Dyslipidaemia in type 2 diabetes: a panel discussion

Abstract

Practical Diabetes InternationalVolume 19, Issue S2 p. S1-S6 Supplement to Practical Diabetes InternationalFree Access Dyslipidaemia in type 2 diabetes: a panel discussion Report of a Round Table Discussion held during the American Diabetes Association, Philadelphia, 27 June 2001 First published: 05 April 2002 https://doi.org/10.1002/pdi.315Citations: 2AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Figures published by the International Diabetes Federation show that at least 151 million people suffer from diabetes worldwide, a figure that is expected to increase to 218 million by the year 2010. In Europe alone, 32 million people could suffer from type 2 diabetes by 2010. In the United States, 16 million people already suffer from diabetes. The continued increase in diabetes prevalence will present a considerable burden on healthcare resources – not only for managing the disease itself but also for treating and reducing the incidence of cardiovascular morbidity and mortality associated with type 2 diabetes. For the well-being of patients, effective therapeutic intervention strategies by healthcare professionals at an early stage of the condition should be paramount and would serve to reduce the incidence and complications of diabetes whilst also being cost effective. Following this year's American Diabetes Association meeting in Philadelphia, PA, USA, a group of distinguished global opinion leaders met to consider the problem of dyslipidaemia in type 2 diabetes and to issue the following consensus statement. Dyslipidaemia in people with type 2 diabetes is associated with insulin resistance and comprises smaller denser LDL particles, raised triglycerides (TG) and reduced HDL-C. People with type 2 diabetes also suffer, to varying degrees, from hyperglycaemia, central obesity, hypertension, insulin resistance and higher thrombotic tendency. All these factors increase the risk of cardiovascular morbidity and mortality in people with type 2 diabetes and are the focus for therapeutic intervention measures. Cardiovascular risk Ischaemic heart disease and stroke are major causes of morbidity and mortality in people with diabetes. Diabetes is reported to be associated with a two- to fourfold increased risk of coronary and cerebrovascular events and the prognosis of clinical cardiovascular disease (CVD) is worse in people with diabetes compared with the general population. Atherosclerosis is the most common complication of dyslipidaemia in people with type 2 diabetes, accounting for about 80% of all deaths. Of these, 75% are attributed to coronary artery disease and the remainder to cerebrovascular or peripheral vascular events1. Associated hypertension and hyperglycaemia have a major impact on the accelerated atherosclerosis of this condition. Although LDL-C levels in people with type 2 diabetes are similar to those of the non-diabetic population, TG levels are usually higher and HDL-C levels lower, contributing to the two- to sevenfold increase in CVD. Therapeutic strategies to reduce the risk of CVD and other complications are of paramount importance in the management of type 2 diabetes. This entails modification of risk factors and a normalisation of dyslipidaemia. Data from studies in Finland2 estimated that factors contributing to increased cardiovascular risk in type 2 diabetes patients with associated insulin resistance syndrome could be defined as follows: blood pressure values > 160 mmHg systolic and/or > 90 mm Hg diastolic plasma triglyceride levels ≥ 1.7 mmol/L (150 mg/dL) plasma LDL-C levels > 3.4 mmol/L (130 mg/dL) plasma HDL-C level ≤ 0.9 mmol/L (35 mg/dL) in men, ≤ 1.0 mmol/L (40 mg/dL) in women obesity defined as BMI ≥ 30 kg/m2 HbAlc levels ≥ 7.5% urinary albumin excretion rate ≥ 20 µg/min. With these levels there was an increased risk of cardiovascular events with odds ratios at 3.0 for CAD events and 1.8 for cardiovascular mortality. Cardiovascular disease can precede or accompany the development of type 2 diabetes. Atherosclerosis may not be entirely a complication of type 2 diabetes, but rather a consequence of common genetic factors. A study was conducted in Sweden with a cohort of people with family histories of type 2 diabetes3. This cohort, before any development of type 2 diabetes, was compared with a normal control group (matched for BMI, age, gender, body fat and TG levels (<1.5 mmol/L). Over a period of 6 hours following a standard mixed meal, those people with family histories of type 2 diabetes demonstrated higher glucose, insulin and TG levels than controls and were shown to be insulin resistant. This finding should increase the awareness of physicians of the need to monitor genetically predisposed patients so that risk factors for development of type 2 diabetes, dyslipidaemia and cardiovascular morbidity can be treated at an early stage. Prevalence of Diabetic Dyslipidaemia Dyslipidaemia is associated with