GALVUS Learning System

Physiology and Pathophysiology of Diabetes

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The Competitor Market

The prevalence of T2DM is expected to increase from 366 million patients in 2011 to 552 million patients by 2030. A number of pharmacologic treatments with different mechanisms of action are available for the treatment of T2DM, such as biguanides, secretagogues, TZDs, alpha-glucosidase inhibitors, GLP-analogues, DPP-4 inhibitors, and insulin. SGLT2 inhibitors have also recently become available for the treatment of T2DM, with the approval of dapagliflozin in the EU market in 2012. Historically, DPP-4 inhibitors have recorded the biggest increase in market share from approximately 3% in 2007 to 17% in 2011. It is projected that incretins (ie, DPP-4 inhibitors and GLP-1 analogues) will experience the biggest increase in market share from 20% in 2010 to 44% in 2020.

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Physiology and Pathophysiology of Diabetes
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Biguanides
Metformin is thought to act as an antihyperglycaemic by way of three different mechanisms: o Reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis o In muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation o Delay of intestinal glucose absorption Metformin is indicated for the treatment of T2DM, particularly in overweight patients, when dietary management and exercise alone do not result in adequate glycaemic control. Metformin carries a black-box warning for lactic acidosis, which is a rare, but serious, metabolic complication. Common AEs associated with metformin include GI disorders. Strengths of metformin include its weight neutrality and lack of hypoglycaemia when administered as monotherapy. Weaknesses of metformin include GI side effects, contraindications in patients with renal insufficiency, heart failure, hepatic insufficiency, and lack of beta-cell function preservation.

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Physiology and Pathophysiology of Diabetes
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Secretagogues
The class of insulin secretagogues includes the SUs and meglitinides, which are all oral agents. As a class, the SUs stimulate insulin release from pancreatic beta cells by blocking ATP-dependent potassium channels. However, the mechanism of action for meglitinides is somewhat different from the SUs, because these agents bind to a different target protein on the SU receptor. Nateglinide and repaglinide have a rapid onset of action (nateglinide more so than repaglinide) and a short duration of activity, which may be preferred for people with irregular meal times. The SUs and repaglinide are generally approved in adults with T2DM when diet and exercise are not sufficient to control blood glucose. Meglitinides are indicated in combination with metformin in patients with T2DM who are not satisfactorily controlled on metformin alone. A key strength of the secretagogues is that they are rapidly effective. Weaknesses include weight gain and risk of hypoglycaemia (least with nateglinide). Also, secretagogues do not preserve beta-cell function.

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Physiology and Pathophysiology of Diabetes
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Thiazolidinediones
TZDs are a class of second-line oral agents used as monotherapy or in combination with metformin and/or an SU for the treatment of T2DM. The primary action of TZD includes decreasing insulin resistance in peripheral tissues and the liver, which results in increased glucose uptake and utilisation in peripheral tissues. In addition to its primary actions, TZDs reduce hepatic glucose production and increase hepatic glucose uptake. Although local indications may differ, pioglitazone is approved for monotherapy, dual oral therapy in combination with metformin or an SU, and as triple oral therapy in combination with metformin and an SU. Pioglitazone is also indicated for combination with insulin in patients with T2DM with insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance. Key strengths of TZD include reduced insulin resistance, preserved beta-cell function, and improved atherogenic lipid profile. Key weaknesses of TZD include possible worsening of diabetic macular oedema, increased risk of fluid retention and cardiac failure, weight gain, and increased incidence of bone fractures. Monitoring of liver function is also recommended.

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Physiology and Pathophysiology of Diabetes
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Alpha-glucosidase Inhibitors
Alpha-glucosidase inhibitors may be considered as adjuncts to diet and exercise in patients with T2DM who have not met glycaemic targets. They are oral antidiabetic drugs that can also be used in combination with other oral antidiabetic agents and/or insulin. Alpha-glucosidase inhibitors slow the breakdown and digestion of carbohydrates. This process delays glucose absorption. In this way, they reduce the postprandial rise in blood glucose, thus reducing blood glucose fluctuations. These drugs are most effective when given with a starchy, highfibre diet with restricted amounts of glucose and sucrose. Common (occurring in 1/100 to <1/10 of patients in placebo-controlled studies) and very common (occurring in 1/10 of patients in placebocontrolled studies) AEs associated with acarbose include flatulence, diarrhoea, and GI/abdominal pain. Key strengths of alpha-glucosidase inhibitors include low risk of hypoglycaemia and weight neutrality. Key weaknesses of alpha-glucosidase inhibitors include GI side effects and modest glucose reduction.It is also recommended that liver enzymes be monitored during the first 6 to 12 months of treatment.

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Physiology and Pathophysiology of Diabetes
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Incretin Therapy
Two classes of drugs with different mechanisms of action are included in the category of incretin therapies: GLP-1 analogues and DPP-4 inhibitors. GLP-1 analogues are incretin mimetics that bind to and activate the GLP-1 receptor, resulting in the following pharmacologic actions:increased glucosedependent secretion of insulin from pancreatic beta cells, suppressed glucagon secretion in a glucose-dependent manner, slowed gastric emptying, and reduced hunger. Key strengths of the GLP-1 analogues include lower postprandial blood glucose and weight loss, and they may improve beta-cell function. Key weaknesses of the GLP-1 analogues include GI side effects, once-daily (liraglutide and lixisenatide) or twice-daily (exenatide) subcutaneous injections with the exception of once-weekly prolonged-release exenatide, and lack of long-term safety data. DPP-4 inhibitors reduce the rate at which GLP-1 is inactivated by the DPP-4 enzyme, which prolongs the insulin-stimulating and glucagon-lowering effects of GLP-1. Key strengths of DPP-4 inhibitors include enhanced beta-cell function in the islet, works only when glucose is elevated, oral administration, and its weight neutrality. Key weaknesses include less clinical experience compared with other classes, and risk of pancreatitis.

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Physiology and Pathophysiology of Diabetes
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SGLT2 Inhibitors
SGLT2 inhibitors work to increase urinary glucose excretion. An increase in urinary glucose excretion results in urinary calorie loss, leading to weight loss. The glucose excretion also leads to reduced fasting plasma glucose, improved glucose tolerance, reduced glucose toxicity and a reduction in HbA1c levels. Key strengths of the SGLT2 inhibitors include no affect on glucose metabolism, so can combine with other oral and injectable treatments,clinically significant weight loss,and blood pressure reduction without hypotension. Key weaknesses include a lack of efficacy in patients with moderate and severe renal impairments,and an increase in genital tract and urinary tract infections.

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Physiology and Pathophysiology of Diabetes
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Insulin
The different types of insulin are characterised based on their onset, peak time, and duration of action: rapid-, regular or short-, intermediate-, and basal or long-acting insulin. Insulin administration in patients with T2DM supplements the basal insulin levels in the body as well as the insulin secreted by the body in response to meals. o Rapid-acting insulin mimics insulin secreted following meals, which provides a bolus effect to help glucose be uptaken by muscle and adipose tissue. o Intermediate- or long-acting insulin mimics basal insulin secretion, which suppresses glucose production by the liver. Key strengths of insulin therapy include no dose limit, rapid efficacy, and improved lipid profile. Key weaknesses of insulin therapy include multiple daily injections, weight gain, and hypoglycaemia. SGLT2 inhibitors work to increase urinary glucose excretion.

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