 Type 2 Diabetes in 2014 Dr. James Mather Clinical Lead for Diabetes SWCCG

2 Diabetes in the UK * Approximately 2.61 million adults suffer from type 2 diabetes in the UK (2011) 1 It is estimated that there are around 850,000 people in the UK who have type 2 diabetes but have not been diagnosed 1 By 2025, it is estimated that 5 million people will have diabetes in the UK 1 1. Diabetes in the UK 2011/2012: key statistics in diabetes

The Challenge of Diabetes 4.2% of population in Wales (1/2 million undiagnosed nationally) prevalence increasing 80% costs related to diabetes complications 8-10% total healthcare costs > £5 billion pa Alcohol £3 Smoking £1.5 Cost pa £billions Diabetes £5.2 MAJOR PUBLIC HEALTH PROBLEM

5 Diabetes and obesity are closely interlinked Relationship between BMI and risk of type 2 diabetes Age-adjusted relative risk of diabetes Normal weightOverweightObese <2222–22.923–23.924–24.925–26.927–28.929–30.931–32.933–34.9 ≥35 BMI Men 2 Women 1 BMI, body mass index. 1. Colditz GA, et al. Ann Intern Med 1995;122:481–6; 2. Chan J, et al. Diabetes Care 1994;17:961–9.

Environmental Causes of Obesity Gluttony or Sloth?

Bariatric Surgery  New NHS service at WRH  Martin Wadley and Anthony Perry  PCT funding is for 50 patients per year-BMI>55kg/m2  Only proven intervention to cure T2DM  Life-changing cost-effective intervention IF THE RIGHT PATIENTS ARE CHOSEN

Steno 2-Multiple risk factor intervention trial: NEJM Jan 2003  All had microalbuminuria  Behaviour modification (smoking, diet,exercise)  Glycaemic control (HbA1c 7.0%)  BP control (< 130/80 vs. 135/85 in conventional)  Lipids (fasting Chol < 4.5, TG < 1.7)  Microalbuminuria treated with ACE  Aspirin 150 mg

10 Steno 2: Event Reduction 53 % 61% 58% 67% cardiovascular disease nephropathyretinopathyautonomic neuropathy Number of events

11 Steno-2 : Conclusion “ A target driven, long-term, intensified intervention aimed at multiple risk factors in …type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50%.”

12 Non-Adherence to Medications In the background-we assume pts are doing as instructed Health gains foregone in England in 5 LTC are approx $930 million per year-$100 million for T2DM and $400 million for hypertension Estimated that improving adherence to 80% would save the NHS in England $500 million per year Worth enquiring about

13 HBGM-Who needs it? National scrutiny of prescribing suggests that we are not following guidance We could save a lot of money and still do the best job for our patients-the figures are staggering HBGM is indicated for patients treated with: Insulin and SUs You may have some unusual characters who want to plot graphs when they are on metformin alone-discussion about the pros and cons need to be blunt INSULIN or SULPHONYLUREAS. (This is a fullstop).

14 The role of the kidney in type 2 diabetes and SGLT2 inhibition

15 Normal renal glucose handling 1–3 SGLT, sodium-glucose co-transporter. 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21. SGLT2 Glucose Majority of glucose is reabsorbed by SGLT2 (90%) Proximal tubule Remaining glucose is reabsorbed by SGLT1 (10%) Minimal to no glucose excretion Glucose filtration

Existing and novel mechanisms to reduce hyperglycaemia in type 2 diabetes 1−4 Insulin sensitisers Thiazolidinediones Metformin Insulin releasers Sulphonylureas GLP-1R agonists* DPP-4 inhibitors* Meglitinides Insulin replacement Insulin Glucose utilisation Insulin-dependent mechanisms Adipose tissue, muscle and liver Pancreas Insulin-independent mechanism SGLT2 inhibition Glucose excretion/caloric loss *In addition to increasing insulin secretion, which is the major mechanism of action, GLP-1 agonists and DPP4 inhibitors also act to decrease glucagon secretion. DDP-4, dipeptidyl peptidase-4; GLP-1R, glucagon-like peptide-1 receptor. 1. Washburn WN. J Med Chem 2009;52:1785–94; 2. Bailey CJ. Curr Diab Rep 2009;9:360–7; 3. Srinivasan BT, et al. Postgrad Med J 2008;84:524–31; 4. Rajesh R, et al. Int J Pharma Sci Res 2010;1:139–47.

