Diabetes mellitus: An update D. Hunt March 2010

Significance of diabetes mellitus 5% of the population has diagnosed diabetes prevalence increases with age: :1% :5% > 65:10% the true prevalence of diabetes is estimated to be twice the prevalence of diagnosed diabetes

Frequency of diagnosed and undiagnosed diabetes and IGT, by age (U.S. data - Harris) Harris. Diabetes Care 1993;16: Significance of diabetes mellitus

Eye Disease Type 1:25% after 15 years Type 2:4% - 12% after 15 years Diabetes is the leading cause of adult-onset blindness

Kidney Disease Type 1:30% after 15 years Type 2:20% after 15 years Diabetes is the leading cause of end-stage renal disease

Foot complications Loss of foot sensation > foot ulcers and infections > foot amputations Amputation rate: /1000 patient-years Diabetes is the leading cause of non-traumatic amputation

Haffner Am J Cardiol 1999;84:11J-4J. Framingham study: diabetes and CAD mortality at 20-year follow-up Cardiovascular Disease Risk is Increased 2 to 4 Times

Blood glucose control reduces the risk of diabetic complications, especially microvascular complications UK Prospective Diabetes Study

20-year Interventional Trial from 1977 to 1997:  5,102 patients with newly-diagnosed DM2  Median follow-up 10.0 years, range 6 to 20 years  Results presented in 1998

Microvascular Endpoints renal failure or death, vitreous haemorrhage or photocoagulation 346 of 3867 patients (9%)

Myocardial Infarction fatal or non fatal myocardial infarction, sudden death 573 of 3867 patients (15%)

UK Prospective Diabetes Study 20-year Interventional Trial from 1977 to 1997  5,102 patients with newly-diagnosed DM2  Median follow-up 10.0 years, range 6 to 20 years  Results presented in year Post-Trial Monitoring from 1997 to 2007  Annual follow-up of the survivor cohort  Clinic-based for first five years  Questionnaire-based for last five years Median overall follow-up 17.0 years, range 16 to 30 years

Post-Trial Changes in HbA 1c UKPDS results presented

Microvascular Disease Intensive (SU/Ins) vs. Conventional glucose control (photocoagulation, vitreous haemorrhage, renal failure) HR (95%CI)

Myocardial Infarction (fatal or non-fatal myocardial infarction or sudden death) Intensive (SU/Ins) vs. Conventional glucose control

All-cause Mortality Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI)

After median 8.5 years post-trial follow-up Aggregate Endpoint Any diabetes related endpoint RRR: 12%9% P: Microvascular disease RRR: 25%24% P: Myocardial infarction RRR: 16%15% P: All-cause mortality RRR: 6%13% P: RRR = Relative Risk Reduction, P = Log Rank Legacy Effect of Earlier Glucose Control

After median 8.8 years post-trial follow-up Aggregate Endpoint Any diabetes related endpoint RRR: 32%21% P: Microvascular disease RRR: 29%16% P: Myocardial infarction RRR: 39%33% P: All-cause mortality RRR: 36%27% P: RRR = Relative Risk Reduction, P = Log Rank Legacy Effect of Earlier Metformin Therapy

Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for MI and death were observed during 10 years of post-trial follow-up UKPDS Conclusions

Pharmacologic Management of Type 2 Diabetes If glycemic targets are not achieved within 2 to 3 months of lifestyle management, pharmacotherapy should be initiated. Timely adjustments should be made to attain target A1C within 6 to 12 months. In patients with marked hyperglycemia (A1C ≥ 9.0%), pharmacotherapy should be initiated concomitantly with lifestyle management, and consideration be given to either combination therapy or insulin.