insulin resistance in people with type 2 diabetes. Elevated levels of free fatty acids (FFAs), as in obesity, can interfere with the cell's ability to take up glucose in response to insulin secreted by the pancreas or injected by the patient and insulin resistance can occur. High amounts of FFA may also damage insulin-producing cells. Insulin resistance can adversely affect levels of blood lipids with increases in TG and decreases in HDL-C, so increasing cardiovascular risk in type 2 diabetes patients. The high prevalence of dyslipidaemia in people with type 2 diabetes was demonstrated in a Botnia study in Finland (Table 1), where, of 1130 type 2 diabetes patients, 45% had TG values > 1.7 mmol/L (150 mg/dL), 86% had LDL-C values > 2.6 mmol/L (100 mg/dL) and 16% had HDL-C values < 0.9 mmol/L (35 mg/dL). A control group (n = 300), comprised of spouses of people with type 2 diabetes, demonstrated that only 18% had TG values > 1.7 mmol/L (150 mg/dL) and 5% HDL-C values < 0.9 mmol/L (35 mg/dL). LDL-C values were similar for the two populations. Table 1. Prevalence (%) of lipid abnormalities in type 2 diabetes patients Type 2 diabetes (n = 1130) Non-diabetic (n = 300) TG > 1.7 mmol/L (150 mg/dL) 45 18 LDL-C > 2.6 mmol/L (100 mg/dL) 87 85 HDL-C < 0.9 mmol/L (35 mg/dL) 16 5 This study demonstrated that type 2 diabetes patients have low HDL-C levels and high triglyceride levels three times more frequently than the non-diabetic population. LDL-C levels are not higher in type 2 diabetes patients, but are often above target levels. Table 2 shows the distribution of LDL-C according to categories of CHD risk: <2.6 mmol/L, 2.6–3.4 mmol/L and >3.4 mmol/L. These findings were confirmed in a second study where LDL-C values greater than the target value, 2.6 mmol/L (100 mg/dL), were seen in 80% of people with type 2 diabetes – of whom 50% had values > 3.4 mmol/L (130 mg/dL) (Table 2). TG values > 1.7 mmol/L (150 mg/dL) were seen in 50% and values > 2.3 mmol/L (200 mg/dL) were seen in 20% of type 2 diabetes patients in another study (Table 3). Table 2. Percentage distribution of LDL-C values in type 2 diabetes patients (n = 1229). <2.6 mmol/L (100 mg/dL) 2.6–3.4 mmol/l (100–130 mg/dL) >3.4 mmol/L (>130 mg/dL) Men 16 29 55 Women 11 25 64 Table 3. Percentage distribution of TG values in type 2 diabetes patients (n = 1680). >1.7 mmol/L (150 mg/dL) >2.3 mmol/L (200 mg/dL) Type 2 diabetes (n = 1680) 50 20 Control (n = 474) 20 5 Studies in the USA have shown that TG levels 2.6 mmol/L (100 mg/dL) were seen in 85% of type 2 diabetes patients whilst 50% of patients had HDL-C values < 0.9 mmol/L (35 mg/dL)4. As discussed, dyslipidaemia is one of the main risk factors for development of cardiovascular complications. A survey of 829 people with type 2 diabetes showed that 65% had LDL-C levels > 3.4 mmol/L (130 mg/dL) and 20–30% had HDL-C levels < 1.2 mmol/L (45 mg/dL). The problems faced by physicians in the management of diabetic dyslipidaemia in people with type 2 diabetes (and in screening for risk factors) were vividly demonstrated by the Canadian Heart Health surveys, which were carried out amongst approximately 19,000 Canadians between 1986 and 19925. More detailed lipid analyses were carried out in the subjects from two of the provinces (n = 3519). As noted in Table 4, although the prevalence of LDL-C values was similar for people with type 2 diabetes and control groups, the type 2 diabetes cohort showed a higher percentage of patients with raised TG and low HDL-C plasma levels. Table 4. Prevalence (%) of lipid abnormalities in type 2 diabetes patients compared with controls. Reproduced with kind permission of the Canadian Medical Association Journal7 Type 2 diabetes Controls LDL-C > 2.6 mmol/L (100 mg/dL) 77 81 LDL-C > 3.4 mmol/L (130 mg/dL) 47 52 HDL-C < 1.15 mmol/L (45 mg/dL) 49 36 TG > 1.7 mmol/L (150 mg/dL) 51 36 TG > 2.3 mmol/L (200 mg/dL) 32 18 All the above data demonstrate the high incidence of dyslipidaemia in people with type 2 diabetes. As a major causative factor for cardiovascular morbidity and mortality, regulation of dyslipidaemia should be addressed as part of all therapeutic plans. Risk factors Obesity, sedentary life style, hypertension and smoking are associated with the development of type 2 diabetes and cardiovascular mortality6. Overweight (BMI > 25 kg/m2) can be the forerunner of metabolic complications. Among people with type 2 diabetes, around 80% are overweight. Weight reduction, lifestyle changes and increases in physical activity are critical for these patients. There is evidence linking smoking with insulin resistance. There appears to be a relationship between smoking and the risk of developing type 2 diabetes and its cardiovascular complications. Smoking cessation increases HDL-C plasma levels and reduces LDL-C despite weight gain in some people. A study in The Netherlands involving type 2 diabetes patients from 20 general practitioner practices showed that the prevalence of risk factors for