Hypoglycemia and Cardiovascular Events

Choosing right therapies and targets, and the right patient



                   ...
Plan

• Show evidence that CV disease is increased in type 2
  diabetes

• Show evidence that multifactorial interventions...
Improved Glycemic Control Has Been Shown
   to Reduce the Risk of Complications
               According to the United Kin...
Intervention Works...but at a
                                     Price: DCCT and UKPDS
                                 ...
Asymptomatic Episodes of
     Hypoglycemia May Go Unreported
                      100



                       75       ...
Reporting hypoglycemia

• Documented symptomatic hypoglycemia: plasma
  glucose < 70 + symptoms
• Severe hypoglycemia: req...
Severe hypoglycemia : definition in
                    ACCORD
      Requiring medical or paramedical attention in which
 ...
Counter regulatory hormone response


82 mg/dl                                      Inhibition of endogenous insulin secre...
Counter regulatory hormone response


           Counter regulation: physiological mechanisms
        that normally preven...
Complications and Sequelae
                               of Hypoglycemia
      Plasma glucose level



                  ...
Cardiovascular benefits of
glycemic control and Multifactorial
          Interventions
UKPDS legacy effect
ACCORD study : ...
ACCORD : Kaplan–Meier Curves for the Primary
   Outcome and Death from any cause




Composite primary outcome            ...
Why was mortality increased ?

   •  Not certain
   •  Speed of HbA1c reduction ( 1.4 % vs. 0.6% in 4 months)
   •  Drug c...
Increased Mortality, Myocardial Infarction, and
        Hypoglycemia With Intensive Therapy:
                    ACCORD Tr...
ACCORD

• Rate of 1-year change in A1c showed that a greater
  decline in A1c was associated with a lower risk of death

•...
ACCORD: Adjusted mortality rates by
               treatment strategy




Riddle MC, Ambrosius WT Epidemiologic relationsh...
ACCORD : Adjusted log HR by
                      treatment strategy

                                                    ...
Higher risk of hypoglycemia

•   Age > 65 years
•   Longer duration of insulin use
•   Higher HbA1c
•   Use of insulin
•  ...
UKPDS: long-term follow-up and legacy
                                  effect

                                          ...
Legacy Effect of Earlier Glucose Control
                      After median 8.5 years post-trial follow-up

Aggregate Endp...
Lessons from UKPDS:
   Legacy Effect of Earlier Metformin Therapy
     UKPDS Trial                                        ...
Legacy Effect

A treatment has a legacy effect if the
intervention, when discontinued, leads to
long term decreased risk o...
VADT

  • Older patients > 60 yrs
  • 12% reduction in risk of cardiovascular events with
    intensive control, but that ...
Predictions from VADT: impact of bad
           glycemic legacy

                   Before entering VADT intensive treatme...
VADT: relationship between coronary
     calcification and outcome




               *
          *

   * Significant even...
VADT: Diabetes duration vs. intensive
       treatment CVD benefit




             Diabetes duration, years
Copyrighted art
          deleted from here




 “ There is a time for everything”


http://connect.in.com/nadodikattu/pho...
Multifactorial intervention and CV
          event reduction : The Steno Trial




Intensive therapy was associated with a...
Steno 2 trial: 13year follow up




Total mortality in the intensive arm was reduced by 46% (RRR) corresponding
to an abso...
Hypoglycemia and CV events

• 14,670 patients with coronary artery disease, recruited
for the Bezafibrate Infarction Preve...
CEREBRAL ISCHEMIA, STROKE, AND
             DEMENTIA
• Severe hypoglycemia has been known to induce focal
  neurological d...
Cardiac Ischemia Associated With Hypoglycemia
                Episodes: More Episodes of Chest Pain and ECG
              ...
Meta-analysis: impact of intensive glucose
           control on coronary heart disease* events

                        I...
Mechanisms by which hypoglycemia
 may affect cardiovascular events




Souza CV . Hypoglycemia, Diabetes, and Cardiovascul...
Which TARGET for WHOM?
WHOEVER
WINS….
  WE
 LOSE.

