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NEW DRUGS FOR DIABETES

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NEW DRUGS FOR DIABETES

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    1. NEW DRUGS FOR DIABETES Dr Helen Gray Consultant Physician CGH

    3. Approved diabetes Medications Nine classes of medications are now available for the treatment of type 2 diabetes, as compared with four barely a decade ago (see table). Although we’ve had biguanides around since the 50’s, metformin was not on the US market until 1995. We haven’t had any new drug classes for diabetes since the late 90’s until now. In 2005, incretin and amylin analogs hit the market. And most recently, DPP-IV inhibitors…the 3 of which I talk about today Nine classes of medications are now available for the treatment of type 2 diabetes, as compared with four barely a decade ago (see table). Although we’ve had biguanides around since the 50’s, metformin was not on the US market until 1995. We haven’t had any new drug classes for diabetes since the late 90’s until now. In 2005, incretin and amylin analogs hit the market. And most recently, DPP-IV inhibitors…the 3 of which I talk about today

    4. New Drugs Incretins GLP1 analogues: Exenatide (Byetta) DPP4 Inhibitors: Sitagliptin (Januvia) Medication affecting the incretin system has been a big advancement in targeting an unmet area in the diabetes physiology. We now have Exenatide, an incretin analog; and now the DDP4 inhibitor, sitagliptin, to help prevent the breakdown of these incretin hormones which all go into more detail soon. We also have an amylin analog and we are now administering insulin by a different route. I will not be going over inhale insulin today, but if you have any pharmacy related questions, feel free to ask me during our lunch session.Medication affecting the incretin system has been a big advancement in targeting an unmet area in the diabetes physiology. We now have Exenatide, an incretin analog; and now the DDP4 inhibitor, sitagliptin, to help prevent the breakdown of these incretin hormones which all go into more detail soon. We also have an amylin analog and we are now administering insulin by a different route. I will not be going over inhale insulin today, but if you have any pharmacy related questions, feel free to ask me during our lunch session.

    5. Role of Incretin in Glucose Homeostasis 2 GI hormones, GIP and GLP-1 are responsible for most of the incretin effect. Those of you that don’t know, INCRETIN, is actually a mnemonic. 2 GI hormones, GIP and GLP-1 are responsible for most of the incretin effect. Those of you that don’t know, INCRETIN, is actually a mnemonic.

    6. GLP-1 and GIP Are Incretin Hormones GLP-1 and GIP Are Incretin Hormones GLP-1 and GIP are the currently identified incretin hormones. An incretin is a hormone with the following characteristics1: It is released from the intestine in response to ingestion of food, particularly glucose. The circulating concentration of the hormone must be sufficiently high to stimulate the release of insulin. The release of insulin in response to physiological levels of the hormone occurs only when glucose levels are elevated (glucose-dependent). GIP and GLP-1 are hormones that fulfill these 3 characteristics, qualifying them as incretins.1 In the fasting state, GIP and GLP-1 circulate at very low levels. Their levels rapidly increase after food ingestion and play a role in the release of insulin.2,3 GLP-1 stimulates insulin response from beta cells in a glucose-dependent manner and suppresses glucagon secretion from alpha cells in a glucose-dependent manner. GIP also potentiates insulin release from beta cells in a glucose-dependent manner.4 Other effects of GLP-1 and GIP are summarized on the slide.GLP-1 and GIP Are Incretin Hormones GLP-1 and GIP are the currently identified incretin hormones. An incretin is a hormone with the following characteristics1: It is released from the intestine in response to ingestion of food, particularly glucose. The circulating concentration of the hormone must be sufficiently high to stimulate the release of insulin. The release of insulin in response to physiological levels of the hormone occurs only when glucose levels are elevated (glucose-dependent). GIP and GLP-1 are hormones that fulfill these 3 characteristics, qualifying them as incretins.1 In the fasting state, GIP and GLP-1 circulate at very low levels. Their levels rapidly increase after food ingestion and play a role in the release of insulin.2,3 GLP-1 stimulates insulin response from beta cells in a glucose-dependent manner and suppresses glucagon secretion from alpha cells in a glucose-dependent manner. GIP also potentiates insulin release from beta cells in a glucose-dependent manner.4 Other effects of GLP-1 and GIP are summarized on the slide.