cardiovascular disease was in the order of 30% or more (Table 5)7. Table 5. Percentage of type 2 diabetes population showing risk factors. Reproduced with kind permission of Diabetologia9 HbA1c > 7.5% 34% Cholesterol > 6.4 mmol/L (250 mg/dL) 28% (15% received therapy within this group) HDL < 0.9 mmol/L (35 mg/dL) 24% TG > 2.2 mmol/L (200 mg/dL) 33% Hypertension > 160/95 mm Hg 30% (67% received therapy within this group) Hypertension is another risk factor strongly associated with type 2 diabetes. In another Dutch survey, involving people with type 2 diabetes, it was found that 66% had systolic blood pressure readings of ≤145 mmHg and 34% had levels above 145 mmHg. Among these patients, 75% had diastolic blood pressure readings of <90 mmHg but 25% had high readings. Even with appropriate therapy 55% of the hypertensive patients did not achieve the goal of 140/90 mmHg or less. Goals of therapy The high prevalence of dyslipidaemia in type 2 insulin resistant diabetic patients poses a serious risk for the development of cardiovascular morbidity and mortality. The goal of all therapeutic strategies is to normalise the abnormal lipid profile and reduce other risk factors if present. In the USA the National Cholesterol Education Programme (NCEP) guidelines8(Adult Treatment Panel III) on treatment of LDL-C abnormalities suggest that type 2 diabetes patients with LDL-C plasma levels > 130 mg/dL (3.4 mmol/L) should receive lipid-lowering therapy in order to reach a recommended goal of <100 mg/dL (2.6 mmol/L). At the same time TG levels > 150 mg/dL (1.7 mmol/L) and HDL-C levels 40 mg/dL (1.0 mmol/L) are considered normal. Implementation of these guidelines will reduce the risk of type 2 diabetes patients developing cardiovascular morbidity and dying. These goals are not always met due to inadequate therapy, infrequent monitoring of patients, poor patient adherence to therapy and poor education of primary and secondary health professions. These issues related to management and screening of dyslipidaemia in people with type 2 diabetes needs to be addressed. Management and Screening A structured approach is essential for effective treatment of dyslipidaemia in people with type 2 diabetes. Such management requires the co-operation of primary and secondary healthcare professionals and patients, along with frequent monitoring, follow-up and education. A study in West Freisland in The Netherlands (unpublished, preliminary observations) used a diabetes care system where all patients were referred to a diabetes care centre within the general practice setting – regarded as the optimum care facility for these patients. The investigators realised that physicians and patients should be educated in optimal diabetes care and motivated to implement care programmes. Nurses were invaluable to the care and education of the patient. From this process it was concluded that achievement of glycaemic control for the overall diabetic population was satisfactory. Blood pressure and lipid control targets were not achieved in a large proportion of patients. The investigators also demonstrated that polypharmacy(unpublished, preliminary observations) was very hard to implement and can lead to non-compliance with therapy and demotivation of the patient (Table 6). Table 6. Calculated medication for a type 2 diabetes patient Tablets per day Hypoglycaemic 1–4 Hypotensives 1–4 Lipid lowering 1–3 Antiplatelet 1 Cardiovascular 1–3 Insulin 1–2 (injections) Total 6–14 tablets daily In the primary care setting, screening for dyslipidaemia and other strategies important in the prevention of cardiovascular morbidity were found to be inadequate in a chart review of diabetic subjects9. Patients had their weight recorded in 50% of visits and were not routinely counselled to cease smoking. Blood pressure was consistently recorded in only 88% of cases, plasma lipid profiles carried out in only 48% of cases and HbAlc tested in only 70% of cases. These numbers are unsatisfactory, especially with less than 50% of the population undergoing lipid profile assessments. General practitioners need to be educated in the routine screening and management of insulin resistant type 2 diabetes patients. Specialist nurses can do a lot to alleviate this problem. In another Canadian chart review study, which included 1745 type 2 diabetes patients, only 54% of patients managed in the primary care setting had LDL-C levels available in their charts. Of those who did, only 13% were treated to LDL-C plasma levels of <2.6 mmol/L (100 mg/dL)10. Only 26% of those with LDL levels in their charts – and who were not at goal – underwent treatment with medication. No drug therapy was used by 74%. From a Canadian survey in primary care that included 3481 type 2 diabetes patients over the age of 40, 92% had lipid levels requiring treatment according to current guidelines. It is clear from these results that the management of dyslipidaemia in people with type 2 diabetes is far from satisfactory