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Diabetes and cardiovascular disease: new perspectives

Peter, Rajesh; Rees, Alan

Current Opinion in Lipidology: April 2009 - Volume 20 - Issue 2 - p 145–146
doi: 10.1097/MOL.0b013e3283295726
Bimonthly update: Edited by Alan Rees
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Department of Diabetes and Endocrinology, University Hospital of Wales, Cardiff, Wales, UK

Correspondence to Rajesh Peter, MRCP, Department of Diabetes and Endocrinology, University Hospital of Wales, Cardiff, Wales, UK Tel: +44 0 2920743000; fax: +44 0 2920744581; e-mail: rajpeter@aol.com

This section provides a rapid update service, covering the whole field of lipidology, and lists papers entered into the publisher's database between 1 December 2007 and 30 November 2008.

Key articles are selected for comment by specialists and are highlighted in the following way:

• Papers considered to be of specialist interest

•• Papers considered to be of outstanding interest

A bibliographic listing follows each comment and selected papers are accompanied by an annotation in which the scope and context of the article are summarized briefly.

Type 2 diabetes (T2DM) is a common disease affecting approximately 5% of the population in the western world with cardiovascular disease (CVD) being an important cause of morbidity and mortality. A link between hyperglycaemia and macrovascular disease has been suspected for decades based on epidemiological and observational studies, but the role of tight glycaemic control in the prevention of CVD has yet to be established. The recently published Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD) study [1••], unexpectedly, demonstrated an increased rate of death from any cause in the intensively treated patients (targeting HbA1c < 6.0%; mean HbA1c 6.4%) compared with patients in the standard glycaemia regimen arm (targeting HbA1c 7.0–7.9%; mean HbA1c 7.5%). Intensive and rapid lowering of glycaemia (absolute decrease in HbA1c of 1.4% within 4 months) in these patients has been put down as one of the reasons for this finding.

Over the years, there have been a number of epidemiological, observational and experimental studies suggesting a link between postprandial hyperglycaemia and CVD [2••]. Moreover, we now appreciate the varying relationship between postprandial glucose (PPG), fasting plasma glucose (FPG) and HbA1c, with the contribution of PPG being predominant in the relatively well controlled patients (HbA1c < ∼8.0%), whereas FPG increasingly contributes as glycaemia deteriorates [3,4]. Hence, if euglycaemia is to be safely attained, treatment must be tailored to the individual patient based on their glycaemic control as measured by HbA1c.

Dipeptidyl peptidase (DPP)-4 inhibitors are a new class of oral hypoglycaemic agents that work by augmenting the incretin effect [5]. It has been demonstrated that DPP-4 inhibitors improve glycaemic control without risk of hypoglycaemia [6,7]. Moreover, these agents, by augmenting levels of glucagon like peptide-1 (GLP-1), predominantly address postprandial glycaemia when used as monotherapy. Analyses of the vildagliptin clinical trials database showed that in treated patients (n = 3784), the overall incidences of cardiovascular and cerebrovascular events using vildagliptin 50 mg daily (0.7%) and 50 mg twice daily (0.6%) were less than placebo (1.3%) [odds ratio (OR) 0.55 and 0.45, respectively; P < 0.05)] [8].

It is now well known that CVD is multifactorial, and an integrated approach to address all conventional risk factors including dyslipidaemia needs to be adopted, as was demonstrated in the follow-up of the Steno-2 study [9••]. The 13.3-year follow-up study demonstrated that intensive intervention with multiple drug combinations resulted in sustained and ongoing benefit with respect to both cardiovascular and all-cause mortality. Risk factors for CVD include hypertriglyceridaemia and low levels of HDL cholesterol (HDL-C) in addition to other conventional risk factors. Niacin (nicotinic acid) is the most effective treatment currently available for raising HDL-C. It also lowers LDL cholesterol, triglycerides, lipoprotein (a), small dense LDL and postprandial lipids [10,11]. Titration of niacin to therapeutic doses (generally 1.5–2 g) in clinical practice often results in flushing in a significant proportion of patients. Use of extended release niacin has led to a reduction of flushing. However, it remains a significant adverse event for many patients. In a recent large study, only 47% of extended release niacin users reached a maintenance dose of at least 1 g, and only 7.6% reached the dose of 2 g [12]. It has been suggested that vasodilator eicosanoids, particularly prostaglandin D2 (PGD2), mediates niacin-induced flushing. PGD2 binds to two G-protein-coupled receptors: DP1 (PGD2 receptor subtype 1) and DP2 [13,14]. Activation of DP1 by PGD2 induces vasodilation [14]. Laropiprant is a selective DP1 receptor antagonist, and, when coadministered with extended release, niacin has been shown to markedly reduce flushing symptoms and also attenuate the increase in malar skin blood flow [15], and this new agent may foster greater acceptance and persistence with niacin regimens. Tredaptive(nicotinin acid/laropiprant – 1000 mg/20 mg; Merck Sharp & Dohme Limited, Hertfordshire, UK)-modified release tablets has recently been approved for the treatment of dyslipidaemia, particularly in patients with combined mixed dyslipidaemia and in patients with primary hypercholesterolaemia. Tredaptive may be used in combination with a statin when the cholesterol-lowering effects of statin monotherapy are inadequate. It can also be used as monotherapy in patients in whom statins are considered inappropriate or not tolerated. It should, however, be noted that at daily doses of 2.5 g or less, niacin is associated with typically minor (∼5%) increases in FPG with greater increases seen in patients with T2DM [16••]. In a small minority, significant idiosyncratic deterioration in glucose tolerance can occur rapidly [17], and hence all patients on the medication must be monitored on initiation and during dose titration. However, in patients with CVD and T2DM, significant reductions in 15-year all-cause mortality with niacin outweigh any increase in FPG or PPG [16••].