Hypoglycemia vs. Hyperglycemia
Factors deciding the target HbA1c

 Several factors can be taken into consideration when
   tailoring treatment including
...
Categorize patients into different
                      groups
•  Newly diagnosed patients
     Obese patients
     Lean ...
Newly diagnosed patients

•Aggressive glycemic control
                                                                   ...
Patients with inadequate glycemic
       control, but no co morbidities
• Bad glycemic legacy                             ...
Patients with CVD
•Long duration of DM                                                                              ACCORD...
High risk group in ACCORD

         Patients with a history of CVD who do not respond to
         aggressive glucose-lower...
Patients with risk of hypoglycemia

•Long duration of DM                                                                  ...
Adverse event concerns of add on
                  therapy
                 Insulin   Sulphonylurea   TZD         GLP-1 / ...
Effective interventions
Messages

• Glycemic control reduces Cardiovascular events

• Benefits of intensive glycemic control on CV events is
  pro...
Disclaimer

 The material for these slides were derived from various sources
including pictures and cartoons from the worl...
Cardiovascular events & Hypoglycemia
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Cardiovascular events & Hypoglycemia

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A talk on hypoglycemia and cardiovascular outcomes for physicians and cardiologists.

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Cardiovascular events & Hypoglycemia

  1. 1. Hypoglycemia and Cardiovascular Events Choosing right therapies and targets, and the right patient Mathew John Endocrinologist Providence Endocrine & Diabetes Specialty Centre Trivandrum, India www.endocrinologydiabetes.com
  2. 2. Plan • Show evidence that CV disease is increased in type 2 diabetes • Show evidence that multifactorial interventions including glycemic control will reduce risk of CV disease • Evaluate hypoglycemia in recent trials • How hypoglycemia is related to CV outcomes • Fitting targets and drugs to the right patient
  3. 3. Improved Glycemic Control Has Been Shown to Reduce the Risk of Complications According to the United Kingdom Prospective Diabetes Study (UKPDS) 35, Every 1% Decrease in A1C Resulted in: 14% 12% 21% 37% Decrease Decrease Decrease Decrease in risk of any in risk of MI in risk of in risk of diabetes-related (P<.0001) stroke microvascular end point (P=.04) complications (P<.0001) (P<.0001) Stratton IM et al. BMJ. 2000;321:405-412.
  4. 4. Intervention Works...but at a Price: DCCT and UKPDS Severe Hypoglycemia 100 DCCT (Type 1) UKPDS (Type 2) Major Episodes 5 Major Episodes Incidence (%) 80 Rate/100 Patient Years 4 60 Intensive 3 Intensive 40 2 20 1 Conventional Conventional 0 0 5 6 7 8 9 10 11 12 13 14 0 3 6 9 12 15 HbA1c (%) During Study Years from Randomization DCCT Research Group, Diabetes. 1997;46:271-286 UKPDS Group (33), Lancet. 352: 837-853, 1998
  5. 5. Asymptomatic Episodes of Hypoglycemia May Go Unreported 100 75 • In a cohort of patients with 62.5 diabetes, more than 50% had Patients, % 55.7 50 46.6 asymptomatic (unrecognized) hypoglycemia, as identified by continuous glucose 25 monitoring1 • Other researchers have n=70 n=40 n=30 0 reported similar findings2,3 All patients Type 1 Type 2 with diabetes diabetes diabetes Patients With ≥1 Unrecognized Hypoglycemic Event, % 1. Chico A et al. Diabetes Care. 2003;26(4):1153–1157. Permission pending. 2. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007;115(8):491–494. 3. Zick R et al. Diab Technol Ther. 2007;9(6):483–492.
  6. 6. Reporting hypoglycemia • Documented symptomatic hypoglycemia: plasma glucose < 70 + symptoms • Severe hypoglycemia: requiring assistance of another person for resuscitation • Asymptomatic hypoglycemia • Probable symptomatic hypoglycemia • Relative hypoglycemia: symptoms of hypoglycemia+ plasma glucose > 70 mg/dl ADA Working Group on Hypoglycemia Diabetes Care 2005: 28(5): 1245-1249.
  7. 7. Severe hypoglycemia : definition in ACCORD Requiring medical or paramedical attention in which there was either a documented capillary glucose level 50 mg/dL (2.8 mmol/L) or in which prompt recovery was achieved with oral carbohydrate, intravenous glucose, or glucagons Severe Hypoglycemia Monitoring and Risk Management Procedures in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial . Am J Cardiol 2007;99[suppl]:80i–89i)
