IGT, measured by sequential carotid ultrasound in a subset of DREAM participants, which is yet to be published. [13]A recent study by Rahman et al. [51] showed that rosiglitazone signiÞ cantly reversed preclinical vasculopathy in newly diagnosed, never treated IGT individuals as evident by signiÞ cant decrease in PWV and AI aft er 1 year of treatment.

Ramipril and Preclinical Vasculopathy
Studies that have focused on the eff ects of antiatherogenic eff ect of ACE inhibitors on diabetes are scarce and no Kim et al. [47] Prediabetes (n=50) or Rosiglitazone 4 mg/day; Duration: PWV was signifi cantly decreased in the nondiabetic metabolic 12 weeks.brachial-ankle PWV rosiglitazone group in comparison to baseline syndrome (n=49) and adiponectin levels; volume plethymographic apparatus Shargorodsky et al. [48] T2DM; n= 52 Rosiglitazone of 4 mg/day; Signifi cant change was observed in small duration: 6 months; large and artery elasticity but no difference in large small artery elasticity; pulse artery elasticity wave contour analysis Pistroch et al. [49] T2DM; n=12 Rosiglitazone (4 mg b.i.d) with Rosiglitazone had therapeutic effects on nateglinide; duration: 12 weeks; endothelial dysfunction in T2DM patients endothelial dysfunction; venous occlusion plethysmography Lonn et al. [53] T2DM; n=732 Ramipril 2.5 mg/d or 10 mg/d and Ramipril 10 mg signifi cantly reduced vitamin E or their matching placebo; progression of carotid artery wall thickness duration: 4.5 years; intima-media thickness (IMT); B-mode carotid ultrasound Rahman et al. [51] Newly research was done to examine the eff ect of ramipril on arterial stiff ness in IGT patients.The antiatherogenic properties of ACE inhibitors may be mediated by the lowering of angiotensin-II and the increasing of bradykinin concentrations.These result in decreased proliferation and migration of smooth muscle cells, decreased accumulation and activation of inß ammatory cells, decreased oxidative stress, and increased endothelial nitric oxide formation, leading to improved endothelial function.The observed beneÞ ts of ramipril may be largely due to a protective effect of ACE inhibitors on the arterial wall. [52]The clinical studies on vasculopathy with ramipril are summarized in Table 6.
The MICRO-HOPE trial, a substudy of the HOPE trial, is Þ rst to examine the cardioprotective eff ects of ramipril on diabetic patients. [39]The study reported that ramipril was beneÞ cial for CV events and overt nephropathy in people with diabetes.The CV beneÞ t was greater than that att ributable to the decrease in blood pressure.The SECURE trial, [53] a substudy of the HOPE Study, has examined the eff ect of ramipril on intima-media thickening.The study found that treatment with ramipril signiÞ cantly reduced the progression of carotid artery wall thickness.In a recent study, Rahman et al. [51] found that ramipril reduced large artery stiff ness as shown by signiÞ cant decrease of AI aft er 1 year of treatment in newly diagnosed, never treated IGT individuals.

Conclusion
Vascular complications are the major causes of morbidity and mortality in patients with diabetes.Limited numbers of studies with diabetic patients have shown the beneÞ cial eff ects of rosiglitazone and ramipril on diabetic vasculopathy.Research Þ nding established the fact that both drugs have the potentiality to off er novel therapeutic strategies to prediabetic vasculopathy in diabetes and IGT patients because of their antiatherogenic eff ects.Clinical trials are needed with IGT patients as more than 8% of adult populations worldwide have either IGT or IFG [54] and every year about 5-10% of these people would develop diabetes who would be at high risk for several chronic complications.It is noteworthy that even at the stage of IGT, before full-blown diabetes has developed, the risk of CVD is already increased by about two times compared to people with normal glucose tolerance. [55]Unless diabetic macrovasculopathy in patients with IGT are identified and treated, the enhanced risk of macrovascular complications will increase in future. [56]Further randomized controlled t rials should be undertaken to show whet her rosiglitazone and ramipril can prevent/reverse the preclinical vasculopathy both in diabetic and in IGT patients.

Figure 1 :
Figure 1: Pathogenesis and pathophysiology of diabetic macrovasculopathy Angiotensin receptor blockersCompetitive inhibition of AT-II receptor (Type 1).Effect more specifi c on Losartan and valsartan AT-II action, less or none on bradykinin production or metabolism.Beta blockersInhibit renin release and AT-II and aldosterone production and lower peripheral resistance; may decrease adrenergic outfl ow from the CNS.Calcium channel blockers Dilate peripheral arterioles and thereby reduce BP by inhibiting calcium infl ux into arterial SM cells.Diuretics Lower BP by depleting body sodium stores resulting in reduction of total blood volume and cardiac output; initially peripheral vascular resistance increases but declines when CO returns to normal level (6-8 weeks) Dyslipidemia Statins Increase lipid profi le and decrease atherogenic tendency.Lower LDL-C, improve TC:HDL-C, lower apo B. Fibric acid derivatives Increase lipid profi le and decrease atherogenic tendency.Lower TGs, raise HDL-C, lower TC:HDL-C and shift LDL from smaller to larger particles.the adenosine diphosphate (ADP) receptor on platelet cell membranes Ticlopidine Interferes with platelet membrane function Rahman, et al.: Rosiglitazone and ramipril in diabetic vasculopathy [Downloaded free from http://www.ijddc.comon Saturday, October 09, 2010, IP: 59.183.146.111]Randomized Controlled Trials with Rosiglitazone and Ramipril: Effects on Diabetes A number of clinical trials were conducted to investigate the effi cacy of rosiglitazone in improving the glycemic status in type 2 diabetes and IGT patients [Table