Hot Topic in Endocrinology 2

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Information about Hot Topic in Endocrinology 2

Published on February 18, 2009

Author: ashrafalabasiry


Hot Topics In Endocrinology II : Hot Topics In Endocrinology II Dr Hussam Abu-Seido Consultant Family Medicine Saad Specialist Hospital Diabetes Type II : Diabetes Type II Recent Studies have thrown up some interesting controversies about screening and management NICE produced a new guidelines in summer 2008 There are confusing plethora of new drugs Diabetes Type II (previous important studies) : Diabetes Type II (previous important studies) Glycemic control: ?for type 1 DM the DCCT trial (NEJM2000:342:381) establishes that ‘intensive’ control, compared to ‘conventional’, reduces microvascular complications. ?for type 2 DM the glycemic arm of the UKPDS study (Lancet1998:352:837) showed that tight control, reduced microvascular but not macrovascular complications. ?Meformin reduces mortality and complications in overweight patients Diabetes Type II (previous important studies) : Diabetes Type II (previous important studies) Blood Pressure: ?The BP-lowering arm of the UKPDS study (BMJ1998;317:703) showed that reducing BP was associated with a significant reduction in complications and mortality Diabetes Type II (previous important studies) : Diabetes Type II (previous important studies) Lipids: ?(Lancet2003:361:2005) and CARDS (Lancet2004:364:685) show statins improve outcomes in diabetes, confirmed in a meta-analysis (Ann Int Med 2004:140:650) Diabetes Type II (Diagnosis) : Diabetes Type II (Diagnosis) WHO Criteria: ?Diabetes symptoms (ie polyurea, polydipsia and unexplained weight loss) Plus: 1. random venous plasma glucose concentration =11.1 mmol/l OR 2. a fasting plasma glucose concentration =7.0 mmol/l OR 3. two hour plasma glucose concentration =11.1 mmol/l after 75g anhydrous glucose in an oral glucose tolerance test (OGTT) Diabetes Type II (Diagnosis) : Diabetes Type II (Diagnosis) WHO Criteria: ?With no symptoms: 1.Diagnosis should not be based on a single test but requires a confirmatory plasma venous determination. At least one additional test on another day with a value in the diabetic range is essential. 2.If the fasting or random values are not diagnostic then the two hour post glucose load should be used Diabetes Type II (Diagnosis) : Diabetes Type II (Diagnosis) WHO Criteria: ?Impaired Glucose tolerance (IGT): Fasting plasma glucose <7.0 mmol/l and OGTT two hour value 7.8 mmol/l to 11.1 mmol/l Diabetes Type II (Diagnosis) : Diabetes Type II (Diagnosis) WHO Criteria: ?Impaired Fasting Glycaemia: 1.Fasting plasma glucose 6.1 mmol/l to 7.0 mmol/l. 2.Diabetes UK recommends that all those with IFG should have an OGTT to exclude the diagnosis of diabetes, and be actively managed with lifestyle advice Diabetes Type II (Epidemiology) : Diabetes Type II (Epidemiology) (BJGP2008:58;533) The diagnosed prevalence of DM has doubled in the last decade. 4.7% of the population now have diabetes, of which 92% is type 2 Increasing prevalence is due to the ageing population, increasing obesity, decreasing physical activity and earlier diagnosis. On a positive note, it is also due to better management and survival of patients with established diabetes Diabetes Type II (Screening) : Diabetes Type II (Screening) BMJ editorial (BMJ2008;336:1180), cost effectiveness paper looking at screening: (BMJ2008:336:1180): This study looked at an above average risk population aged over 45, and screened for diabetes and impaired glucose tolerance. Those diagnosed received lifestyle intervention or drugs as appropriate. The conclusion of this study was that screening in this group is cost effective Diabetes Type II (Screening) : Diabetes Type II (Screening) Diabetes fulfils many of the criteria for a screening programme: ?detected by a simple test ?studies have shown that early intervention strategies are clinically cost-effective ?DM is a powerful risk factor for CVD and lowering BP and lipids in this group could save lives Diabetes Type II (Screening) : Diabetes