  8. 8. Counter regulatory hormone response 82 mg/dl Inhibition of endogenous insulin secretion 70 mg/dl Counterregulatory hormone release GLUCAGON, CATECHOLAMINES Onset of autonomic and 50-60 mg/dl neuroglycopenic symptoms Cognitive dysfunction < 50 mg/dl coma, < 30 mg/dl convulsions Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes Diabetes Care 2005: 28: 12: 2948-2961
  9. 9. Counter regulatory hormone response Counter regulation: physiological mechanisms that normally prevent or rapidly correct hypoglycemia • Glucagon : predominant hormone • Catecholamines • Cortisol • Growth hormone Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes Diabetes Care 2005: 28: 12: 2948-2961
  10. 10. Complications and Sequelae of Hypoglycemia Plasma glucose level 110 6 100 Increased risk of 5 90 cardiac arrhythmia • Abnormal prolonged cardiac repolarization— 80 Release of ↑in QTc and QTd—associated with ↑ levels of epinephrine and 4 epinephrine and hypokalemia 70 norepinephrine • Cardiac death 60 3 Neuroglycopenia 50 • Reduced attention span 40 • Inability to focus 2 • Personality change 30 • Confusion 1 20 • Seizure mmol/l • Coma 10 mg/dl • Brain death Cryer PE. J Clin Invest. 2006:116:1470–1473.
  11. 11. Cardiovascular benefits of glycemic control and Multifactorial Interventions UKPDS legacy effect ACCORD study : subgroups VADT : subgroups
  12. 12. ACCORD : Kaplan–Meier Curves for the Primary Outcome and Death from any cause Composite primary outcome Death from any cause Nonfatal MI + nonfatal stroke + Intensive vs. Std death from CV causes 257 vs. 203 (6.9% in Intensive vs. 7.2% in std therapy group 5 % vs. 4 % , HR 1.22 95 % HR 0.90 CI 0.78-1.04, p: 0.16) CI : 1.01-1.46, p=0.04) Not significant
  13. 13. Why was mortality increased ? • Not certain • Speed of HbA1c reduction ( 1.4 % vs. 0.6% in 4 months) • Drug combinations • Unidentified hypoglycemia • Weight gain • Hypoglycemia unawareness (associated cardiac autonomic neuropathy) Analysis proves that the increased mortality rates are not related to 1. Specific OAD ( Rosiiglitazone, SU , Insulin etc) 2. Changes in other medications( Statins,Aspirin etc) Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials Diabetes Care January 2009 vol. 32 no. 1 187-192
  14. 14. Increased Mortality, Myocardial Infarction, and Hypoglycemia With Intensive Therapy: ACCORD Trial Mortality (% per year)1 ≥1 severe hypoglycemia 3.1 (n = 705) No hypoglycemia 1.2 (n = 9,546) a Defined by requirement for medical or paramedical intervention, with documented glucose <50 mg/dL and relief by parenteral or oral glucose or by glucagon. 1 Bloomgarden ZT. Diabetes Care. 2008;31(9):1913–1919. 2. Dluhy RG, McMahon GT. N Engl J Med. 2008;358:2630–2633.
  15. 15. ACCORD • Rate of 1-year change in A1c showed that a greater decline in A1c was associated with a lower risk of death • 20% higher risk of death for every 1% higher A1c level above 6%, suggesting that lower blood glucose levels may be a worthy target in some patients • Patients with the [consistently] lowest A1c levels had the lowest risk. The excess mortality risk was in those patients who failed to achieve and sustain A1c levels between 6% and 7%. Update on ACCORD. International Diabetes Federation 2009 World Diabetes Congress. October 22, 2009; Montreal, QC. American Diabetes Association (ADA) 69th Scientific Sessions: Abstract 468-P. Presented June 9, 2009
  16. 16. ACCORD: Adjusted mortality rates by treatment strategy Riddle MC, Ambrosius WT Epidemiologic relationships between A1C and all cause mortality during a median 3.4- year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010;33: 983–990
  17. 17. ACCORD : Adjusted log HR by treatment strategy The excess risk associated with intensive glycemic treatment occurred among those participants whose average A1C, contrary to the intent of the strategy, was >7%. Riddle MC, Ambrosius WT Epidemiologic relationships between A1C and all cause mortality during a median 3.4- year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care 2010;33: 983–990
  18. 18. Higher risk of hypoglycemia • Age > 65 years • Longer duration of insulin use • Higher HbA1c • Use of insulin • Use of SU • Older age • Renal dysfunction, • Mental health issues,( e.g. dementia)
  19. 19. UKPDS: long-term follow-up and legacy effect Intervention ends UKPDS UKPDS 10 Active Follow-up 0 9 –5 Conventional Median HbA1c (%) Relative risk reduction (%) 9% –10 P = 0.040 13% 8 Biochemical 15% data no P = 0.007 longer –15 P = 0.014 7 Intensive collected –20 24% 6 –25 P = 0.001 0 5 10 15 5 10 –30 1977 1997 2007 Years from randomization Bailey CJ & Day C. Br J Diabetes Vasc Dis 2008; 8:242–247. Holman RR, et al. N Engl J Med 2008; 359:1577–1589.
