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Lobna eltoony.hypoglycemia and weight gain


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  • 1. Barriers to Achieving Glycaemic Goals:A Focus on Hypoglycemia and Weight Gain Lobna F El toony Head Of Diabetes & Endocrinology Unit Internal Medicine Department Assuit University UEDA – Aswan 2012
  • 2. Diabetes is the epidemic of the new century
  • 3. Egypt will face explosive growth of diabetes 9,000 Due to a rapidly increasing & ageing population, Egypt will 8,000Source: Diabetes Atlas, have the larg umber of 2003 people 7,000 6,000 2025 with diabetes in the region by2nd edition, IDF 5,000 4,000 2025 3,000 2,000 1,000 0 ia n q an co ia ia a an in a E pt n t ai Ira Ira bi no by A er yr s ra gy rd ud oc uw ni ra U lg ah S Li ba Jo E Tu or A S A K B Le M di au S
  • 4. Dual Defects in Type 2 DiabetesGenes Environment Genes EnvironmentInsulin Resistance ß-cell Dysfunction IGT Type 2 Diabetes
  • 5. ADA and AACE/ACE Guidelines: Treatment Goals for A1C, FPG, and PPG Normal1,2 ADA3 AACE/ACE2 Parameter Level Goal Goal FPG, mg/dL <100 90–130 <110 PPG, mg/dL <140 <180 <140 A1C, % 4–6 <7a ≤6.5 aThe goal for an individual patient is to achieve an A1C as close to normal (<6%) as possible without significant hypoglycemia.FPG=fasting plasma glucose; PPG=postprandial glucose; ADA=American Diabetes Association; AACE=American Association of Clinical Endocrinologists;ACE=American College of Endocrinology.1. Adapted from Buse J et al. In: Williams Textbook of Endocrinology. 10th ed. 2003. Permission requested.2. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007;13:(suppl 1)3–68.3. ADA. Diabetes Care. 2007;30:S4–S41.
  • 6. Two thirds of individuals do notachieve target HbA1c Saydah SH, et al. JAMA 2004; 291:335–342. Liebl A, et al. Diabetologia 2002; 45:S23–S28.
  • 7. Diabetes management guidelines:a sense of urgency HbA1c“... the results of the UKPDS mandate that treatment of type 2 diabetes include aggressive efforts to lower blood glucose levels as close to normal as possible” American Diabetes Association Diabetes must be… diagnosed earlier. And once diagnosed, all types of diabetes must then be managed much more aggressively” Canadian Diabetes Association “ 1American Diabetes Association. Diabetes Care 2003; 26:S28–S32. 2Canadian Diabetes Association. Can J Diabetes 2003; 27 (Suppl. 2):S1–S152.
  • 8. Deaths related to 21% diabetesHbA1c Microvascular 37% complications1% Myocardial 14% infarction Stratton IM, et al. BMJ 2000; 321:405–412.
  • 9. Tight Glycaemic control • HypoglycaemiaMacrovascular •Weigh gain & MicrovascularRisk Reduction
  • 10. Barriers to Achieving Glycaemic Goals: A Focus on Hypoglycaemia422HQ11NP 027
  • 11. Classification of Hypoglycemic Episodes Based on whether individuals can treatthemselves.  Symptomatic definitions:  Mild hypoglycemia: Adrenergic Symptoms (BG<70mg/dl)  (The patient is able to self-treat)) Moderate hypoglycemia: Cognitive impairment (BG<50mg/dl)  “Severe Hypoglycemia”: Unconscious (BG ???)  Unconsciousness and seizures.12
  • 12. Causes of hypoglycaemia The main cause of hypoglycaemia in people with type 2 diabetes is their diabetes medication  Hypoglycaemia occurs when there is an absolute or relative excess of therapeutic insulin in the presence of impaired counter-regulatory mechanisms  This commonly occurs with the use of insulin secretagogues or insulin, which raise insulin levels independently of blood glucose Amiel SA, et al. Diabet Med. 2008;25:245-54.
