Diabetes: a therapeutic framework

Understanding Type 1 and Type 2
Diabetes and Disease Progression
Buge Apampa PhD MRPharmS Some Questions to start off! 1. How many people are expected to have diabetes in the UK by 2025? [5m] 2. What is the estimated hourly cost of diabetes to 3. How many diabetic patients are dying avoidably each year? [24,000] 4. How many parameters must be checked annually in diabetic patients? [9] 5. What % of patients treated with insulin for < 2y reported a hypoglycaemic episode? [51%] Objectives
•Burden of Diabetes Mellitus •Refresher of Type 1 & Type 2 DM •Evidence base for management •Optimising your professional role Burden of Diabetes Mellitus Commonest
Single largest cause
of blindness
Kidney Disease
Stroke – 2-4 x
Heart attack: 2-4 x death
increased risk
• 10% of NHS budget • 2002- NHS spend of £1.3 billion • 2011- NHS spend on diabetes nearly £10 • Net ingredient cost of £760.3m (9% of all total cost of Rxs) NICE 2008 Targets Average 6.5% 48 mmol/mol Total Cholesterol Nine Diabetes Checks 1. Blood pressure 2. Weight and waist circumference 4. HbA1C 5. Urinary albumin 6. Serum creatinine 7. Foot & leg check 8. Smoking status 9. Eyes- retinal screening National Diabetes Audit • Reviewed records of 1.7m diabetics in England & Wales for 9 recommended checks • 50% of Type 2 DM received the checks • 33% of Type 1 DM received the checks • Completion influenced by ethnicity & age • Younger people less likely to receive checks Preventing additional deaths in people
with Diabetes (Diabetes health Intelligence YHPHO)
• England 2011, diabetics had 39.9% greater risk of dying compared to general population • Over 20,000 additional deaths among diabetics • If all PCTs with highest additional risk of diabetics dying reduced the risk to the England ave 2150 fewer deaths in 2011

Preventing Disease Progression: Is there a Role for Pharmacists? Some Facts about Diabetes • About 3 million people with diabetes in UK • Represents 72% of estimated prevalence • 12 times more type 2 than type 1 • Prevalence increasing- ageing population and obesity • 8% Type 1 diabetes - can occur at any age after 18m but has peak incidence in children aged10-15y • 92% Type 2 diabetes • 850,000 thought to be undiagnosed • 40% increased prevalence among people in deprived • Prevalence of diabetes nearly 4 times higher than prevalence of all cancers combined Possible signs/symptoms of diabetes • Increased thirst • Polyuria • Recurrent infection • Diabetic complication • Weight loss • Extreme tiredness or lethargy • Slow wound healing • Itchy skin rash • Blurred vision • Tingling pain & numbness in feet, legs or hands WHO diagnostic thresholds for venous plasma glucose (mmol/l) Diabetes ≥ 7.0
≥11.1 ≥11.1
Impaired N/A
< 11.1 ≥7.8
Impaired 6.1-<7.0
48 mmol/mol by food
Type 1 vs. Type 2 diabetes Lambert P, et al. Medicine 2006; 34(2): 47-51 Nolan JJ. Medicine 2006; 34(2): 52-56 Features of type 1 diabetes
Features of type 2 diabetes
Usually presents in over-30s (but
also seen increasingly in younger childhood/adolescence • Lean body habitus • Associated with overweight/obesity • Acute onset of osmotic • Onset is gradual and diagnosis often missed (up to 50% of cases) • Ketosis-prone • Not associated with ketoacidosis, though ketosis can occur • High levels of islet • Immune markers in only 10% • Family history is often positive with • High prevalence of genetic almost 100% concordance in 1. Gestational diabetes: Diabetes first diagnosed in pregnancy irrespective of cause 2. Latent autoimmune diabetes of adults (slowly progressing type 1?) 3. Type 2 diabetes presenting with diabetic ketoacidosis (common in UK black population; acute partial temporary β-cell failure; complete remission) 4. Type 2 diabetes presenting in children and Complications of Diabetes Disease Progression • In the late 80s, 44% o f patients in the West with type 2 DM, died within 10 years of diagnosis mostly due to macrovascular disease • Incidence & mortality from CVD 2-3 x greater than the general population • Complications present in up to 50% at • Other risk factors for CVD (hypertension, hyperlipidaemia) present • Long term damage of eyes, kidney, nerves, heart and blood vessels UKPDS: Progressive Deterioration in Glycemic Control Over Time Macrovascular Complications • More common in Type 2
• Myocardial infarction • Ischaemic heart disease • Cerebrovascular disease • Peripheral vascular disease Microvascular Complications • More common in Type 1