in Canada and could be similar for other countries world-wide. The consequences of inadequate screening programmes for patients at high risk of developing type 2 diabetes need to be considered. Early diagnosis of type 2 diabetes is essential to ensure treatment and subsequent reduction in cardiovascular morbidity and mortality at a later stage. Additionally, 90% of patients with a diagnosis of dyslipidaemia and type 2 diabetes will ultimately need some form of pharmacological therapy. General practitioners need to be educated in the detection and management of insulin resistant type 2 diabetes patients, but additional resources are required to implement the recommendations. Specialist nurses can do a lot to alleviate this problem, by undertaking some of the screening and management responsibilities. Patients, meanwhile, need to be kept motivated and fully informed of their condition and the accompanying risks, especially if they do not adhere to prescribed therapy. Treatment options Therapies instituted for the treatment of diabetic dyslipidaemia and insulin resistance are continually changing, with many new drugs coming to clinical practice over the past five years. The approach to treatment in both diabetes and the at-risk population is to reduce all important risk factors with dietary and lifestyle modifications. In addition, medication is frequently required to achieve treatment goals. For hyperglycaemia (which may accelerate microvascular damage) sulphonylureas biguanidines (metformin) or the newer prandial regulators that enhance first phase insulin secretion are commonly used. As the disease progresses and oral hypoglycaemic agents fail to adequately control hyperglycaemia, insulin may be necessary to achieve sufficient glycaemic control. Metformin is reputed to reduce – albeit minimally – elevated plasma levels of LDL-C and TG and reduces weight gain in obese subjects. The risk of lactic acidosis is low if contraindications to therapy are recognised and followed. Hypoglycaemic agents will reduce the onset and severity of microvascular complications and may influence, to a lesser extent, the macrovascular complications. Efforts to improve glycaemic control should not be pursued to the exclusion of other abnormalities that may have a greater relevance to CVD outcomes. The goal for blood pressure reduction is ≤130/80 mmHg in the USA and 140/88 mmHg in the UK11, 12. There are several issues specific to diabetes regarding anti-hypertensive therapy. Insulin resistance may weaken the blood pressure lowering effect of some drugs. Certain drugs may even affect glucose tolerance and insulin sensitivity. For example, high dose thiazide diuretics and non-selective beta-blockers may unmask latent glucose intolerance or worsen metabolic control. ACE inhibitors and angiotensin II receptor antagonists are sometimes recommended as combination therapy to obtain optimal benefit in blood pressure lowering, as well as reno-protective and cardio-protective effects. Alpha blockers are not now recommended and calcium channel blockers could be a suitable alternative. Lipid lowering therapy Treatment of the major dyslipidaemic risk factors for cardiovascular morbidity and mortality is critical. These major risk factors are increased levels of LDL-C and TG and reduced levels of HDL-C. The aim of therapy is to reduce and maintain LDL-C levels to 2.6 mmol/L (130 mg/dL), reduce TG levels to <1.7 mmol/L (150 mg/dL) and elevate HDL-C levels to above 1.0 mmol/L (40 mg/dL). Statins Statins are commonly used for therapy of dyslipidaemia in people with type 2 diabetes and are effective in lowering plasma levels of total cholesterol (by as much as 30–40%), LDL-C and TG but HDL-C levels may remain low. Additional therapy with a fibrate may be instituted to further lower TG levels and raise HDL-C levels. Studies have shown that in people with type 2 diabetes lowering LDL-C can reduce coronary mortality by up to 28% and reduce major coronary events by up to 42%13, 14. The Medical Research Council/British Heart Foundation Heart Protection Study (HPS) revealed that cholesterol-lowering treatment can protect a far wider range of people than was previously thought, and that it can prevent strokes as well as heart attacks. Clinical studies such as the Cholesterol and Recurrent Events (CARE) trial15 and HPS have showed that people with type 2 diabetes obtain substantial benefit from statin therapy. The incidence of fatal MI in the sub-group with type 2 diabetes was reduced by 46%, and non-fatal MI by 18%. In addition to their action on dyslipidaemia, other mechanisms have been suggested to underlie the ability of statins to reduce the risk of fatal and non-fatal CVD events. Statins have the ability to ‘shrink’ the lipid rich cores of atheromatous plaques, which pose the greatest threat in acute coronary events, reduce the numbers of inflammatory cells, especially macrophages and T-lymphocytes that weaken the outer cap of atheromatous