Type II (Screening) Concerns remain regarding potential risks of increasing health anxiety The false reassurance of negative tests in at risk patients Will a reduction in blood glucose in these patients translate into meaningful clinical outcomes for patients? Diabetes Type II (screening) : Diabetes Type II (screening) The ISAIAH Study (BJGP2008:58:533) Small (n=33), short term (6 month) lifestyle feasibility study for pre-diabetes based in primary care in Sheffield Study showed it was feasible to deliver such programme in UK general practice More studies are urgently needed to test the clinical effectiveness of such interventions in everyday practice Diabetes Type II (management) : Diabetes Type II (management) UKPDS: controlling patients BP and reducing CV risk is the most important part UKPDS: intensive glycemic control aiming for FBG <6 reduced microvascular, but not macrovascular, complications ?NNT 196 per year to prevent one event UKPDS: tight glycemic control had no effect on diabetes related or overall mortality Recent studies suggest that aggressively trying to lower HBA1c may even make outcomes worse Diabetes Type II (Management) : Diabetes Type II (Management) Accord Study ( NEJM2008:358;2545) ?Would creating ‘normal’ levels of HBA1c reduce CV events in high risk patients? ?10000 patients, mean age 63, HBA1c >7.5%, were randomized to intensive treatment (HBA1c <6%) or standard (HBA1c 7-7.9%) ?Intensive treatment arm often included multiple insulin injections and OHGs Diabetes Type II (management) : Diabetes Type II (management) Accord Study ( NEJM2008:358;2545) ?The study was stopped early after 3.5 years because intensive treatment group was associated with an increase in mortality and did not reduce CV events ?The cause of increase in mortality was uncertain and was not associated with any particular drug such as glitazone (although those were widely used) ?The authors propose the increased deaths may have been precipitated by hypoglycemia in vulnerable patients Diabetes Type II (management) : Diabetes Type II (management) Advance Study (NEJM2008:358;2560) ?The glycemic control arm of Advance. ?RCT 11000, DM type 2 and established micro or macro vascular disease or another risk factor ?Standard and intensive control ?Intensive group received gliclazide SR and other drugs (metformin, glitazones, and insulin) to reach target of HBA1c <6.5% ?Followed up for 5 years ?Intensive group achieved a mean HBA1c of 6.5% versus 7.3% in the control arm Diabetes Type II (management) : Diabetes Type II (management) Advance Study (NEJM2008:358;2560) ?No significant difference between the two groups in mortality or macrovascular events ?The intensive group did reduce the incidence of the combined end-point of micro and macrovascular events, which was mostly seen in a reduction in the incidence of nephropathy Diabetes Type II (management) : Diabetes Type II (management) Advance Study (NEJM2008:358;2560) ?Associated editorial (NEJM:358;54) discusses that there is a link between hyperglycemia and CVD, but lowering glucose does not seem to reduce CV risk ?These findings supports UKPDS study as reducing HBA1c from 8 to 7% did not reduce CV events, although a subgroup group of overweight patients on metformin did have reduced CV events and mortality Diabetes Type II (management) : Diabetes Type II (management) The conclusion from ACCORD and ADVANCE is that near normal glycemic control for up to 5 years does not reduce CV events Diabetes Type II (management) : Diabetes Type II (management) The NEJM conclude that: ?Most mortality in diabetes is due to CVD, and there is clear evidence that smoking cessation, exercise, diet, statins, lowering BP and aspirin are effective in type 2 DM ?Reducing CV risk should be our management priority ?Reducing blood sugar remains important with the most appropriate target for HBA1c at 7%. But reducing BP and lipids is more important Diabetes Type II (management) : Diabetes Type II (management) (BJGP2007:57:296) (BJGP2005:55:298) ?Qualitative research tells us that patients perceive microvascular