• Retinopathy present in all patients after 20
years. Can lead to blindness • Nephropathy accounts for 1 in 4 kidney • 40% Type 1 and 20% Type 2 develop end stage renal disease • Neuropathy (nerve pain, amputation, ED)

Type 1 Diabetes - A Refresher Type 1 Diabetes
• Autoimmune destruction of pancreatic β cells (viral or autoimmune) • Immediate and permanent requirement for • Insulin requirement may be minimal during ‘honeymoon' period (6-18 months after diagnosis) • Fatal if not treated Clinical presentation • Rapid/abrupt onset of acute osmotic symptoms • Ketonuria and / or metabolic acidosis at presentation • Unintentional weight loss which may or may not be accompanied by ketoacidosis • Vascular complications not evident at presentation Pharmacotherapy-Type 1 DM
• Insulin: all Type 1 DM will require insulin • Subcutaneous route is preferred however intravenous route is used (soluble insulin) in emergencies • 3 main types of insulin available: • Short acting - soluble insulin, lispro and aspart, • Intermediate - isophane zinc and insulin zinc susp. • Slower onset and longer acting - crystalline insulin zinc susp, detemir, glargine Goals of Insulin Treatment
• To mimic both types of insulin secretion • Require basal insulin and meal-related insulin • General requirements: 1unit/kg/24h in type 1 • Insulin analogues e.g. Humalog, NovoRapid → better mimic physiological profile of insulin, improved control • More convenient for patients, can be used 15mins before to immediately after a meal • Reduced frequency of "hypos" due to shorter Approximate pharmacokinetic profiles of human insulin and insulin analogues Hirsch IB. N Engl J Med 2005; 352: 174-83 N.B. Duration of action will vary widely between and within people NPH = neutal protamine hagedorn/isophane insulin Insulin choices in adults: • Meal time insulin
– soluble – rapid acting analogues where "hypos" a • Basal Insulin
– Isophane (NPH) at bedtime or bd – Long acting analogues (glargine) where night time "hypos" or morning "hypers" a problem with NPH or rapid acting meal time analogues used NICE Insulin Regimens • Multiple insulin injections: for adults who prefer
them as part of an integrated package of education, food, skills training and self-monitoring
Twice-daily insulin regimens:
1. for those who find adherence difficult
2. adults with learning difficulties who may require
3. where no of injections is a quality of life issue 4. Biphasic insulin preparations are often the preparation of choice 5. Biphasic rapid-acting insulin analogue premixes may give an advantage to those prone to hypoglycaemia at Supporting Evidence Base: DCCT 1993
• Intensive treatment vs conventional
• 1,441 patients with Type 1 diabetes, mean age 27
Active group- insulin 3-4 times a day with >4 blood
tests a day supported by monthly clinics • Control group received twice daily insulin and
standard monitoring • 60% reduction in microvascular complications
• 44% reduction in macrovascular complications
Conclusion: Tight control with intensive insulin therapy
reduces development & progression of microvascular outcomes Factors affecting insulin requirements Increased insulin
Decreased insulin requirements
• Renal failure • Adrenal insufficiency • Increased exercise • Inactivity • Hyperthyroidism • Cushing disease Type 2 Diabetes - A Refresher Type 2 Diabetes
• Relative insulin deficiency due to disorders of insulin action (insulin resistance) or secretion • Progressive disease; β cell dysfunction to IGT to T2DM • β cell dysfunction starts before blood glucose rises and worsens after diabetes develops • Failure of β cell to adequately compensate for insulin • Strong genetic basis for β cell failure (Asians, Middle Eastern, African-Caribbeans & Africans) • Linked to hypertension and obesity (most common cause of insulin resistance) Risk factors for Type 2 diabetes
• Obesity, BMI > 30; 47% of Type 2 DM in England (NAO) • Age (> 40 if white; > 25 if black, asian) • Waist measurement > women 31.5in; 35in Asian men; 37in white or black men • Sedentary lifestyle – 30-40% increased risk • Ethnicity: African-Caribbean, South Asian, Middle • Family history – 1st degree relative Other Risk Factors for Type 2 diabetes
• Social deprivation- diabetes-related mortality higher in lower SEGs • Large birth weight baby > 4.5kg • Previous gestational diabetes • Hypertension or dyslipidaemia (metabolic • Impaired fasting glycaemia and impaired glucose tolerance Clinical Presentation • Onset of osmotic symptoms over a variable period • Positive family history- 1st degree relatives • Variable weight loss • Glucose excellent medium for microbial growth - presenting symptoms may include recurrent vaginal, respiratory infections • Hypergylcaemia – 7-10 years pre-diagnosis • 20% have microvascular or macrovascular complications Selected evidence base for Type 2 • Finnish, DPP, Da Qing: Intensive lifestyle intervention studies • UKPDS: Blood glucose and BP in patients with • ACCORD & ADVANCE: Impact of intensive glucose lowering in patients with high cardiovascular risk • VADT: Impact of intensive glucose lowering in patients with low cardiovascular risk • HOPE: (Ramipril) • HPS (Simvastatin) 1. Lifestyle intervention
• Intensive lifestyle interventions prevent or
delay risk of progression to diabetes
• 42% reduction in Da Qing Study (China, 1997) • 58% reduction in Finnish Diabetes Prevention • 58% reduction Diabetes Prevention Program 2. UKPDS, 1998
• 20 year multi-centre RCT involving 5102 patients with type 2 diabetes aged 25-65 years • Randomised to intensive treatment or diet only therapy • Research question:
1. Would intensive glycaemic control &/or tight BP control
reduce the risk of complications? 2. Does any specific treatment for blood sugar or blood pressure control confer particular benefit? 2.1 UKPDS findings: Blood
SU/Insulin vs conventional treatment lasted
• Lowering blood glucose reduced risk of; – Eye disease by 25% – Kidney disease by 25% • Every 1% reduction in HbA1c reduced; – Retinopathy, neuropathy & nephropathy by 2.2 UKPDS findings: Metformin
• Median follow up was 10.7 years • Metformin compared with conventional treatment (diet) reduced the risk of: • Any diabetes-related endpoint by 32%
• Diabetes –related death by 42%
• All cause death by 36%
• Myocardial infarction by 39%
Conclusion: MTF decreases the risk of death and
of having an MI, but not the risk of microvascular