Management of hyperglycemia in type 2 diabetes A1C >9.0% Symptomatic with metabolic decompensation A1C <9.0% Initiate pharmacotherapy immediately without waiting for effect from lifestyle interventions: Consider initiating metformin concurrently with another agent from a different class or Initiate insulin Initiate metforminInitiate insulin ± metformin If not at target LIFES T Y L ELIFES T Y L E Clinical Assessment Lifestyle intervention (initiation of nutrition therapy and physical activity)

Oral agents: (agents listed in alphabetical order) ClassA1CHypoglyc.AdvantagesDisadvantages Alpha-glucos. inhibitor ↓RareImproved postprandial control weight neutral GI side effects Incretin: DPP-4 inhib. ↓ - ↓↓ RareImproved postprandial control; weight neutral New agents (unknown long-term safety) Insulin↓- ↓↓↓ YesNo dose ceilingWeight gain Meglitinides Sulfonylureas ↓ - ↓↓ ↓↓ Yes Improved postprandial control Newer sulfonylureas (gliclazide) are associated with less hypoglycemia than glyburide Requires TID to QID dosing Weight gain *less hypoglycemia in the context of missed meals TZD↓ RareDurable monotherapy 6-12 weeks for maximal effect Edema, rare CHF, fractures in females ↓ = < 1.0% decrease in A1C ↓ ↓= 1.0–2.0% decrease in A1C ↓ ↓ ↓ = >2.0% decrease in A1C Oral agents beyond metformin

If not at target Add another drug from a different class; or Add bedtime basal insulin to other agent(s); or Intensify insulin regimen Timely adjustment to and/or addition of antihyperglycemic agents should be made to attain target A1C within 6 to 12 months Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada; Canadian Journal of Diabetes: 2008 Vol:32 Supplement

Natural History of Type 2 Diabetes Henry. Am J Med 1998;105(1A):20S-6S.

 cell function in type 2 diabetic patients Natural deterioration of  -cell function Years after diagnosis  -cell function

HbA 1c

Insulin TypeStartsPeaksDuration Lispro Aspart Glulisine 5-10 min0.5-1 hrs3.5 hrs Regular Toronto 30 min2-4 hrs6-8 hrs N/NPH1-2 hrs6-10 hrs16-24 hrs Detemir-6 – 8 hrsUp to 24 hrs Glargine1.5 hrsNoneUp to 24 hrs

Insulin regimens – Type 2 DM Many different potential regimens! –Oral + hs insulin (basal) –Oral + AM insulin (basal) –Pre-mixed insulin with breakfast and supper –Short-acting with meals + bedtime basal

Holman RR. NEJM 2009;361:

Aims First Phase  One-year head-to-head comparison of the efficacy of three different types of analogue insulins, when given in addition to dual oral antidiabetic therapy:  Biphasic insulin  Prandial insulin  Basal insulin

Patient Disposition 235 Assigned to biphasic insulin (biphasic aspart) 234 Assigned to basal insulin (detemir) 239 Assigned to prandial insulin (aspart) 34 Discontinued 45 Discontinued51 Discontinued 201 (86%) Completed three years 189 (81%) Completed three years 188 (79%) Completed three years  Overall, 18.4% of patients did not complete three years  No difference in proportions between groups (p=0.15)  No difference in baseline characteristics between those who completed or did not complete three years follow up

Aims First Phase  One-year head-to-head comparison of the efficacy of three different types of analogue insulins, when given in addition to dual oral antidiabetic therapy Second Phase  Evaluation over two further years of the need for more complex insulin regimens, and the overall efficacy of three different randomized insulin treatment strategies

Transition to a Complex Insulin Regimen * Intensify to a complex insulin regimen in year one if unacceptable hyperglycaemia 708 T2DM on dual oral agents Add biphasic insulin* twice a day Add prandial insulin* three times a day R First Phase Add basal insulin* once (or twice) daily Add prandial insulin at midday Add basal insulin before bed Second Phase Add prandial insulin three times a day From one year onwards, if HbA 1c levels were >6.5%, sulfonylurea therapy was stopped and a second type of insulin was added

Demographic Characteristics Biphasic N=235 Prandial N=239 Basal N=234 Male68%64%61% White Caucasian94%90%93% *Diabetes duration (yrs)9 (6-12)9 (6-14)9 (6-12) Taking sulfonylurea98%100%99% Taking metformin96%95%97% Age (years)61.7± ± ±10.0 Body mass index (kg/m 2 )30.2 ± ± ±4.6 HbA 1c (%)8.6 ± ±0.8 *interquartile range No significant differences between groups

Glycaemic targets and Insulin Injections Fasting and pre-meal: mmol/l (72-99 mg/dl)‏ Two-hours post meal: mmol/l ( mg/dl)‏ Biphasic Basal Prandial * * Twice a day if required