  • 13. Severe hypoglycaemic episodesincrease with duration of Proportion reporting at least one episode of T2D sulphonylureas (n= 103)treatment 0.6 T2D T2D T1D <2 years insulin (n= 85) >5 years insulin (n= 75) <5 years (n= 46) severe hypoglycaemia T1D >15 years (n= 54) 0.4 Annual 0.2 Prevalence = 7% 0.0 Treated with <2 yrs >5 yrs <5 yrs >15 yrs sulphonylurea of insulin treatment of insulin treatment Type 2 diabetes (T2D) Type 1 diabetes (T1D)Error bars, 95% confidence interval.  The proportion of patients with type 2 diabetes experiencing severe hypoglycaemia was similar for those treated with sulphonylureas or insulin for <2 years (7% in both groups) UK Hypoglycaemia Study Group. Diabetologia. 2007;50:1140-7.
  • 14. Consequences of hypoglycaemia422HQ11NP 027
  • 15. History of hypoglycaemia and risk ofcognitive decline in older type 2 diabetespatients History of severe hypoglycaemic episodes are associated with a significantly greater risk of dementia No. of Antecedent Severe Adjusted Hazard Ratio* for Incident Dementia Hypoglycaemic Episodes (95% Confidence Interval) ≥1 1.44 (1.25-1.66) 1 1.26 (1.10-1.49) 2 1.80 (1.37-2.36) ≥3 1.94 (1.42-2.64) *Adjusted for age (as time scale), BMI, race/ethnicity, education, sex, duration of diabetes, comorbidities, 7-year mean HbA1c level, diabetes treatment, and years of insulin use Whitmer RA, et al. JAMA. 2009;301:1565-72.
  • 16. Hypoglycaemia was a major predictor of cardiovascular death in the VADT study Hazard Ratio (confidence limits) P Value Hypoglycaemia 4.042 (1.449, 11.276) 0.01 HbA1c 1.213 (1.038, 1.417) 0.02 HDL 0.699 (0.536, 0.910) 0.01 Age 2.090 (1.518, 2.877) <0.01 Prior event 3.116 (1.744, 5.567) <0.01 0 2 4 6 8 10 12 Previous hypoglycaemia may impair cardiovascular autonomic function Hazard ratio (confidence limits) Cardiovascular autonomic testing in 20 healthy subjects showed reduced baroreflex sensitivity and reduced mucsle response to vasodilation in those who had experienced a previous hypoglycaemic episode Duckworth W. Presented at the ADA 68th Scientific Sessions, 2008. Available at: Accessed: 12 Nov, 2010.
  • 17. Potential impact of hypoglycaemiaLikely consequences of hypoglycaemia include: Physical and psychological morbidity and, in severe cases, fatality Compromised physiological and behavioural defences against subsequent falling plasma glucose concentrations, causing a vicious cycle of recurrent episodes Hypoglycaemia may preclude the maintenance of euglycaemia over a lifetime of diabetes and therefore limits the vascular benefits from glycaemic control Cryer PE. Diabetes. 2008;57:3169-76
  • 18. Current goals and the importanceof individualisation Current guidelines generally recommend:1-4 HbA1c level ≤7.0% (53 mmol/mol) to lower the risk of micro and macrovascular complications OR HbA1c level ≤6.5% (48 mmol/mol) to achieve near normoglycaemic control - Episodes of hypoglycaemia should be carefully titrated against this - Individuals with hypoglycaemia unawareness or severe hypoglycaemia should raise their glycaemic targets to avoid further episodes of hypoglycaemia Selecting the most appropriate therapy and individualising treatment are key to reducing the prevalence of hypoglycaemia Education and motivation are important to avoid hypoglycaemia 1. Canadian Diabetes Association. Can J Diabetes. 2008;32(Supp1):S1-S201. 2. American Diabetes Association. Diabetes Care. 2009;32(Suppl 1):S13-61. 3. Matthaei S, et al. Exp Clin Endocrinol Diabetes. 2009;117:522-57. 4. Rydén L, et al. Eur Heart J. 2007;28:88-136.