    7. The Incretin Effect in Healthy Subjects Most of you have seen this slide before, but let me show it to you again because it is crucial to understanding the use of the drugs we now have available and those that you will be using in the future. If you give a patient oral glucose, you will get an increase in plasma glucose and an increase in insulin. If you infuse glucose in a way that reproduces glucose levels to what you would see on an oral glucose tolerance test, the insulin response to intravenous glucose is much less than when you give glucose orally. Something is happening when you take the nutrients orally to stimulate insulin production, and that differential in insulin levels is called the incretin effect. It accounts for maybe 60% to 80% of postprandial insulin production. It is reduced in people who have type 2 diabetes. SLIDE BACKGROUND: Young healthy subjects (n = 6), given 50 g oral glucose load or isoglycemic IV glucose infusion Food elicits dynamic changes in insulin secretion, beginning with the cephalic phase, in which anticipation of a meal results in central nervous system (CNS)-mediated release of insulin An early prandial phase, mediated by gut-derived incretin hormones (eg, GLP-1 and gastric inhibitory polypeptide [GIP]) occurs after food intake but before the ingested nutrients appear in the circulation (or reach the intestinal L cells that secrete GLP-1) Cleavage of proinsulin generates both insulin and the C-peptide, which are stored together and cosecreted; therefore, C-peptide serves as a marker for insulin secretionMost of you have seen this slide before, but let me show it to you again because it is crucial to understanding the use of the drugs we now have available and those that you will be using in the future. If you give a patient oral glucose, you will get an increase in plasma glucose and an increase in insulin. If you infuse glucose in a way that reproduces glucose levels to what you would see on an oral glucose tolerance test, the insulin response to intravenous glucose is much less than when you give glucose orally. Something is happening when you take the nutrients orally to stimulate insulin production, and that differential in insulin levels is called the incretin effect. It accounts for maybe 60% to 80% of postprandial insulin production. It is reduced in people who have type 2 diabetes. SLIDE BACKGROUND: Young healthy subjects (n = 6), given 50 g oral glucose load or isoglycemic IV glucose infusion Food elicits dynamic changes in insulin secretion, beginning with the cephalic phase, in which anticipation of a meal results in central nervous system (CNS)-mediated release of insulin An early prandial phase, mediated by gut-derived incretin hormones (eg, GLP-1 and gastric inhibitory polypeptide [GIP]) occurs after food intake but before the ingested nutrients appear in the circulation (or reach the intestinal L cells that secrete GLP-1) Cleavage of proinsulin generates both insulin and the C-peptide, which are stored together and cosecreted; therefore, C-peptide serves as a marker for insulin secretion

    8. Loss of Incretin Effect The results in this slide are those Nauck obtained in his study that proved the hypothesis that the incretin effect was reduced in type 2 diabetes. In this study, the incretin effect in patients with type 2 diabetes was quantified. The differences in secretory responses to oral and intravenous glucose seen in patients with type 2 diabetes are caused by factors other than glucose. This is the incretin effect. The contribution of incretin factors to insulin responses is lower in patients with type 2 diabetes than it is in patients with normal glucose tolerance (NGT). In type 2 DM, GLP-1 concentrations are reduced in response to a meal, whereas GIP concentrations are normal or increased. This observation suggest resistance to the actions of GIP, which make GLP-1 the favored potential therapeutic target.The results in this slide are those Nauck obtained in his study that proved the hypothesis that the incretin effect was reduced in type 2 diabetes. In this study, the incretin effect in patients with type 2 diabetes was quantified. The differences in secretory responses to oral and intravenous glucose seen in patients with type 2 diabetes are caused by factors other than glucose. This is the incretin effect. The contribution of incretin factors to insulin responses is lower in patients with type 2 diabetes than it is in patients with normal glucose tolerance (NGT). In type 2 DM, GLP-1 concentrations are reduced in response to a meal, whereas GIP concentrations are normal or increased. This observation suggest resistance to the actions of GIP, which make GLP-1 the favored potential therapeutic target.

    9. Incretins: The medications

    10. New Therapies: Incretin System Mechanism of Action of Sitagliptin This illustration describes the mechanism of action of sitagliptin. The incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon levels, along with higher insulin levels, lead to reduced hepatic glucose production and are associated with a decrease in blood glucose levels in the fasting and postprandial states. The effects of GLP-1 and GIP are glucose dependent. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly inactivates incretin hormones. Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones.Mechanism of Action of Sitagliptin This illustration describes the mechanism of action of sitagliptin. The incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon levels, along with higher insulin levels, lead to reduced hepatic glucose production and are associated with a decrease in blood glucose levels in the fasting and postprandial states. The effects of GLP-1 and GIP are glucose dependent. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly inactivates incretin hormones. Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones.

    11. New Therapies: Incretin System Mechanism of Action of Sitagliptin This illustration describes the mechanism of action of sitagliptin. The incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon levels, along with higher insulin levels, lead to reduced hepatic glucose production and are associated with a decrease in blood glucose levels in the fasting and postprandial states. The effects of GLP-1 and GIP are glucose dependent. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly inactivates incretin hormones. Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones.Mechanism of Action of Sitagliptin This illustration describes the mechanism of action of sitagliptin. The incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon levels, along with higher insulin levels, lead to reduced hepatic glucose production and are associated with a decrease in blood glucose levels in the fasting and postprandial states. The effects of GLP-1 and GIP are glucose dependent. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly inactivates incretin hormones. Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones.