  20. 20. Legacy Effect of Earlier Glucose Control After median 8.5 years post-trial follow-up Aggregate Endpoint 1997 2007 Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040 Microvascular disease RRR: 25% 24% P: 0.0099 0.001 Myocardial infarction RRR: 16% 15% P: 0.052 0.014 All-cause mortality RRR: 6% 13% P: 0.44 0.007 RRR = Relative Risk Reduction, P = Log Rank
  21. 21. Lessons from UKPDS: Legacy Effect of Earlier Metformin Therapy UKPDS Trial POST-Trial Intervention Monitoring 1977 - 1997 Diabetes-related deaths 1997 - 2007 -42% -30% All –Cause Mortality -36% -27% Myocardial Infarction -39% -33% CV Complications CV Complications reduced and Survival reduced and Survival increased versus other increase maintained therapies UKPDS 34. Lancet 1998; 352: 854-65 UKPDS 80. NEJM 2008; 359: 1577-89
  22. 22. Legacy Effect A treatment has a legacy effect if the intervention, when discontinued, leads to long term decreased risk of outcome. http://www.ganfyd.org/index.php?title=Legacy_effect
  23. 23. VADT • Older patients > 60 yrs • 12% reduction in risk of cardiovascular events with intensive control, but that did not nearly reach statistical significance," • The risk of having a primary cardiovascular event among patients with diabetes of 10 to 15 years' duration was reduced 40% with intensive glucose control • Increased incidence of severe hypoglycemia in the intensive treatment group. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129–139
  24. 24. Predictions from VADT: impact of bad glycemic legacy Before entering VADT intensive treatment arm After entering VADT intensive treatment arm 9.5 Generation of a Drives risk of ‘bad glycemic complications 9.0 legacy’ 8.5 HbA1c (%) 8.0 7.5 7.0 6.5 6.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Time since diagnosis (years) Del Prato S. Diabetologia 2009; 52:1219–1226.
  25. 25. VADT: relationship between coronary calcification and outcome * * * Significant event reduction with CAC score <100, not >100
  26. 26. VADT: Diabetes duration vs. intensive treatment CVD benefit Diabetes duration, years
  27. 27. Copyrighted art deleted from here “ There is a time for everything” http://connect.in.com/nadodikattu/photos-390645-4018893.html
  28. 28. Multifactorial intervention and CV event reduction : The Steno Trial Intensive therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio, 0.43; 95% CI, 0.19 to 0.94; P=0.04) and of cardiovascular events (hazard ratio, 0.41; 95% CI, 0.25 to 0.67; P<0.001).
  29. 29. Steno 2 trial: 13year follow up Total mortality in the intensive arm was reduced by 46% (RRR) corresponding to an absolute risk reduction of 20% N Engl J Med. 358:580-591,2008
  30. 30. Hypoglycemia and CV events • 14,670 patients with coronary artery disease, recruited for the Bezafibrate Infarction Prevention study over an 8-year mean follow-up, hypoglycemia was a predictor of increased all-cause mortality (with a HR of 1.84) • Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes: more cardiac events were documented in patients after institution of intensive glycemic control versus standard control (32 vs. 20%) Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129–139
  31. 31. CEREBRAL ISCHEMIA, STROKE, AND DEMENTIA • Severe hypoglycemia has been known to induce focal neurological deficits and transient ischemic attacks, which are reversible with the correction of blood glucose • Recurrent or severe hypoglycemia may predispose to long-term cognitive dysfunction and dementia. • Conversely, severe cognitive dysfunction has been associated with increased risk of hypoglycemia
  32. 32. Cardiac Ischemia Associated With Hypoglycemia Episodes: More Episodes of Chest Pain and ECG Abnormalities Study included patients (n=19, mean age, 58±16 years) with type 2 diabetes, history of frequent hypoglycemia, HbA1c of 8%, and coronary artery disease (defined as history of myocardial infarction, coronary bypass surgery, or angioplasty). CGMS and Holter monitoring abnormalities Episodes with Episodes Total chest pain/ with ECG episodes angina abnormalities Hypoglycemia 54 10* 6* Symptomatic 26 10* 4* Asymptomatic 28 — 2 Normoglycemia without rapid changes N/A 0 0 Hyperglycemia 59 1 0 Rapid changes in glucose (>100 mg dl-1 h-1) 50 9* 2 *P<0.01 vs episodes during hyperglycemia and normoglycemia. ECG=electrocardiographic; CGMS=continuous glucose monitoring system. Desouza C et al. Diabetes Care. 2003;26:1485–1489.