  • 19. Risk factors for hypoglycaemia Behavioural Physiological Therapeutic  Missed or irregular meals  Advancing age  Glucose-lowering therapy  Alcohol or drug use  Longer diabetes duration  Concurrent medication (e.g. aspirin,  Exercise  Presence of comorbidity warfarin, NSAIDs)  Incorrect use  Deterioration of renal and of glucose-lowering hepatic function medication  Loss of awareness of hypoglycaemia Amiel SA, et al. Diabetic Med. 2008;25:245-54.
  • 20. Glucose-lowering agents classifiedby risk of hypoglycaemia High risk1,2 Low risk1,2 Insulin Metformin Sulphonylureas -glucosidase inhibitors Glinides Pioglitazone GLP-1 receptor agonists DPP-4 inhibitors 1. Nathan DM, et al. Diabetologia. 2009;52:17-306. 2. Cefalu WT. Nature. 2007;81:636-49.
  • 21. Hypoglycaemia in elderly people with type 2 diabetes422HQ11NP 027
  • 22. The problem of hypoglycaemia inelderly patients Potentially serious, sometimes life-threatening consequences • Impairment in heart and brain function • Cardiovascular events • Falls and injury • Cognitive decline Detection is more problematic • Blunted symptoms (may be different from younger patients) • Impaired cognition Presence of multiple risk factors •Multiple comorbidities and medication •Renal impairment •Poorly-adapted behaviour response •Rare use of self-monitoring and lack of education Lecomte P. Diabetes Metab. 2005;31:5S105-5S111.
  • 23. Hypoglycaemia may be underestimated inelderly people with type 2 diabetes Symptoms of hypoglycaemia are not specific in nature:  Weakness  Unsteadiness  Sleepiness  Feeling faint  Feeling light-headed  Poor concentration Neurological symptoms of hypoglycaemia may be misinterpreted as...  Transient cerebral ischaemia  Vertebrobasilar insufficiency  Vasovagal attacks  Cardiac dysrhythmia McAulay V, et al. Diabet Med. 2001;18:690-705.
  • 24. Summary 1Hypoglycaemia is a potentially serious complication in type 2diabetes, especially in the elderly Hypoglycaemic episodes may be associated with cardiovascular death, MI, cardiac arrhythmias, nervous system abnormalities and cardiac ischaemia Individualised treatment is key in order to avoid hypoglycaemia and glucose-lowering medication must be adapted to each person’s needs and lifestyle. Several glucose-lowering agents (e.g. insulin secretagogues and insulin therapy) may increase the risk of hypoglycaemia Fear of hypoglycaemia and the risks associated with treatment may cause individuals to stop taking their medication – a major barrier to achieving glycaemic control
  • 25. Barriers to Achieving Glycaemic Goals: A Focus on Weight Gain and Obesity
  • 26. Overweight/obesity: classification Cut-off points for overweight and obesity in European and Asian populations BMI (kg/m2) BMI (kg/m2) European1 Asian2Normal 18.5–24.9 18.5–22.9Overweight (pre-obese) 25–29.9 23–24.9Obese ≥30 ≥25 The optimum population BMI is considered to be ~213 1. Tsigos C, et al. Obes Facts. 2008;1(2):106-16. 2. WHO Expert Consultation. Lancet. 2004 Jan 10;363(9403):157-63. 3. James WPT. J Intern Med. 2008;263:336-52.
  • 27. The vast majority of people with type 2diabetes are overweight or obese Normal A large proportion of 10% people have metabolic syndrome 90% Overweight/obese Individuals with type 2 diabetes World Health Organization Fact sheet: Obesity and overweight. Available at: Accessed: 12 Nov, 2010.
  • 28. Prevalence of Sedentary Life &Obesity in EgyptPrevalence of sedentary lifestyle & obesity in the Egyptian populationaged ≥ 20 years by residence and socio-economic status (1992-1994) Residence & Prevalence of Sedentary Prevalence of Obesity Socio- economic Lifestyle (%) Status (%)  Rural 52 16  Urban (Lower SES) 73 37  Urban (Higher SES) 89 49  Total 63 27 SES= Socio-economic status
  • 29. Visceral fat independently predictsall-cause mortality in men Modeled data for odd ratios for mortality with increasing visceral fat mass after control for age and follow-up time 6 N=291 p<0.05 5 Odds ratios for mortality 4 3 2 1 0 0 0.25 0.5 0.75 1 1.25 Visceral Fat (kg) Kuk JL, et al. Obesity. 2006;14:336-41.