Starting Doses for Second Type of Insulin Biphasic group  Add midday prandial insulin - 10% of current total daily biphasic insulin dose (limited to 4-6 units) Prandial group  Add basal insulin at bedtime - 10 units Basal group  Add prandial insulin at breakfast, lunch and dinner - 10% of current total daily basal insulin dose at each time point (limited to 4-6 units)

Complex Insulin Regimens Proportion eligible for a second type of insulin per protocol Proportion taking two types of insulin

Insulin Doses Over 3 Years Median±95% confidence interval Biphasic ±prandial Prandial ±basal Basal ±prandial

Total Daily Insulin Doses at 3 Years Median±95% confidence interval

HbA 1c Values Over 3 Years Median±95% confidence interval Biphasic ±prandial Prandial ±basal Basal ±prandial Overall 6.9% (6.8 to 7.1)

Primary Outcome: HbA 1c at 3 Years Median±95% confidence interval

Distribution of HbA 1c Values at 3 Years Proportion ≤6.5% Biphasic31.9% Prandial44.8% Basal43.2% p=0.006 p=0.55 p=0.03 Biphasic ±prandial Prandial ±basal Basal ±prandial Baseline Proportion ≤7.0% Biphasic49.4% Prandial67.4% Basal63.2% p<0.001 p=0.22 p=

Decrease in SMBG Levels Over 3 Years Mean±1SD

Body Weight over 3 Years Median±95% confidence interval Biphasic ±prandial Prandial ±basal Basal ±prandial

Increase in Body Weight Over 3 Years Mean±1SD

Increase in Waist Circumference Over 3 Years Mean±1SD

Hypoglycaemia Categorised as  Grade 1 - Symptoms only with glucose (if measured) ≥3.1 mmol/l (≥56 mg/dl)  Grade 2 - Symptoms plus glucose <3.1 mmol/l (<56 mg/dl)  Grade 3 - Third party assistance required

Grade 2 or 3 Hypoglycaemia Over 3 Years Biphasic ±prandial Prandial ±basal Basal ±prandial

Grade 2 or 3 Hypoglycaemia Over 3 Years All patients Patients with HbA 1c ≤6.5%

Adverse Events Biphasic N=235 Prandial N=239 Basal N=234 p value Any serious event105 (44.7%) 79 (33.1%) 78 (33.3%) Death from any cause7 (3.0%) 9 (3.8%) 4 (1.7%) 0.23 Cardiovascular death4 (1.7%) 9 (3.8%) 1 (0.4%) Any adverse event228 (97.0%) 235 (98.3%) 227 (97.0%) 0.58 No significant differences were seen between groups in:  Serious adverse events occurring in more than 1% in any group  Non-serious adverse events occurring in more than 10% in any group

Safety Data No clinically relevant differences were seen between the groups with respect to changes in:  Blood pressure  Lipid profiles  Alanine aminotransferase  Plasma creatinine  Ratio of urinary albumin to creatinine

Relative Changes over 3 Years and Hypoglycaemia

Overview of Main Results BiphasicPrandialBasal Fewer hypoglycaemic episodes Less weight gain ++++ Less increase in waist circumference ++++

4T trial  Three quarters of patients added a second insulin  Those commencing therapy with a basal or prandial insulin more often achieved glycaemic targets than patients commencing with a biphasic insulin  Patients commencing therapy with basal insulin had fewer hypoglycaemic episodes and less weight gain These findings provide clear evidence in people with type 2 diabetes to support starting insulin therapy with a once a day basal insulin, and then adding a mealtime insulin if glycaemic targets are not met

Beyond Glycemic Control Blood pressure control Lipid therapy Microvascular complication screening and management

Blood Pressure Control Study UK Prospective Diabetes Study

Randomisation

Blood Pressure : Tight vs Less Tight Control cohort, median values Less tight control Tight control

mmHg baselinemean over 9 years Less tight control 160 / / 87 Tight control161 / / 82 difference1 / 010 / 5 pn.s.< ACE inhibitor159 / / 83 Beta blocker159 / / 81 difference0 / 01 / 1 pn.s. n.s. / p=0.02 Mean Blood Pressure