• ACCORD study: Intensive therapy (A1c < 6%) led to increased mortality • No effect on primary endpoint (MI, stroke or CV death) • ADVANCE study: Intensive therapy (A1c < 6.5%) had no significant effect on macrovascular events or all-cause mortality, but it did reduce nephropathy • VADT study, 2009:Tight control of glucose did not reduce the risk of major CV events, microvascular complications or death • Patients in the intensive treatment arm were more likely to experience hypoglycaemic episodes 5. UKPDS: Blood Pressure
UKPDS: Tight BP control decreased the risk of diabetes
related death, stroke and microvascular disease • Lowering blood pressure reduced – Any diabetes related end point by 24% – Diabetes-related deaths by 32% – Strokes by 44% – Diabetes-related microvascular end points by 37% • HOPE study: Ramipril significantly reduced the risk of MI,
stroke or CV death cf placebo – MI 33% – Stroke 33% – CV death 37% • HPS: In high-risk patients with a wide range of baseline cholesterol values • Simvastatin 40mg reduced: • All-cause mortality • Coronary deaths • Major vascular events 7. Diastolic BP and Aspirin
• HOT trial: In patients with diabetes • Lowering DBP to 80mmHg – Reduced risk of major CV events by 51% • Aspirin 75mg – Reduced major cardiovascular events by – Reduced MI by 36% (P=0.002) – no effect on stroke incidence Pharmacotherapy of Type 2 Goals of management www.npci.org.uk • Manage symptoms • Prevent acute and late complications • Improve quality of life • Avoid premature diabetes-associated death • An individualised approach (e.g. diet & exercise) Microalbuminuria Key Actions to Prevent progression of Type 2 diabetes 1. Intensive lifestyle intervention 3. Statin therapy 4. Metformin and aspirin 5. Blood glucose control 3 Add statin
4 Add metformin
2 Control BP
(and aspirin if
5 consider
tight glucose