  33. 33. Meta-analysis: impact of intensive glucose control on coronary heart disease* events Intensive treatment/standard Odds ratio Odds ratio treatment (95% CI) (95% CI) Participants Events UKPDS 3,071/1549 426/259 0.75 (0.54–1.04) PROactive 2,605/2633 164/202 0.81 (0.65–1.00) ADVANCE 5,571/5,569 310/337 0.92 (0.78–1.07) VADT 892/899 77/90 0.85 (0.62–1.17) ACCORD 5,128/5123 205/248 0.82 (0.68–0.99) Overall 17,267/15,773 1,182/1,136 0.85 (0.77–0.93) 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Intensive treatment better Standard treatment better *Included non-fatal myocardial infarction and death from all cardiac mortality. Reproduced from Ray KK, et al. Lancet 2009; 373:1765–1772.
  34. 34. Mechanisms by which hypoglycemia may affect cardiovascular events Souza CV . Hypoglycemia, Diabetes, and Cardiovascular Events DIABETES CARE, VOLUME 33, NUMBER 6, JUNE 2010
  35. 35. Which TARGET for WHOM?
  36. 36. WHOEVER WINS…. WE LOSE. Hypoglycemia vs. Hyperglycemia
  37. 37. Factors deciding the target HbA1c Several factors can be taken into consideration when tailoring treatment including • Duration of diabetes • Stage of disease • Life expectancy • Risk of hypoglycemia • Risk factors for CV disease (CVD).
  38. 38. Categorize patients into different groups • Newly diagnosed patients Obese patients Lean patients • Patients with inadequate glycemic control, but no co morbidities • Patients with CVD • Individuals at risk of hypoglycemia S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidance from the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304
  39. 39. Newly diagnosed patients •Aggressive glycemic control UKPDS Legacy •Use agents with minimum risk of Effect hypoglycemia •Target HbA1c < 6.5-7 % •Chose therapies with likely beta cell preservation •Address cardiovascular risk factors •Consider insulin if HbA1c > 9 % S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidance from the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304
  40. 40. Patients with inadequate glycemic control, but no co morbidities • Bad glycemic legacy UKPDS Legacy •Likely to have one /more microvascular Effect complication •Aggressive glycemic control •Gradual reduction in HbA1c •Diabetes education •Assess risk of hypoglycemia S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidance from the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304
  41. 41. Patients with CVD •Long duration of DM ACCORD •Poor glycemic control VADT • •Large pill burden ADVANCE • Benefits of good glycemic control vs. risk of hypoglycemia •Gradual reduction in HbA1c • Consider contraindications of agents used • Assess risk of hypoglycemia S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidance from the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304
  42. 42. High risk group in ACCORD Patients with a history of CVD who do not respond to aggressive glucose-lowering strategies may be more susceptible to CV events Calles J, Banerji M, Bonds DE et al. Baseline characteristics and mortality in ACCORD. Diabetes 2009; 58 (Suppl. 1): A24.
  43. 43. Patients with risk of hypoglycemia •Long duration of DM ACCORD •Previous history of hypoglycemia VADT •Reduced Creatinine clearance ADVANCE •Irregular eating/lifestyle habits • Less stringent HbA1c targets •Gradual reduction in HbA1c • Consider agents with less hypoglycemia • Assess risk of hypoglycemia S. Del Prato; J. LaSalle; S. Matthaei; C. J. Bailey Tailoring Treatment to the Individual in Type 2 Diabetes Practical Guidance from the Global Partnership for Effective Diabetes Management Int J Clin Pract. 2010;64(3):295-304
  44. 44. Adverse event concerns of add on therapy Insulin Sulphonylurea TZD GLP-1 / DPP4 inhibitors Hypoglycemia Weight gain CV safety Ischemic MI Preconditioning Fluid UKPDS/ UGDP retention Other concerns Fractures Pancreati Macular tis edema Nausea
  45. 45. Effective interventions
  46. 46. Messages • Glycemic control reduces Cardiovascular events • Benefits of intensive glycemic control on CV events is pronounced when it is achieved early in the course of diabetes • Identify patients with high CV risk and high hypoglycemia risk • Individualize treatment
  47. 47. Disclaimer The material for these slides were derived from various sources including pictures and cartoons from the world wide web. I have tried my best to acknowledge all possible sources and references. However, if I have overlooked any particular reference, it is not done intentionally. Anyone reproducing materials from this presentations should acknowledge the author of the original work. Cartoons are made to simplify certain concepts. The presenter should attach explanations to all cartoons or else it will appear quite amateurish.
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