Presentation on theme: "Combination Therapy in Type 2 Diabetes"— Presentation transcript:
1 Combination Therapy in Type 2 Diabetes Slide 35Speaker notes:In the next several slides, we will review the benefits of combination therapy, the most commonly used agents, and some recent results obtained with combination regimens.
2 Combination Therapy for Type 2 Diabetes J. Robin Conway M.D.Diabetes ClinicSmiths Falls, ON
3 Natural History of Type 2 Diabetes Metformin/ThiazolidinedionesLifestyleInsulinSecretagoguesNatural History of Type 2 DiabetesPrior to the manifestation of the metabolic defects that lead to type 2 diabetes, fasting and postprandial insulin levels are similar and constant. In the majority of patients that go on to develop type 2 diabetes, increasing insulin resistance leads to compensatory increases in circulating insulin, which prevents an increase in glucose levels. As time progresses, the insulin resistance reaches a peak and stabilizes while the compensatory increase in insulin continues to prevent fasting glucose levels from becoming abnormal.Impaired Glucose Tolerance (IGT): However, at some point in time, either due to early -cell dysfunction or due to a natural limit of -cell capacity, challenge of this delicate balance with a glucose load may demonstrate that, although fasting glucose levels remain normal, postprandial glucose levels become abnormal as a limitation in insulin response is reached.Type 2 Diabetes: Following the onset of -cell dysfunction, insulin levels can no longer overcome insulin resistance, and fasting and postprandial glucose levels increase progressively over time.References: 1. Henry RR. Type 2 diabetes care: the role of insulin-sensitizing agents and practical implications for cardiovascular disease prevention. Am J Med 1998;105(1A):20S-6S.Henry. Am J Med 1998;105(1A):20S-6S.
4 Oral Agents for Type 2 Diabetes Combination at less than maximal doses result in more rapid improvement of blood glucoseCounsel patients about hypoglycemia prevention and treatmentSMBG is recommended at least once dailyCanadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Cdn J Diabetes 2003; 27 (suppl 2)
5 antihyperglycemic agent Clinical assessment and initiation of nutrition and physical activityMild to moderate hyperglycemia (A1C <9.0%)Marked hyperglycemia (A1C 9.0%)Overweight(BMI 25 kg/m2)Non-overweight(BMI 25 kg/m2)2 antihyperglycemic agentsfrom different classes †Basal and/orpreprandial insulinbiguanideinsulin sensitizer*insulin secretagogueinsulinalpha-glucosidaseinhibitorL I F E S T Y L EBiguanide alone or incombination with 1 of:1 or 2† antihyperglycemicagents from differentclassesinsulin sensitizer*insulin secretagogueinsulinalpha-glucosidaseinhibitorbiguanideinsulin sensitizer*insulin secretagogueinsulinalpha-glucosidaseinhibitorIf not at targetIf not at targetIf not at targetIf not at targetAdd a drug from a different classorUse insulin alone or in combination with:Add an oralantihyperglycemic agentfrom a differentclass of insulin*Intensify insulinregimen or addbiguanideinsulin secretagogueinsulin sensitizer*alpha-glucosidase inhibitorbiguanideinsulinsecretagogue**insulin sensitizer*alpha-glucosidaseinhibitorTimely adjustments to and/or additions of oral antihyperglycemic agentsand/or insulin should be made to attain target A1C within 6 to 12 months
6 Pharmacologic Management of Type 2 Diabetes Add anti-hyperglycemic agents if:Diet & exercise therapy do not achieve targets after 2-3 month trialornewly diagnosed and has an A1C of 9%A1C& BMISuggested starting agent< 9%BMI 25Biguanide alone or in combinationBMI < 251 or 2 agents from different classes 9%--2 agents from different classes or insulin basal and/or preprandialCan remove the last columnSee flipchart pharmacological management of type 2, I like the simple chart as well describing A1CIntensify to reach targets in 6-12 months
7 Targets for Glycemic Control Under Normal range please change to – if it can safely be achievedI would suggest removing the recommendation, however mentioning #1 under the chart* Treatment goals and strategies must be tailored to the patient, with consideration given to individual risk factorsTo achieve an A1C 7.0%, patients should aim forFPG, preprandial and postprandial PG targets
8 Need for Combination Therapy in UKPDS % of PatientsSlide 37Speaker notes:Because diabetes follows a deteriorating course, most patients will eventually require combination therapy.In the UKPDS, at the 3-year point, 50% of patients required combination therapy to maintain glycemic control at previous levels; at the 9-year point, 75% of patients needed a combination regimen.Turner RC, Cull CA, Frighi V et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 2000 Jun 2;281(21);
9 Dose-Response Curve Dose-Response Curve Dose-Response Curve Metformin 30201050010001500200025000.51.01.52.0DoseGI Distress Patients (%)Reduction vs. placebo, HbA1c(%)MetforminDose-response curve showing GI related effectsRiddle M. Combiningsulfonylureasand other oral agents.Am J of Med. 2000; 108(6A):15S-22S.