1 Lifestyle
(exercise, diet,
stop smoking)
Let's give our diabetic patients a hand!

Lifestyle modification • Weight reduction (5-10%) if • Low GI CHO - pasta, basmati, oats, beans, peas, lentils, seeds • Replace saturated fats with mono-unsaturated fats • Fruits & vegetables- 5 portions • Regular intake of fish • Less than 6g salt/day • Portion control • Control alcohol intake: 3u/2u

Lifestyle modification: Activities of daily living • Moderate intensity exercise 150 min / 5 days • More walking, cycling, swimming, gardening • Reduce sedentary • Stop Smoking 2. BP: Choice of antihypertensive NICE Diabetes Clinical Guideline 66;May 2008. NICE Full Diabetes • BP target: <140/80 or <130/80 if complications • First-line BP lowering therapy should be a once-daily, generic ACE inhibitor • Exceptions to this are: – People of African / African-Caribbean descent – Who should receive an ACE inhibitor plus either a diuretic or a calcium-channel blocker (CCB) • Women for whom there is a possibility of becoming pregnant, who should receive a CCB • Intolerance in the form of troublesome cough, substitute an angiotensin-II receptor antagonist for the ACE inhibitor Most patients will be on ACEI, diuretic and one other BP drug
3. Management of blood lipids NICE Diabetes Clinical Guideline 66;May 2008. NICE Full Diabetes • Overwhelming evidence that statins prevent CV events • Generic simvastatin (to 40mg) or a statin of similar efficacy and cost should be initiated in people: Aged under 40 years with poor CV risk factor profile Aged 40+ years with low CV risk for someone with type 2 diabetes but CV risk assessed as > 20% over 10 years using UKPDS risk engine Aged 40+ years and normal to high CV risk for someone with type 2 diabetes Increase dose to simvastatin 80mg daily unless total cholesterol <4.0mmol/L or LDL-cholesterol <2.0mmol/L Management of blood lipids NICE Diabetes Clinical Guideline 66;May 2008. NICE Full Diabetes • Intensify therapy with a more effective statin or
ezetimibe if existing or newly diagnosed CV disease or increased albumin excretion rate • To achieve a total cholesterol level below 4.0mmol/L or LDL-cholesterol level below 2.0mmol/L • If TG levels remain above 4.5 mmol/L despite attention to other causes, prescribe a fibrate
Fibrate may be added to statin therapy if TG levels
remain in the range 2.3–4.5 mmol/L despite statins 3. Statin Therapy • Not in patients considered at low CV risk • Not overweight • No microalbuminuria • No history of CVD • No family history of CVD • Normotensive (BP<140/80) • No high-risk lipid profile • At high risk unless all above apply 4. Antithrombotic Therapy NICE Diabetes Clinical Guideline 66;May 2008. NICE Full Diabetes • Aspirin 75mg or if intolerance, clopidogrel should be initiated in people: 1. Aged 50+ years with BP < 145/90 mmHg 2. Aged < 50 years with significant CV risk factors such features of metabolic syndrome, strong early family history of CV disease, receiving treatment for hypertension, smokers Antithrombotic Therapy • Aspirin is not licensed for the primary prevention of vascular events • If used in primary prevention, the balance of benefits and risks should be considered for each individual • Presence of risk factors for vascular disease (including conditions such as diabetes) and the risk of gastrointestinal bleeding 5. Pharmacotherapy:
Blood Glucose
• OHAs may be classed according to their mode of 1. Improve sensitivity to insulin: Biguanides & glitazones 2. Insulin secretagogues: Sulphonylureas & meglitinides 3. Reduce glucose absorption: Acarbose 4. Incretins: GLP-1 analogues & DPP4 inhibitors 5. Sodium- glucose co-transporter 2 (SGLT2) inhibitor: Dapagliflozin - reversible inhibitor (monotherapy and in combination with insulin and other antidiabetics except PIO) 6. Insulin: commonly used in combination with OHA Strongly preferred when dual therapy fails Drug treatment for blood glucose control Based on NICE Clinical Guideline 87; May 2009 and MeReC Bulletin Vol. 21, No. 5, Third-line