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

1•• The Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD). Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545–2559. The intensive glycaemia treatment arm had to be terminated prematurely due to increased mortality. It highlights the potential dangers associated with achieving near normal glycaemia quickly in high-risk patients with T2DM and once again highlights need for individualizing treatments. The higher mortality in this study is probably a result of higher incidence of hypoglycaemia associated with intensity of treatment.
2•• Peter R, Rees A. Postprandial glucose and cardiovascular disease. Br J Diab Vasc Dis 2008; 8:8–14. This review article summarizes the evidence for the impact of PPG on CVD.
3 Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycaemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care 26:881–885.
4 Peter R, Luzio SD, Dunseath G, et al. Relationship between HbA1c and indices of glucose tolerance derived from a standardized meal test in newly diagnosed treatment naïve subjects with type 2 diabetes. Diab Med 2006; 23:990–995.
5 Elrishi MA, Khunti K, Jarvis J, et al. The dipeptidyl-peptidase-4 (DPP-4) inhibitors: a new class of oral therapy for patients with type 2 diabetes mellitus. Pract Diabetes Int 2007; 24:474–482.
6 Qi DS, Teng R, Jiang M, et al. Two year treatment with sitagliptin and initial combination therapy of sitagliptin and metformin provides substantial and durable glycaemic control in patients with type 2 diabetes [abstract OP73]. EASD 2008.
7 Goodman M, Thurston H, Minic B, et al. Improved glycaemic control with vildagliptin 100 mg administered either as a morning or evening dose as add-on therapy to metformin in type 2 diabetes mellitus [abstract P913]. EASD 2008.
8 Kothny W, Gimpelewicz C, Byiers S, et al. Cardiovascular safety profile of vildagliptin, a new DPP-4 inhibitor for treatment of type 2 diabetes [abstract P915]. EASD Sep 2008.
9•• Gaede P, Henrik LA, Parving HH, Pedersen O. Effect of multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358:580–591. This study demonstrates that in high-risk patients with T2DM, intensive intervention by targeting the various risk factors has sustained benefits with respect to vascular complications, cardiovascular and all-cause mortality.
10 Moon YS, Kashyap ML. Niacin extended release/lovastatin: combination therapy for lipid disorders. Expert Opin Pharmacother 2002; 3:1763–1771.
11 Crouse JR III. New developments in the use of niacin for treatment of hyperlipidaemia: new considerations in the use of an old drug. Coron Artery Dis 1996; 7:321–326.
12 Kamal-Bahl SJ, Burke TA, Watson DJ, Wentworth CE. Dosage, titration and gaps in treatment with extended release niacin in clinical practice. Curr Med Res Opin 2008; 24:1817–1821.
13 Monneret G, Gravel S, Diamond M, et al. Prostaglandin D2 is a potent chemoattractant for human eosinophils that acts via a novel DP receptor. Blood 2001; 98:1942–1948.
14 Hirata M, Kakizuka A, Aizawa M, et al. Molecular characterization of a mouse prostaglandin D2 receptor and functional expression of the cloned gene. Proc Natl Acad Sci U S A 1994; 91:11192–11196.
15 Lai E, Lepeleire De I, Crumley TM, et al. Suppression of niacin induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1. Clin Pharmacol Ther 2007; 81:849–857.
16•• Goldberg RB, Jacobson TA. Effects of niacin on glucose control in patients with dyslipidaemia. Mayo Clin Proc 2008; 83:470–478. This good review article examines the evidence for the effect of niacin on glycaemic control and CVD risk in dyslipidaemic patients with or without diabetes mellitus. It concludes that on a population basis, significant reductions in cardiovascular events in patients with diabetic dyslipidaemia outweigh the mild effects of this therapy on glycaemic control. However, on an individual-patient basis, glucose control should be monitored on initiating or increasing the dosage of niacin in patients with T2DM.
17 Mukherjee A, Rees A. Type 2 diabetes requiring insulin therapy precipitated by nicotinic acid in a patient with severe dyslipidaemia. Pract Diab Int 2006; 23:112–114.
© 2009 Lippincott Williams & Wilkins, Inc.