10 Mechanisms To Lower Glucose Decrease glucose production: biguanides (or thiazolidinediones)Increase muscle glucose uptake: thiazolidinediones (or biguanides)Stimulate insulin secretion: repaglinide or sulfonylureasRetard carbohydrate absorption: alpha-glucosidase inhibitorsCorrect insulin deficiency: insulin or insulin analoguesThere are several mechanisms by which glucose levels can be lowered. Various medications are available which act upon these different mechanisms.
12 Metformin - Advantages Corrects a primary pathophysiologic impairment: insulin resistanceHigh initial response rateLong record of relative safetyNo weight gain or modest weight lossAdvantageous lipid profileAdvantages of metformin include:Insulin sensitivity improvedHigh initial response rateLong-term safetyModest weight loss or no weight gainBeneficial effects on lipid profile.
13 Metformin - Disadvantages GI side effects on initiationMust be held prior to, and after, radiologic studies using intravascular iodinated contrast mediaRisk of lactic acidosis: caution inimpaired renal functionimpaired hepatic functionpharmacologically treated CHFalcoholismDisadvantages of metformin include:Gastrointestinal symptoms (eg, diarrhea, nausea, vomiting, abdominal bloating, flatulence, anorexia) are the most common adverse effects experienced. However, these symptoms usually diminish with continued treatment.Metformin must be held prior to, and after, radiologic studies using intravascular iodinated contrast media.If metformin accumulates during treatment, there is a risk of lactic acidosis. Therefore, metformin should be used cautiously in patients with impaired renal function, impaired hepatic function, pharmacologically treated congested heart failure, or alcoholism.
14 Thiazolidinediones: mechanism of action Blood glucoseMuscle and adipose tissue insulin resistance glucose uptakeLiver insulin resistance hepatic glucose productionPancreasdemand for insulin secretionß-cell insulin content
15 Thiazolidinediones - Advantages Corrects a primary pathophysiologic impairment: insulin resistancePossible once-daily dosingImproves Lipids, Lower serum triglycerideMay be used in renal insufficiencyAdvantages of thiazolidinediones include:Lowers blood glucose by improving target cell response to insulin.Possible once-daily dosing.Lowers serum triglycerides.Dose adjustment in renal insufficiency is unnecessary with some thiazolidinediones.
16 Thiazolidinediones - Disadvantages Delayed action (onset: 3 wks, full effect: wks)Variable response in monotherapyWeight gainIncreased LDL-cholesterol (short-term)Few long-term studiesDisadvantages of thiazolidinediones include:Rare cases of severe, idiosyncratic, hepatocellular injury have been reported with troglitazone, some of which have been fatal.Initial benefits may not be seen until 3 weeks of therapy with full effect expected in 10 weeks to 12 weeks.There is a variable response seen when used as monotherapy, both in terms of degree of response and differences among agents.Patients may experience weight gain.Although serum triglycerides are lowered, LDL-cholesterol is increased (short-term).Long-term side effects are unknown.