  • 30. Atherosclerosis in youth is linked toobesity Mean extent of right coronary artery lesions by BMI and panniculus thickness in young men (N=2133) Panniculus thickness ≤ median for sex and BMI Panniculus thickness > median for sex and BMI 12 4 Fatty Streaks Raised Lesions Surface area involved (%) Surface area involved (%) 10 3 8 6 2 4 1 2 0 0 <25 25-30 >30 <25 25-30 >30 Body mass index (kg/m2) Body mass index (kg/m2) McGill HC, et al. Circulation. 2002;105:2712-8.
  • 31. Overweight/obesity is animportant risk factorfor cardiometabolic disease Abdominal obesity = cardiometabolic risk Excess body weight, especially intra-abdominal fat, adversely impacts many cardiometabolic risk factors, including:  Hypertension  Dyslipidaemia  Insulin resistance  Type 2 diabetes Hamdy O, et al. Curr Diabetes Rev. 2006 Nov;2(4):367-73.
  • 32. Mechanisms linking excess body fat and obesity to disease422HQ11NP057
  • 33. Adipose tissue is a dynamicendocrine organ ↑Insulin Hypertension ↑IL-6 ↑Angiotensinogen Inflammation ↑Insulin ↑ Insulin ↑TNF ↑FFA Dyslipidaemia Adipose tissue ↑Resistin ↑Insulin ↑Adipsin (Complement D) ↑Leptin ↑Insulin ↑Leptin Type 2 Diabetes ↓Adiponectin ↑PAI-1 Atherosclerosis Thrombosis ↑Insulin Lyon CJ, et al. Endocrinology 2003;144:2195-200. Trayhurn P, Wood IS. Br J Nutr 2004;92:347-55.
  • 34. Adiponectin has beneficial effectson the cardiovascular system Adiponectin protects cardiovascular tissues under conditions of stress TZDs Caloric restriction Adiponectin Angiogenesis Hypertrophy  Apoptosis Fibrosis  Inflammation  Cardiovascular protection Shibata R, et al. Circ J 2009; 73: 608-14.
  • 35. People with diabetes, especially obeseindividuals, are characterised by elevationsin free fatty acids (FFAs) In diabetes, elevated plasma FFAs fail to decline normally in response to insulin Similar abnormalities in FFA metabolism are found in individuals with impaired glucose tolerance and in non-diabetic, insulin-resistant, obese individuals Increased visceral fat is specifically related to FFA-associated insulin resistance Subcutaneous fat Visceral fat Bays H, et al. J Clin Endocrinol Metab. 2004;89:463-78.
  • 36. Involvement of adipose tissue, liverand muscle in obesity-induced CV Macrophage recruitmentdisease NEFAs RBP-4 (visceral) Ectopic Myocellular fat adipose tissue ectopic fat IL-6MCP-1 NEFAs TNF- Insulin Diabetes Adiponectin  resistance VLDL ROS INFLAMMATION CRP PAI-1 LDL-ox ICAM-1 Endothelial dysfunction Atherosclerosis Van Gaal LF, et al. Nature. 2006;444(7121):875-80.
  • 37. Cross-talk among adipocytes, macrophagesand endothelial cells in inflamed adiposetissue Monocyte rolling Attachment Transendothelial migration Cross-talk CCR2 CCL2 Macrophage Adipocyte MCP-1 Insulin Adipokines resistance IL-6 IL-1b TNF- Local insulin resistance? Systemic insulin resistance? Local angiogenesis Proinflammatory cytokines/chemokines Angiogenic factors Neels JG, Olefsky JM. J Clin Invest. 2006;116:33-5.