17 Dapagliflozin: A novel insulin-independent approach to remove excess glucose Proximal tubule Glucose filtration 1. FORXIGA Summary of Product Characteristics Dapagliflozin selectively inhibits SGLT2 in the renal proximal tubule 1 SGLT2 Glucose Dapagliflozin SGLT2 Dapagliflozin Increased urinary glucose excretion

18 The benefits of dapagliflozin’s novel mechanism of action Dapagliflozin offers an insulin-independent mechanism that can be used as add-on therapy 1,4 Dapagliflozin inhibition of SGLT2 results in daily urinary glucose excretion of approximately 70g, 2 providing: Significant and sustained HbA 1c reductions versus placebo when added to metformin 1,3 Secondary benefit of weight loss 1 1. Bailey CJ, et al. Lancet 2010;375:2223–33; 2. List JF, et al. Diabetes Care 2009;32:650–7; 3. Bailey CJ, et al. Poster 988-P. Poster presented at 71st Scientific Sessions of the American Diabetes Association, San Diego, California, 24–28 June, FORXIGA Summary of Product Characteristics

19 Dapagliflozin is indicated in adults aged 18 and over with type 2 diabetes to improve glycaemic control as: Add-on combination therapy 1 In combination with other glucose ‑ lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. Monotherapy 1 When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance 1. FORXIGA Summary of Product Characteristics The use of dapagliflozin with pioglitazone is not recommended. Dapagliflozin has not been studied in combination with DPP-4 inhibitors or GLP-1 analogues.

20 Dapagliflozin dosing FORXIGA Summary of product characteristics Dapagliflozin 10mg daily can be used in patients with mild or moderate hepatic impairment In patients with severe hepatic impairment, a starting dose of 5 mg is recommended. If well tolerated, the dose may be increased to 10 mg No known pharmacokinetic drug–drug interactions with other commonly prescribed type 2 diabetes treatments

21 Summary. 1. Bailey CJ, et al. Lancet 2010;375:2223–33; 2. Bailey CJ, et al. Poster 988-P. Poster presented at 71st Scientific Sessions of the American Diabetes Association, San Diego, California, 24–28 June, 2011; 3. FORXIGA. Summary of product characteristics; In patients with type 2 diabetes uncontrolled on metformin FORXIGA ® (dapagliflozin) offers; Significant and sustained HbA 1c reductions 1-3 Secondary benefit of weight loss 1-3 Low incidence of hypoglycaemia when added to metformin 1 Oral, once daily dosing 3 1-4

Insulin Use in Type 2 Diabetes

This document is designed to aid product choice when using insulin in type 2 diabetes. The most cost effective product in each section is highlighted in green although the decision to prescribe a particular insulin may be influenced by the choice of delivery device. For example, elderly people with dexterity or visual problems may find an injection device with a large visible dial easier to use.

Start with human isophane insulin (NPH) taken at bedtime or twice daily according to need. Human Isophane Insulins (Intermediate acting) Pre-filled Pens Insuman Basal SoloSTAR5 x 3ml£19.80 Humulin I KwikPen5 x 3ml £21.70 Cartridges Insuman Basal Cartridge (Autopen 24 & ClickSTAR)5 x 3ml£17.50 Humulin I Cartridge ( Autopen Classic or HumaPen range)5 x 3ml£19.08 Insultard Penfill Cartridge (NovoPen 3 demi, NovoPen Junior or NovoPen 4)5 x 3ml£22.90 Vials Insulatard Vial10ml £7.48 Insuman Basal vial5ml£5.61 Humulin I Vial10ml£15.68

Consider a once-daily long-acting insulin analogue (insulin detemir, insulin glargine) if:  the person needs help with injecting insulin and a long-acting insulin analogue would reduce injections from twice to once daily, or  the person's lifestyle is restricted by recurrent symptomatic hypoglycaemic episodes, or  the person would otherwise need twice-daily basal insulin injections plus oral glucose-lowering drugs, or  the person cannot use the device to inject NPH insulin. Long-acting insulin analogues are considerably more expensive than isophane insulin.

Long Acting Analogues Pre-filled Pens Insulin glargine (Lantus SoloSTAR)5 x 3ml£41.50 Insulin detemir (Levemir FlexPen) 5 x 3ml£42.00 Insulin detemir (Levemir InnoLet) 5 x 3ml£44.85 Cartridges Insulin glargine cartridge (Autopen 24 and ClickSTAR)5 x 3ml£41.50 Insulin detemir cartridge (NovoPen 3 demi, NovoPen Junior or NovoPen 4)5 x 3ml£42.00 Vials Insulin glargine vial10ml £30.68

Consider switching to a long acting analogue from human isophane insulin if the patient:  does not reach target HbA1c because of hypoglycaemia or  has significant hypoglycaemia with human isophane insulin irrespective of HbA1c or  cannot use the delivery device for human isophane insulin but could administer a long acting analogue or  needs help to inject insulin and could reduce the number of injections with long acting analogues.