17 UKPDS demonstrated loss of glycemic control with all agents studied 98(%)ConventionalGlyburideChlorpropamideMetforminInsulinA1C7UKPDS showed that as type 2 diabetes progresses, monotherapy with traditional agents fails to maintain glycemic control.Of 1,704 overweight (>120% ideal bodyweight) patients with newly-diagnosed type 2 diabetes recruited to the study, 753 were included in a randomised trial of conventional therapy (diet alone, n = 411) versus intensive blood glucose control with metformin.A secondary analysis comparing the 342 patients allocated metformin with 951 overweight patients allocated intensive blood-gluose control with chlorpropamide (n = 256), glibenclamide (n = 277), or insulin (n = 409) found that over 10 years, median HbA1c was 7.4% in the metfromin group, compared with 8.0% in the conventional group. The patients assigned intensive control with sulfonylurea or insulin had similar HbA1c to the metformin group.UK Prospective Diabetes Study Group. UKPDS 34. Lancet 1998; 352:854–865.Upper limit of of normal = 6.2%6246810Years from randomizationOverweight patients Cohort, median valuesUK Prospective Diabetes Study Group. UKPDS 34. Lancet 1998; 352:854–865.
18 Sulfonylurea Study - Long-term Mean Changes in HbA1C from Baseline ***A long-term, open-label extension of patients receiving 30 mg pioglitazone in combination with a sulphonylurea maintained metabolic control. This publication reported on data of up to 40 weeks of therapy. All reductions of mean HbA1c were statistically different from baseline (p< 0.05). Overall mean HbA1c reductions at the different time points were about 1.5% points.Double-blind phaseOpen-label phase* p<0.05Hanefeld M et al. Exp Clin Endocrinol Diabetes 2000;108 (suppl 2):S256-66
19 Metformin Study - Open Label Extension In an open label extension to the double blind study, further reductions in HbA1c and fasting plasma glucose were observed. Patients treated with pioglitazone and metformin for 72 weeks had mean changes from baseline of 1.4% in HbA1c and 3.5 mmol/L in fasting plasma glucose.Change in HbA1c (%)Change in fasting glucose (mmol/L)Einhorn et al. Clin Therapeutics 2000;12:
21 Sulfonylureas - Advantages Improve a primary pathophysiologic impairment: insulin secretionPhysiologic route of insulin deliveryHigh initial response rateNo lag period before responseAdvantages of sulfonylureas include stimulation of insulin secretion, physiologic route of insulin delivery, and rapid onset of action.
22 Sulfonylureas - Disadvantages Hypoglycemiamay be prolonged or severeWeight gainDrug interactions (especially 1st generation)Hyponatremia (with chlorpropamide)Cannot use if allergic to sulfa compoundsDisadvantages of sulfonylureas include:Prolonged or severe hyperglycemia is possible.Patients may experience weight gain.Must be cautious of drug interactions especially with 1st generation drugs.Chlorpropamide has been shown to cause hyponatremia.Should not use if allergic to sulfa compounds.
23 Insulin - Advantages Will control virtually all patients Can be used to overcome glucose toxicityFlexibility in dosing and lifestyleMultiple preparations with different action profilesAdvantages of insulin are as follows:Virtually all patients can be controlled with insulin.Insulin is beneficial in overcoming glucose toxicity.Dosing regimens and methods of delivery allow for flexibility.Various insulin preparations are available.
24 Insulin - Disadvantages HypoglycemiaWeight gainNeed for injectionsNon-physiologic route of administration (peripheral)Patient and physician non-acceptanceDisadvantages of insulin include:Hypoglycemia may result in certain situations, particularly with increased activity or prolonged interval between food intake.Patients may experience weight gain as glycemic control is improved.Delivery by injection may be less acceptable by patient and physician.