Any diabetes-related endpoints risk reduction 24% p=0.0046

Diabetes-related deaths risk reduction 32% p=0.019

Any DM-related endpoint24% p= Diabetes-related deaths32%p=0.019 Stroke44%p=0.013 Microvascular disease37%p= Heart failure56%p= Retinopathy progression34%p= Deterioration of vision47%p= Blood Pressure Control Study

Blood Pressure Study ACCORD ACCORD Study Group. NEJM 2010

ACCORD BP Trial ACCORD Study Group. NEJM 2010  4,733 patients with DM2; high CVS risk  SBP 130 – 180  Randomized to target SBP <140 v. <120  Primary outcome: nonfatal MI, nonfatal CVA; CVS death  Follow-up: 4.7 years; 95% complete

Baseline Characteristics <120<140 N Age62 % females48% Hx CVS event34%33% SBP Duration DM910 GHb (%)8.48.3

ACCORD BP Trial ACCORD Study Group. NEJM 2010  Achieved SBP: 119 v. 133  Antihypertensive medications: 3.4 v. 2.3

ACCORD BP Trial ACCORD Study Group. NEJM 2010  Achieved SBP: 119 v. 133  Antihypertensive medications: 3.4 v. 2.3  Primary outcome:  Nonfatal MI, nonfatal CVA, CVS death (%/year):  1.9% v. 2.1%; HR 0.88 (0.73 – 1.06, p=0.20)

ACCORD BP Trial: Outcomes ACCORD Study Group. NEJM 2010  Nonfatal MI, nonfatal CVA, CVS death (%/year):  1.9% v. 2.1%; HR 0.88 (0.73 – 1.06, p=0.20)  Total mortality: 1.3% v. 1.2%, p=0.55  CVS death: 0.5% v. 0.5%  Stroke: 0.3% v. 0.5%, p=0.01

ACCORD BP Trial: Conclusion ACCORD Study Group. NEJM 2010  Targeting a SBP < 120, as compared to a SBP < 140, does not improve CVS outcomes in patients with DM2 at high risk of CVS events

Lipid Therapy Study ACCORD ACCORD Study Group. NEJM 2010

ACCORD Lipid Trial ACCORD Study Group. NEJM 2010  5,518 patients with DM2; high CVS risk  LDL 1.5 – 4.6; HDL < 1.4; TG < 8.5  All patients received open label simvastatin  Randomized to fenofibrate (160 mg) v. placebo  Primary outcome: nonfatal MI, nonfatal CVA; CVS death  Follow-up: 4.7 years

Baseline Characteristics FenofibratePlacebo N Age62 % females31% Hx CVS event36%37% LDL2.6 HDL1.0 TG2.1

ACCORD Lipid Trial ACCORD Study Group. NEJM 2010  Achieved LDL: 2.1 v. 2.1  Achieved HDL: 1.1 v. 1.0  Achieved TG: 1.7 v. 1.9

ACCORD Lipid Trial ACCORD Study Group. NEJM 2010  Achieved LDL: 2.1 v. 2.1  Achieved HDL: 1.1 v. 1.0  Achieved TG: 1.7 v. 1.9  Primary outcome:  Nonfatal MI, nonfatal CVA, CVS death (%/year):  2.2% v. 2.4%; HR 0.92 (0.79 – 1.08, p=0.32) Total mortality: 1.5% v. 1.6%, p=0.33

ACCORD Lipid Trial: Outcomes ACCORD Study Group. NEJM 2010  Nonfatal MI, nonfatal CVA, CVS death (%/year):  2.2% v. 2.4%; HR 0.92 (0.79 – 1.08, p=0.32)  Total mortality: 1.5% v. 1.6%, p=0.33

ACCORD Lipid Trial: Outcomes ACCORD Study Group. NEJM 2010 Pre-specified subgroups:  Sex:  Men: 11.2% v. 13.3%  Women: 9.1% v. 6.6%, p=.01  Dyslipidemia (HDL 2.3):  Dyslipidemia patients: 12.4% v. 17.3%  Non-dyslipidemic patients: 10.1% v. 10.1%, p=.057

ACCORD Lipid Trial: Conclusions ACCORD Study Group. NEJM 2010  Routine fenofibrate therapy, in addition to simvastatin, does not improve CVS outcomes in patients with DM2 at high risk of CVS events  Addition of fenofibrate to simvastatin may benefit patients with significant dyslipidemia

Glycemic control BP control Lipid management Conclusions