plaques, and reduce pro-inflammatory factors, e.g. cytokines, interleukin-6 (IL-6) and TNF-alpha. Statins correct only part of the diabetic dyslipidaemia, but their additional properties may increase their effectiveness. They may be used safely in combination with any hypoglycaemic agent. Fibrates Increased levels of TG > 1.7 mmol/L (150 mg/dL) are recognised as a synergistic coronary artery disease risk factor and should be reduced initially by diet, exercise and weight control. If this approach fails then fibrates, e.g. gemfibrozal/fenofibrate, may be effective in decreasing plasma TG. Fibrates primarily reduce TG by up to 50% and increase HDL-C concentrations by up to 20%. The effect on LDL-C is variable. In the Veterans Affairs High-Density Lipoprotein Intervention Trial (VAHIT), there was a 23% reduction of non-fatal myocardial infarction and coronary heart disease death with gemfibrozil treatment in men with diabetes and pre-existing CAD. Thiazolidinediones (TZDs) Recently (1997) a new class of drugs, the thiazolidinediones (TZDs), have been introduced, and troglitazone, pioglitazone and rosiglitazone have been widely used in clinical practice. These agents have been reported to reduce insulin resistance, decrease HbAlc and fasting plasma glucose levels and decrease the LDL-C/HDL-C ratio. Pioglitazone may be effective in inducing a sharp reduction of triglycerides with a parallel increase in high-density lipoprotein plasma concentration16. It can exert a beneficial effect on atherosclerosis through inhibition of calcium influx stimulated by its action at peroxisome proliferator-activated receptor gamma (PPARγ) on vascular smooth muscle, endothelial cells and macrophages16. TZD therapy has been shown to be associated with reductions in pro-inflammatory markers such as interleukin-6 and C-reactive protein17-19, which may have potential beneficial consequences for long-term CVD risk. The activity profile of some TZDs when used to lower blood sugar may be well suited as adjunctive treatment or for diabetic dyslipidaemia. In various countries, pioglitazone and rosiglitazone have been approved either for monotherapy or combination therapy with sulphonylureas or metformin. In the USA, pioglitazone is approved for use with insulin therapy. TZDs are contra-indicated in patients with hepatic impairment or a past or present history of cardiac failure, New York Heart Association (NYHA) Class III and IV. The panel concluded that the TZDs, because of their broad spectrum of activity for treating insulin resistance and diabetic dyslipidaemia, could have an important impact on future diabetes care. The panel indicated that more clinical evidence of their efficacy and safety will be required. Summary This report should serve as a basis for understanding the magnitude of the problems that exist in the diagnosis, treatment and care of dyslipidaemic insulin resistant type 2 diabetes patients. There is currently an inadequacy of screening programmes for at-risk patients leading to many patients going undiagnosed. Of those that are diagnosed, up to 90% require some form of therapy. Even when patients do receive therapy there is an inadequacy of total care and follow-up and in a high proportion of them therapies do not meet the goals recommended in national guidelines. This is possibly due to non-adherence of patients with their poly-medication. Therefore, motivation and knowledge of the condition for clinicians and patients are necessary, as is adequate support for the treating physicians through structured care. Recommendations from this discussion include the following: Institute and maintain educational programmes in diabetes care for both the public and healthcare professionals, including information about the consequences of inadequate treatment. Promote the importance of therapeutic goals. People at risk of type 2 diabetes should be screened at an early stage to include full lipid profile assessments. People with diabetic dyslipidaemia and at risk of developing CVD should receive immediate appropriate therapy according to the clinical practice guidelines. There should be global risk assessments with the goal of achieving optimum glycaemic and blood pressure control, aggressive lowering of LDL-C levels and lowering of triglyceride levels. People with an LDL-C plasma value of 3.4 mmol/L (130 mg/dL) or greater should receive treatment with statins to reach a goal of 2.6 mmol.L (100 mg/dL). Other risk factors should be reduced by encouraging cessation of smoking, weight loss, a good level of physical activity and good nutrition. Therapy should be instigated in a step-wise fashion, depending on the severity of the condition. The (TZD) insulin sensitisers, e.g. pioglitazone, should be considered as therapy where the condition is inadequately controlled with other hypoglycaemic agents. (Note, to date, in Europe, their use is only licensed as combination therapy.) 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