  • 38. Increased body weight is associated withincreased death rates for cancer Mortality from cancer according to BMI for men Type of Cancer (highest BMI category) Prostate (35) 1.34 Non-Hodgkin’s lymphoma 1.49 (35) All cancers (40) 1.52 All other cancers (30) 1.68* Kidney (35) 1.70 Multiple myeloma (35) 1.71 Galbladder (30) 1.76 Colon and rectum (35) 1.84 Oesophagus (30) 1.91* Stomach (35) 1.94 Pancreas (35) 2.61* 4.52 Liver (35) 1 2 3 4 5 6 7 Relative Risk of Death (95% Confidence Interval) For each relative risk, the comparison was between men in the highest body-mass-index (BMI) category (indicated in parentheses) and men in the reference category (body-mass index, 18.5 to 24.9). Asterisks indicate relative risks for men who never smoked. Results of the linear test for trend were significant (P≤0.05) for all cancer sites Calle EE, et al. N Engl J Med 2003;348:1625-38.
  • 39. Obstructive sleep apnoea (OSA) associatedwith type 2 diabetes and obesity Excess weight is an important risk factor for OSA1  41–58% of OSA is estimated to be attributable to excess weight Increasing evidence suggests that OSA has adverse effects on glucose metabolism and risk of diabetes, independent of degree of obesity2 OSA is also a significant risk factor for CV disease and mortality2 Physicians should be aware of the extremely high prevalence (>86%) of undiagnosed OSA 1. Young T, et al. J Appl Physiol. 2005;99:1592-9. 2. Tasali E, et al. Chest. 2008;133;496-506. 3. Foster in GD, et al. Diabetes Care. 2009;32:1017-9. obese individuals with type 2 diabetes3
  • 40. Mechanistic Links: Sleep Apnea and Metabolic DysfunctionSleep Fragmentation Sympathetic Activation Insulin Sleep Apnea HPA dysregulation Type 2 Diabetes Resistance Systemic Inflammation b-cell Dysfunction ? Intermittent Hypoxemia
  • 41. Weight gain as a consequence of treatment422HQ11NP057
  • 42. overweight/obesity, diabetes and CV risk:potential impact of treatment-relatedweight gain + Weight gain/ obesity Treatment- related weight + gain, and/or weight gain through Diabetes CV risk “defensive snacking” because of - hypoglycaemia Glucose- lowering therapy Increases CV risk Decreases CV risk Peters AL. Cleve Clin J Med. 2009 Dec;76 Suppl 5:S20-7.
  • 43. Most current therapies result in weight gainover time UKPDS: up to 8 kg ADOPT: up to 4.8 kg in 12 years1 in 5 years2 8 100 Annualised slope (95% CI) Insulin (n=409) Rosiglitazone, 0.7 (0.6 to 0.8) 7 Metformin, -0.3 (-0.4 to -0.2) Glibenclamide, -0.2 (-0.3 to 0.0) 6 96 Change in weight (kg) 5 Weight (kg) Glibenclamide (n=277) 4 92 3 2 Conventional (n=411)* 88 Treatment difference (95% CI) 1 Rosiglitazone vs metformin 6.9 (6.3 to 7.4); P<0.001 Rosiglitazone vs glibenclamide, 0 2.5 (2.0 to 3.1); P<0.001 Metformin (n=342) 0 0 3 6 9 12 0 1 2 3 4 5 Years Years * Conventional treatment; diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/L (>270 mg/dL) n=at baseline On 23 September 2010, the European Medicines Agency recommended suspension of marketing authorisations for rosiglitazone 1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65. 2. Kahn SE, et al (ADOPT). N Engl J Med. 2006;355:2427-43.
  • 44. Glucose-lowering medications andweight profile Range of weight change (kg) in response to diabetes medications Sulphonylureas Glinides Thiazolidinediones Insulin DPP-4 inhibitor (sitagliptin) Metformin GLP-1 receptor agonist (exenatide) -6 -4 -2 0 2 4 6 8 10 Range of weight change (kg) Mitri J, Hamdy O. Expert Opin Drug Saf. 2009;8:573-84.