complications as the greatest risk and reducing blood sugar as the most important part of management ?We need to make our patients aware that the priority is reducing CV risk Diabetes Type II (management) : Diabetes Type II (management) New drugs: Exenatide ?An incretin mimetic that stimulates post-prandial insulin secretion ?Given by Sub-cut injection using a pen device ?In RCTs in patients poorly controlled with metformin it shows similar results to insulin in reducing HBA1c by about 1% compared to placebo ?Compared to insulin it does not cause weight gain ?RCTs suggest it is less likely than insulin to cause hypos with severe hypoglycemia reported very rarely (0.2%) ?Nausea and vomiting are common (17%) ?NICE have accepted the drug as an alternative option to insulin in obese patients with a HBA1c >7.5% despite metformin and gliclazide Diabetes Type II (management) : Diabetes Type II (management) New Drugs: Vildagliptin and Sitagliptin ?Inhibit an enzyme, DPP-4, that breaks down endogenous incretins thereby indirectly increasing endogenous insulin secretion ?Meta-analyses suggest they only modestly reduce HBA1c compared to placebo ?Vildagliptin is available as a combination tablet with metformin ?No trials have been done looking at clinical end-points ?The Scottish Medicines Consortium have accepted gliptins for use in combination with metformin if a sulphonylurea is contraindicated or not tolerated Diabetes Type II (management) : Diabetes Type II (management) New Drugs: Vildagliptin and Sitagliptin ?Recent Editorial (BJGP2008:58:531) ?More positive in its appraisal of their usefulness, particularly in terms of reducing hypos and weight gain seen with other hypoglycemic agents ?They conclude that these and other emerging therapies will offer new opportunities for patients to have ‘individually tailored’ therapy Diabetes Type II (management) : Diabetes Type II (management) New Drugs: (DTB2008:46:49) review On the basis of the evidence, they cannot recommend their routine use but exenatide may prove to be useful alternative to insulin in some patients Diabetes Type II (management) : Diabetes Type II (management) Glitazones: ?Recent studies show that glitazones do not improve clinically important end-points (Cochrane2006:4) ?Significant reduction in HBA1c, but no clear reduction in clinical events ?May increase fracture risk (NEJM2006:355:2427) ?May increase risk of cardiac death (NEJM2007:356:2522) meta-analysis of 42 RCTs ?Increase heart failure risk (Lancet2007:370:1129) ?Drug Safety Update 2007;1:5 advises not to use glitazones in heart failure, and caution in patients with ischemic heart disease ?MHRA advised patients not to stop glitazones but to ‘discuss with their doctor at their visit’ Diabetes Type II (management) : Diabetes Type II (management) Good Old Metformin: ?Recent Review (BMJ2006:333:1200) re-confirms that metformin is first choice because: is relatively effective, safe and cheap 2.Decrease vascular events in overweight type 2 diabetics 3. the only OHG shown to decrease mortality in type 2 diabetes 4. Does not cause weight gain and will not adversely affect patients attempts to lose weight Diabetes Type II (management) : Diabetes Type II (management) Good Old Metformin: ?Systematic Review of 136 trials (ANN Intern Med2007:147:6) found that: 1. Newer, more expensive drugs have no advantage over metformin 2. All drugs reduce HBA1c but only metformin does not cause weight gain and improves clinical outcomes 3. Concluded that Metformin should remain first choice with the addition of a sulphonylurea when one drug is not enough Diabetes Type II (management) : Diabetes Type II (management) Good Old Metformin: ?