26 Alpha-Glucosidase Inhibitors - Advantages Good safety profileNo weight gain or modest weight lossDose coupled to mealsAdvantages of alpha-glucosidase inhibitors include:Good safety profileNo weight gain and or modest weight lossDosing with meals.
27 Alpha-Glucosidase Inhibitors - Disadvantages Modest effect on fasting plasma glucose and HbA1CFlatulence, gastrointestinal side effectsCannot treat hypoglycemia with sucrose, maltose, or starchuse glucose, fructose, or lactoseDisadvantages of alpha-glucosidase inhibitors include:Modest effect on fasting plasma glucose and hemoglobin A1C (HbA1C).Flatulence is the most common adverse event seen with these agents. Other gastrointestinal effects such as diarrhea and abdominal pain also are common.Limited options allowed for treatment of hypoglycemia.
28 Changing Therapies to Address Diabetes Progression Lifestyle ChangeMonotherapyCombination oral agentsInsulin + oral agentsOld ParadigmNew ParadigmSlide 39Speaker notes:The traditional stepwise approach, depicted here, may be replaced by a new paradigm that begins with combination therapy.Beginning with a combination has the advantage of achieving glycemic goals with submaximal drug doses. Thus, the potential for side effects and glucose toxicity is reduced.
29 Type 2 Diabetes: Key Concepts Dual impairment:ß-cell function: insulin secretioninsulin action: insulin resistance“Glucose toxicity” aggravates both impairmentsMultiple mechanisms to correct hyperglycemiaMost patients require combination therapyKey concepts of type 2 diabetes include:In type 2 diabetes there is an impairment of ß-cell function resulting in reduced insulin secretion and an impairment of insulin action with subsequent insulin resistance.Hyperglycemia causes further aggravation of ß-cell function impairment and insulin action impairment.Glucose can be lowered by various mechanisms.Most patients require combination therapy sooner or later to achieve goal.
30 Combination Therapy Summary The magnitude of the diabetic epidemic dictates more aggressive approaches to treatmentEvidence clearly suggest that early intensive treatment results in significant decrease in complicationsTo reduce macrovascular disease more strict glucose control might be needed (HbA1c <6%)Slide 49Speaker notes:In summary, the magnitude of the diabetic epidemic means that unless good diabetic control can be achieved, there will be a deluge of complications that are costly in both individual and societal terms. This situation dictates a more aggressive approach to treatment.We have reviewed some studies that form part of a growing body of evidence for the value of initiating intensive therapy early.We know that microvascular complications can be significantly reduced. To reduce macrovascular disease as well, it is possible that very strict glycemic control—HbA1c levels < 6%—might be required. This question is being addressed by studies that are already underway.In order to achieve very tight levels of control, combination therapy will need to be introduced early, and the components will need to be tailored to the patient’s particular metabolic defects. In some patients, insulin formulations that target PPG may be the only route to optimal control.
31 In Conclusion Prevalence of type 2 diabetes is increasing dramatically Majority of patients are diagnosed and treated by the family physicianNew paradigm: need to be much more aggressive early in the treatment of these patients utilizing dual therapiesHypoglycemia can be managed through proper treatment choices and lifestyle managementGlucose is a continuous progressive risk factor for cardiovascular diseaseSlide 50Speaker notes:In conclusion, the prevalence of type 2 diabetes mellitus is increasing at a dramatic and alarming rate. Most patients with diabetes will be diagnosed and treated by family physicians.A new paradigm dictates that in order to avoid complications and deterioration of glycemic control, early and aggressive therapy will be required. Almost inevitably, this will involve the use of oral combination regimens.If patients and physicians are aware of it, hypoglycemia can be managed with judicious choices of agents and by appropriate lifestyle management.Finally, the plasma glucose level is a continuous and progressive risk factor for cardiovascular disease, even at levels that fall below the definitions of diabetes. Very tight glycemic control that includes targeting of PPG therefore has the potential to reduce macrovascular complications such as CV events.