NPH insulin*
or other higher level Safety and
metformin plus
(48mmol/mol) or other higher level First-line
*other options are available in specific circumstances UKPDS: Progressive Deterioration in Glycemic Control Over Time

Newer agents: Incretins • Dual & Triple Therapy • GLP-1 agonists & DPP-4 inhibitors • Clinical Effects: • Reduce post-prandial hyperglycaemia • Increase glucose-mediated insulin secretion • Suppress glucagon secretion, slow gastric emptying • Decrease appetite • DPP-4 inhibitors (sitagliptin, vildagliptin): continue use only if HbA1c lowered by ≥ 0.5% in 6 months • Exenatide: continue use only if HbA1c lowered by ≥ 1.0% & ≥ 3% initial body weight in 6 months GLP-1 agonist: Exenatide 5-10ug bd Dual therapy with MTF, SU or PIO • Triple therapy with MTF + SU if BMI ≥35 or BMI < 35 and insulin not acceptable or weight loss necessary • Practice points: 1. s.c.injection within 60 min before meals 2. Missed doses must not be compensated • Safe in liver impairment & renal impairment where eGFR 3. Enteric coated formulations, OC, antibiotics- to be taken 1hour before or 4h after exenatide • Advantages: Weight loss, low risk of hypos except when used with SU or SU/MTF • Adverse effects: Nausea in 60% of patients; rarely acute pancreatitis (persistent severe abdominal pain) GLP-1 agonist: Liraglutide 0.6mg-1.2mg OD • Once daily administration independent of meals • Dual therapy with MTF or SU • Triple therapy with MTF & SU or MTF & PIO • Not recommended in hepatic impairment • Renal impairment: use only if eGFR>60ml/min • Adverse effects: Nausea • Liraglutide 1.8mg not recommended Insulin Therapy in T2DM • Persistent symptoms - hyperglycaemia, lethargy, muscle weakness despite maximal dual therapy or during intercurrent illness • Known safety profile, superior glycaemic control not proven in trials or often evident in practice • Similar glycaemic benefits as non-insulin combination • Does not improve microvascular/macrovascular outcomes compared with other agents with similar A1C effects Insulin initiation in type 2 diabetes • Preferred 3rd line (after MTF + SU)
NPH insulin- preferred basal insulin; at bedtime or bd
• To start:
• Continue with optimised MTF or SU
• Start fixed dose basal insulin (10-16units) at bedtime
• Insulin titrated at a fixed rate (e.g. 2 units/week) or a %
(e.g. 10% of existing dose) • Individualised fasting glucose targets (e.g. 5.5 – 6.0 • Low starting dose but will increase with time (up to • Weight gain (4-6kg) over 3-6 years • A1c lowering of 1.5% (17mmol/mol) Other Insulin Regimens in T2DM Once daily long acting insulin analogue (detemir or glargine )
for patients :
– Help with injecting
– Recurrent symptomatic hypos which severely affects their
– Unable to use the Isophane injection device – Require basal insulin injections BD as well as oral therapy Biphasic human insulin (biphasic isophane insulin) once or
twice daily (if HbA1c ≥9%) is another option
Biphasic insulin analogues (e.g. biphasic insulin aspart):
– If immediate injection before meal is preferred
– Hypos are a problem
– Post prandial hyperglycaemia is an issue
Preventing Disease Progression: Optimising your professional role – Identifying the estimated 850,000+ undiagnosed, health checks, spreading awareness • Adherence support: – 73.3% increase in diabetes Rx items over the last 6 years – 30-50% of dispensed items not taken as intended – OHA: 70% of people do not take them as prescribed – MURs, NMS, what else? • Structured Education: Signposting, enhanced service • Smoking: Status checks & support • PHARMACEUTICAL CARE??? – DTPs: Appropriateness, effectiveness, safety Diabetes Care: The Alphabet Strategy (George Elliot Hospital NHS Trust) • Advice- smoking, diet, alcohol, exercise, weight, education, driving • Blood Pressure - <130/80 • Cholesterol – TC <4; HDL normal • Diabetes Control – A1c < 6.5%; avoid hypos • Eye Screening - annual • Feet Screening - annual Guardian Drugs – ACEI, ARB, Cholesterol lowering

Thank You, Any Questions?

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