A biphasic preparation containing a soluble insulin and an isophane insulin might be considered first-line if the person's diabetic control is particularly poor — for example, when glycated haemoglobin (HbA1c) is more than 9.0% (75 mmol/mol). For people taking isophane insulin or a long-acting analogue, a switch to a biphasic insulin preparation should be considered if:  Their HbA1c remains above target — particularly if the value is 9% (75 mmol/mol) or more, or  They have persistent post-prandial hyperglycaemia (greater than 8.5 mmol/L).

 Biphasic preparations of soluble insulin and isophane insulin Pre-filled Pens Insuman Comb 25 SoloStar5 x 3ml£19.80 Humulin M3 KwikPen 5 x 3ml£21.70 Cartridges Insuman Comb 15 Cartridges (Autopen 24 & ClickSTAR)5 x 3ml£17.50 Insuman Comb 25 Cartridges (Autopen 24 & ClickSTAR)5 X 3ml£17.50 Insuman Comb 50 Cartridges (Autopen 24 & ClickSTAR) 5 x3ml£17.50 Humulin M3 Cartridge ( Autopen Classic or HumaPen range)5 x 3ml£19.08 Vials Insuman Comb 25 Vial5ml £5.61 Humulin M3 Vial10ml£15.68 Only consider prescribing a biphasic insulin preparation containing a rapid-acting analogue (insulin aspart or insulin lispro) if any of the following apply: The person prefers to inject the insulin immediately before a meal. Hypoglycaemia is a problem. Blood glucose levels increase markedly after meals.

Pre-filled Pens NovoMix 30 (Aspart/protamine insulin)5 x 3ml£29.99 Humalog Mix 25 KwikPen (lispro/protamine insulin) 5 x 3ml£30.98 Humalog Mix 50 KwikPen (lispro/protamine insulin) 5 x 3ml£30.98 Cartridges NovoMix 30 Penfill Cartridge (NovoPen 3 demi, NovoPen Junior or NovoPen 4)5 x 3ml£28.84 Humalog Mix 25 Cartridge ( Autopen Classic or HumaPen range)5 x 3ml£29.46 Humalog Mix 50 Cartridge ( Autopen Classic or HumaPen range)5 x 3ml£29.46 Vials Humalog Mix 2510ml £16.61

Consider intensifying insulin treatment with a short-acting insulin if there is post-prandial hyperglycaemia or if glycated haemoglobin (HbA1c) levels remain elevated despite optimum titration of a basal insulin or a biphasic insulin. Add a short-acting insulin to the basal regimen, usually given with the largest meal. If this is insufficient, the short-acting insulin can be added sequentially to the second and third largest meals (leading to a basal bolus regimen).

Short-acting soluble insulins (also known as regular, rapid-acting, or neutral insulins) Pre-filled Pens Insuman Rapid cartridge (Autopen 24 and ClickSTAR)5 x 3ml£17.50 Humulin S cartridge (Autopen Classic or HumaPen range) 5 x 3ml£19.08 Vials Actrapid vial10ml £7.48 Humulin S vial10ml £15.68 Rapid-acting analogues Pre-filled Pens Insulin glulisine (Apidra SoloSTAR) 5 x 3ml£28.30 Insulin Lispro (Humalog KwikPen) 5 x 3ml£29.46 Insulin Aspart (NovoRapid FlexPen) 5 x 3ml£30.60 Insulin Aspart (NovoRapid FlexTouch) 5 x 3ml£32.13 Cartridges Insulin glulisine (Autopen 24 and ClickSTAR)5 x 3ml£28.30 Insulin Lispro ( Autopen Classic or HumaPen range)5 x 3ml£28.31 Insulin Aspart (NovoPen 3 demi, NovoPen Junior or NovoPen 4)5 x 3ml£28.31 Vials Insulin glulisine vial10ml £16.00 Insulin Aspart vial10ml £16.28 Insulin Lispro vial10ml £16.61

 References  NICE Clinical Guideline 87. Type 2 diabetes. May 2009  Clinical Knowledge summaries accessed at: diabetes

 Ultra long acting basal analogue insulin  Twice the price of insulin glargine  This insulin is designed to be given daily or in some cases alternate days  It’s place is in patients T1 or T2 who cannot achieve optimal control with other insulins without significant nocturnal hypos  Studies show a significant drop in severe nocturnal hypos in both T1 and T2  Expensive but in the correct patients will save money and improve life quality

My Two Cents  Basic principles still apply- Steno 2 shows we can make a real difference  Never under-estimate the power of weight loss at diagnosis  Therapeutic options after weight loss are varied  Bariatric surgery cures type 2 diabetes  Newer treatments have a place if used in the right patients.