    12. GLP-1 ANALOGS Stable analog not cleaved by DDP-4 Exendin-4 in saliva of Gila Monster lizard is 50% similar to human GLP-1 Exenatide ( Byetta) is a synethic formof this

    13. DDP-4 Inhibitors DDP-4 inhibitor and so prolong action of endogenous GLP-1 Sitagliptin (Januvia)-OD Vildagliptin (Galvus)-OD with SFU,bd with metformin or TZD

    14. DPP-4 Inhibitors and Incretin Mimetics Injections are given to the thigh, abdomen, or upper arm. Exenatide is not recommended for patients with severe renal impairment or end-stage renal disease and has not been studied in patients with severe gastrointestinal disease. Injections are given to the thigh, abdomen, or upper arm. Exenatide is not recommended for patients with severe renal impairment or end-stage renal disease and has not been studied in patients with severe gastrointestinal disease.

    15. DPP-4 Inhibitors and Incretin Mimetics Patients who take exenatide in combination with SFU have an increased risk of hypoglycemia Long term data on weight loss is unclear, but it continues to decrease over time because people continue to eat less. However, the individual differences in the magnitude and the pattern of weight loss are large. Some patients lose dramatic amounts of weight, while others lose only a few pounds. More obese patients seem to lose the most weight. Some people do not lose weight in the beginning but lose weight later, while others lose a lot of weight initially and then their weight loss slows. Exenatide is contraindicated for patients with type 1 diabetes because the pharmacologic action of exenatide in part requires the presence of functional pancreatic ß cells.Patients who take exenatide in combination with SFU have an increased risk of hypoglycemia Long term data on weight loss is unclear, but it continues to decrease over time because people continue to eat less. However, the individual differences in the magnitude and the pattern of weight loss are large. Some patients lose dramatic amounts of weight, while others lose only a few pounds. More obese patients seem to lose the most weight. Some people do not lose weight in the beginning but lose weight later, while others lose a lot of weight initially and then their weight loss slows. Exenatide is contraindicated for patients with type 1 diabetes because the pharmacologic action of exenatide in part requires the presence of functional pancreatic ß cells.

    16. Comparison: DPP-4 Inhibitors and Incretin Mimetics Advantages: DPP-4 inhibitors have an advantage over the incretin mimetic, especially to the patient, because it is available PO. Compared older agents on the market, DDP-4 inhibitors and incretin mimetics have an advantage in terms of weight. Sitagliptin produces no weight gain (or weight lost) and exenatide produces a weight loss, independent from its nausea side effect. We have animal studies and 1 human study that I know of, that describes b-cell proliferation…however, we do not know the long term effects of this. Disadvantages: DPP-8 and -9 have a role in our immunity. DDP-4 agents are supposed to be specific enough not to affect our immune system. However, it is interesting to see, that in clinical trials, respiratory tract infections and nasopharyngitis are listed as side effects for sitagliptin. The data that we currently have suggests a slightly better A1C reduction with injectable incretin mimetics versus DDP-4s.Advantages: DPP-4 inhibitors have an advantage over the incretin mimetic, especially to the patient, because it is available PO. Compared older agents on the market, DDP-4 inhibitors and incretin mimetics have an advantage in terms of weight. Sitagliptin produces no weight gain (or weight lost) and exenatide produces a weight loss, independent from its nausea side effect. We have animal studies and 1 human study that I know of, that describes b-cell proliferation…however, we do not know the long term effects of this. Disadvantages: DPP-8 and -9 have a role in our immunity. DDP-4 agents are supposed to be specific enough not to affect our immune system. However, it is interesting to see, that in clinical trials, respiratory tract infections and nasopharyngitis are listed as side effects for sitagliptin. The data that we currently have suggests a slightly better A1C reduction with injectable incretin mimetics versus DDP-4s.

    17. NICE Guidance DPP-4 inhibitors Consider adding 2nd line therapy instead of SFU with metformin if risk of hypoglycaemia Instead of metformin if intolerant As triple therapy if insulin unacceptable/inappropriate Continue only if HBA1c drop of 0.7% by 6 months May be preferable to TZD those in whom weight gain an isuue

    18. NICE Guidance GLP-1 mimetic Consider adding to SFU and metformin if:-BMI> 35 -BMI<35 and wt loss would benefit other significant co morbities Continue if HbA1C 1% reduction at 6 months AND wt loss of at least 5% at 1 year-and maintained

    19. PATIENT 1 RPV 52 year old staff nurse BMI 40 WT 80.5kg Type 2 DM 2003 HbA1c 9.5% RX Metformin 1g BD AND Gliclazide 80 mg BD What next?