  • 45. Combination therapy and weightgain Consensus statements from the AACE-ACE Insulin + SUs Combined use of any 2 or all 3 Insulin + TZDs of these agents may result in an increased risk of weight gain SUs + TZDsAACE: American Association of Clinical EndocrinologistsACE: American College of Endocrinology Rodbard HW, et al. Endocr Pract. 2009;15:540-59.
  • 46. Some medications have a weight-neutral effect DPP-4 inhibitors have weight-neutral effect in T2D patients, either as monotherapy and as add-on therapy to other oral agents Intestinal TG  Apo B-48 - absorption DPP-4 inhibitors + Lipolysis FFA + Fat oxidation - Blocks +Promotes Foley JE, et al. Vasc Health Risk Manag. 2010 Aug 9;6:541-8.
  • 47. Defensive snacking as a potentialmechanism for weight gain in diabetes  In the DCCT, insulin-treated patients with severe hypoglycaemia had a significantly (P<0.05) greater increase in weight than those without severe hypoglycaemia during the study Patients with severe hypoglycaemia +6.8 kg Patients without severe hypoglycaemia +4.6 kg 0 2 4 6 8 Weight gain (kg)  A potential explanation for this is “defensive snacking” – an increase in a patient’s carbohydrate intake following hypoglycaemia due to their fear of further events Russell-Jones D, Khan R. Diabetes Obes Metab. 2007;9:799-812.
  • 48. Beneficial effects of modest and major weight reduction422HQ11NP057
  • 49. Weight loss: a cost-effective meansof controlling diabetes  The advantages of weight loss are its pleiotropic benefits, safety profile and low cost1 Improves blood glucose, blood pressure and lipids1 Reduces the risk of progression from pre-diabetes to overt diabetes2Body weight May help to avoid other comorbidities associated with obesity (e.g. degenerative joint disease and urinary incontinence)3 Needs to be maintained in the long term1 1. Nathan DM, et al. Diabetologia. 2009;52:17-306. 2. Knowler WC, et al. N Engl J Med. 2002;346:393-403. 3. Bouldin MJ, et al. Am J Med Sci. 2006;331:183-93.
  • 50. Major weight reduction (>10-15%):Recommendations for bariatricsurgery Surgery should be considered:  For patients with a BMI of 30−35* kg/m2 whose diabetes is not adequately controlled by optimal medical regimens, especially when there are other major co- morbidities Surgery should be an accepted option:  For individuals with type 2 diabetes and a BMI of 35 kg/m2 or more *In Asian and some other ethnicities of increased risk, BMI action points may be reduced by 2.5 kg/m2 1. IDF position statement. Available at: Bariatric-Surgery.pdf. Accessed 2 Aug 2011.
  • 51. Different bariatric procedures
  • 52. Major weight loss may be associated with recovery of type 2 diabetes in some individuals1,2 Recovery of type 2 diabetes in severely* obese individuals receiving either bariatric surgery or conventional therapy2 100 Patients with diabetes remission (%) p<0.001 N = 2037 80 72% p<0.001 60 40 36% 21% 20 13% 0 Surgical Control Surgical Control (N=342) (N=248) (N=118) (N=84) 2 Years 10 Years*With a BMI of approximately 40 kg/m2Recovery based on fasting plasma glucose <7.0 mmol/l and not receiving hypoglycaemic therapy 1. Colquitt JL, et al. Cochrane Database Syst Rev. 2009;(2):CD003641 2. Buchwald H, et al. Am J Med. 2009;122:248-256.e5. 3. Sjostrom L, et al. N Engl J Med. 2004;351:2683-93.
  • 53. Summary 2  Most people with type 2 diabetes (T2D) are overweight or obese  T2D as a result of obesity is responsible for a significant proportion of obesity-related disability and life-years lost  Abdominal obesity is most strongly associated with a constellation of risk factors linked with diabetes and cardiovascular disease  Other comorbidities such as obstructive sleep apnoea and depression may be associated with obesity in type 2 diabetes  Glucose-lowering medications provide options to choose weight-neutral or weight-loss drugs  Bariatric surgery should be considered for severely obese patients with T2DM