(BMJ2007;335:508) paper reviews evidence There is a concern that metformin is under-prescribed because of fear of lactic acidosis. Many patients are denied metformin because of listed contraindications e.g. CCF, CKD, recent MI and age over 80 Most of the reported cases of lactic acidosis are old and there is a question mark over whether they were due to metformin Epidemiological studies show a similarly low incidence of lactic acidosis in diabetics with or without metformin and despite the increasing use of metformin there has been no increase in cases The authors conclude that there is ‘an increasing body of evidence’ that suggests metformin alone will not cause lactic acidosis, it is not contraindicated in heart failure and it remains the drug of first choice for the vast majority with type 2 diabetes Care is however needed with CKD, NICE recommends reviewing metformin dose if eGFR <45 and stopping if eGFR <30 Diabetes Type II (management) : Diabetes Type II (management) Good Old Metformin: ?It may delay the onset of diabetes in high-risk patients ?Meta-analysis (Am J Med 2008;121:149) ?Looked at 31 trials comparing metformin to placebo, including 4500 patients with up to 2 years follow up ?Metformin was associated with a 6% absolute risk reduction in the risk of developing diabetes Diabetes Type II (management) : Diabetes Type II (management) Self-monitor blood glucose (SMBG) ?(BMJ2008:336;1139) despite previous meta-analyses showing minimal or no benefit, (SMBG) has increased ?DiGEM trial (BMJ2007:337:132) combined SMBG with clear instruction about how to adjust diet, exercise and the use of OHGs in response to the results. It found a 0.17% difference in HBA1c i.e. not clinically significant Diabetes Type II (management) : Diabetes Type II (management) Self-monitor blood glucose (SMBG) ?ESMON study (BMJ2008:336:1174) looking at patients with newly diagnosed type 2 diabetes. ?It was thought that perhaps SMBG might be more helpful in this specific group ?But SMBG did not improve control but increased depression scores Diabetes Type II (management) : Diabetes Type II (management) Self-monitor blood glucose (SMBG) Follow up paper of the DiGEM study (BMJ2008:336:1177) reports that SMBG reduces quality of life, increases anxiety scores and costs £90 per patient p.a. Diabetes Type II (management) : Diabetes Type II (management) Self-monitor blood glucose (SMBG) ?The authors of BMJ editorial (BMJ2008:336;1139) ?Argue that this changes the ethical position on SMBG as this new evidence not only re-confirms that SMBG is not helpful, it shows that it has the potential for harm, whilst costing the UK £100M pa ?They point out that it also distracts attention from more effective disease control measures, notably BP, cholesterol, weight and physical activity Diabetes Type II (management) : Diabetes Type II (management) Self-monitor blood glucose (SMBG) ?DTB remind us (DTB2007:45:65) ?SMBG still has a role: 1. It remains as essential part of management for type 1 DM 2. It can be helpful in patients with type 2 DM having Hypos 3. in Type 2 DM if there is low risk for hypos or reasonable control then there is no indication for SMBG. Use HBA1c for monitoring Diabetes Type II (management) : Diabetes Type II (management) Self-monitor blood glucose (SMBG) ?The NICE 2008 guidance ?SMBG should be offered to 1. patients on insulin 2. those on OHGs to provide information on Hypoglycemia 3. to assess changes relating to medication change or intercurrent illness or to ensure safety during activities such as driving Diabetes Type II (management) : Diabetes Type II (management) BP Management: ?ADVANCE study; the BP lowering arm (Lancet2007:370:370:829) ?Should all diabetics have an ACEI+diuretic combination? ?11000 patients with DM type 2 and one other risk factor, regardless of BP level. ?Randomised to: A fixed combination of perindopril/indapamide (2mg/0.625mg) or placebo Diabetes Type II (management) : Diabetes Type II (management) BP Management: ADVANCE ?Compared to placebo, the active treatment group had mean systolic BP 5.6mmHg lower and lower incidence of CV events ?The authors conclude that the simple prescription of this combination to all type 2 diabetics, regardless of BP, will reduce complications and save lives ?Critics argue that the benefit seen is due to the lower BP, and this paper just to re-confirms that in diabetes aggressive treatment of blood pressure improves outcomes Diabetes Type II (management) : Diabetes Type II (management) Lipid management: Several trials over the last few years have suggested that virtually all diabetics could benefit from a statin Diabetes Type II (management) : Diabetes Type II (management) Lipid management: ?Recent systematic review gives us the best evidence we have ?Meta-analysis (Lancet2008:371:117) of 14 RCTs looking at 19000 people mostly with type 2 DM ?They found that statins are effective for all diabetics regardless of sex, baseline lipid level or overall CV risk ?The greater the baseline absolute risk the greater the absolute benefit ?The authors conclude that all diabetics should be considered for a statin, regardless of type Diabetes Type II (management) : Diabetes Type II (management) Lipid management: ?Recent Study (diabetes Care2007:30:2025) ?Efficient and effective strategy would be to treat, irrespective of their cholesterol level: 1. all male diabetics over 40 2. all female diabetics over 45 Diabetes Type II (management) : Diabetes Type II (management) Lipid management: ?SIGN 2007: ?all diabetics over 40 should also be prescribed a statin and aspirin ?Those aged 18-39 if complications, hypertension, metabolic syndrome, TC>6 or a strong FH of vascular disease. Type 2 Diabetes, NICE 2008 : Type 2 Diabetes, NICE 2008 Blood Pressure management: ?Target is 140/80, or 130/80 if small vessel disease ?Start A (or ARB if not tolerated). If African-Caribbean descent start with A+D or A+C. if possibility of pregnancy start with C ?C or D as second-line, add the other drug as third line e.g. A then A+D then A+D+C ?Add other agents (e.g. alpha or beta-blocker) as required Type 2 Diabetes, NICE 2008 : Type 2 Diabetes, NICE 2008 Glucose Lowering: ?Over all target is HBA1c 6.5% but individual targets with will be higher. Check every 6/12 once stabilised.Lifestyle change first-line intervention ?Metformin first-line drug, if target not reached with lifestyle change. Step-up dose to minimise GI side effects and consider slow-release if poor GI tolerability ?Add Sulphonylurea second-line (or singly if metformin not tolerated) ?If HBA1c > 7.5% consider insulin or glitazone. Exenatide may be considered in obese patients Type 2 Diabetes, NICE 2008 : Type 2 Diabetes, NICE 2008 CVD risk management: ?Statins (simvastatin first choice) in most patients over 40, and under 40 if risk factor profile. Standard dose 40mg, but consider dose increase to 80mg to reach target ot TC < 4 (LDL < 2). If still fails to reach target and has existing vascular disease or microalbuminuria consider more potent statin or ezetimibe. If high CV risk and Tg > 2.3 consider adding fibrate ?Aspirin to all over 50 with BP controlled <145/90, and to others if additional risks such as microalbuminuria Type 2 Diabetes, NICE 2008 : Type 2 Diabetes, NICE 2008 Kidney: ?Calculate albumin:creatinine ratio (on first pass EMU) and eGFR once a year ?If diabetic nephropathy confirmed (offer ACEI with dose titration to maximum dose, substitute ARB if not tolerated and maintain BP<130/80 Type 2 Diabetes, NICE 2008 : Type 2 Diabetes, NICE 2008 Eye: ?Retinal screening at diagnosis, and annual thereafter, using digital photography programme Type 2 Diabetes, NICE 2008 : Type 2 Diabetes, NICE 2008 Neuropathic Complications: ?Pain: Formally ask. Offer low dose TCAs as first line. Second-line duloxetine,gabapentin or pregalbin ?Gastroparesis: Suspect with unexplained bloating or vomiting, trial of metoclopramide or domperidone ?Erectile dysfunction: Review annually. Offer a phosphodiesterase-5 inhibitor unless complications ?Foot ?Depression: Ask Diabetes: Possible take aways : Diabetes: Possible take aways Intensive lowering of HBA1c <7% may be harmful. Aerobic exercise improves HBA1c, metformin remains first choice OHG Control of BP and lipids is most important part in management Negotiate individual realistic targets with patients SMBG is not helpful for most patients, and may be harmful Actively ask about, and treat, neuropathic complications Hot Topics In endocrinology : Hot Topics In endocrinology Thank you

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