    20. PATIENT 1 RPV Take metformin regularly Started Orlistat 6 months later Wt 82.1KG but HbA1c 7.5% What next? Started Byetta 3 months later Wt 81kg BUT HbA1c 6.7% and advised to reduce gliclazide because of hypos and eating to prevent these Further 3 month review ??

    21. PATIENT 2 AC 57 year old man (awaiting TKR ) 2008 Morbid obesity (Wt 151kg BMI 50) with Obstructive sleep apnoea 2009 Type 2 Diabetes FPG 26 mmol/l- started gliclazide 160mg bd Would you send him to hospital for admission? What next?

    22. PATIENT 2 AC Started on OD Lantus-and Orlistat added 1 month later HBGM 6-12 2 months later BMI Wt 143.4kg and hypos so Lantus reduced 4 months later Wt 141.5 kg BMI 47 and still hypos so insulin stopped ALT 169 ?NASH-confirmed on U/S-metformin and statin started Aim Wt 120kg BMI 40 to be eligible for surgery

    23. PATIENT 3 AL 45 year old HGV driver Type 2 Diabetes 1999 BMI 32 Rx Gliclazide and Metformin Asymptomatic BUT HbA1c 9.0% What next?

    24. PATIENT 3 AL Add glitazone-but what about wt gain? Add DDP-4 inhibitor Or consider Byetta Will lose his licence with insulin And tackle all other risk factors agressively

    25. Questions

    26. DIABETES AND PREGNANCY Dr Helen Gray Consultant Physician CGH

    27. Babies of women with diabetes in England, Wales and N Ireland continue to have an increased risk of perinatal mortality and congenital anomaly Key finding 1: Outcome Compared mortality with national rates and congenital abnormalities to eurocrat 2002-3 197 abnormalities in 148 patients Consider in context of St Vincent Declaration – is this achievable? Compared mortality with national rates and congenital abnormalities to eurocrat 2002-3 197 abnormalities in 148 patients Consider in context of St Vincent Declaration – is this achievable?

    29. DIABETES AND PREGNANCY Contraception Preconception : Type 1 & Type 2 Antenatal care: Postnatal care

    30. NICE JULY 2008 Diabetes in pregnancy Management of diabetes and its complications from pre-conception to postnatal period Type 1/Type 2 and GDM

    31. Contraception in Diabetes A Reliable Method is more important than risk Most reliability associated with the OCP Most risk associated with the OCP

    32. PRE CONCEPTION CARE Starting from adolescence Risk of diabetes and pregnancy “ establishing good glycaemic control will reduce risk of miscarriage, congenital malformation and still birth”

    33. PRE-PREGNANCY(2) Planned pregnancy Diet/tablets to insulin as part of plan Good glycaemic control (with hypo education) Nausea and DKA Retinal screening and BP/renal assessment Other medication? Folic acid 5mg Alcohol and smoking Clinic information/contacts

    34. SAFETY OF MEDICATIONS Continue Metformin Stop statins and ACE/ATII blockers All insulin safe (NICE suggest Isophane insulin as long acting of choice!)

    35. BLOOD GLUCOSE MONITORING AND TARGETS PRE -PREGNANCY Individualised targets Monthly HbA1C (“aim <6.1% if safe”) Any reduction may reduce risks Advise women with HbA1c > 10% to avoid pregnancy Remember risks of of rapid optimisation of glycaemic control and retinal changes

    36. PRACTICAL ADVICE Refer all women with diabetes for pre conceptual counselling Actively advice not to conceive if HbA1c>10% Start folic acid 5mg od Continue metformin Antenatal care is NOW at GRH

    37. THANKS Richard Hayman (Consultant Obstetrician) Helen Giles,Julie Campbell (DSNS) Penny Lock Pullan (Dietician) Peter Scanlon and all retinal screening team

    38. DIABETES AND PREGNANCY 27 year old primagravida,Type 1 15 years. HbA1c 9% Microalbuminuria on ACE Hypercholesterolaemia on Statin Hypothyroid on thyroxine Wants to become pregnant What Advice does she need ?

    39. DIABETES AND PREGNANCY 35 year old Type 2 for 5 years Gravida 2 (6&8 years old) BMI 35 Gestational diabetes in first pregnancy HbA1c 8.5 % on Metformin 850mg bd On antihypertensives, statin and aspirin Wants another baby What do you advise?

    40. DIABETES AND PREGNANCY Can a woman with diabetes bear children successfully? Is the pregnancy dangerous to the mother? What are the short term risks to the foetus? Will the baby develop diabetes? What about the mothers long term health?

    41. DIABETES AND PREGNANCY Risk of death same as for any pregnant woman Congenital malformations but remember even with poor control only 10-20% risk of abnormality Risk of Type 1 is 1.3% if mother has diabetes but 6.1% if father ris the affected parent Risk of Type 2 15-30% Risk of worsening renal disease and retinopathy

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