NEWSLETTER
Type 2 Diabetes in 21 st Century:Handout from Medscape summarizing Current modalities of treatment in type 2 DM
Courtesy Dr. Abdul Jabbar FRCP. Badruddin Hasanali Ajanee Professor of Medicine. Consultant Endocrinologist & Diabetologist. The Aga Khan University.Medication
Pharmacologic therapy has changed dramatically in the last 10 years. New drug classes and new drugs effectively treat type 2 diabetes mellitus, allowing glycemic control previously beyond the reach of medical therapy. Traditionally, diet modification has been the cornerstone of diabetes management. Weight loss is more likely to control glycemia in patients with recent onset of the disease than in patients who are significantly insulinopenic. Medications that induce weight loss, such as orlistat, may be effective in highly selected patients but are not generally indicated in the treatment of the average patient with type 2 diabetes mellitus. At presentation, patients who are symptomatic may require transient treatment with insulin to reduce glucose toxicity (which may reduce beta cell insulin secretion and worsen insulin resistance) or an insulin secretagogue to rapidly relieve symptoms such as polyuria and polydipsia.
Patients with HbA1c less than 8% are usually treated initially with single oral agents. Patients with initial HbA1c greater than 9-10% may benefit from initial therapy with 2 oral agents.
Various categories of therapeutic agents effectively treat type 2 diabetes mellitus. Comparisons of studies looking at glycemic efficacy of individual agents are highly affected by 2 study conditions: level of glycemia prior to treatment and percent of study population previously untreated with drugs. These 2 factors make comparison of drug studies quite difficult, because all agents are more effective in a population of patients with poor glycemic control at baseline (a large decrease in glucose concentrations occurs, but the treatment often leaves the patients with poorly controlled glucose levels) and in patients who previously were diabetes-drug naive.
Sulfonylureas
Sulfonylureas are time-honored insulin secretagogues (i.e., oral hypoglycemic agents) and probably have the greatest efficacy for glycemic lowering of any of the oral agents. The UKPDS confirmed their safety after years of suspicion from the University Group Diabetes Program (UGDP).
Meglitinides
Meglitinides are much more short-acting insulin secretagogues than sulfonylureas, with preprandial dosing potentially achieving more physiologic insulin release and less risk for hypoglycemia. Their glycemic efficacy is possibly less than sulfonylureas.
Biguanides
Biguanides are old agents that reduce hepatic glucose production and may have a minor effect on glucose utilization in the periphery (i.e., antihyperglycemics, hepatic insulin sensitizers). Insulin must be present for biguanides to work. Phenformin was taken off the market in the United States in the 1970s because of its risk of causing lactic acidosis and associated mortality (rate of approximately 50%). Metformin has proved effective and safe.
A nested case-control analyses found that, as with other oral antidiabetic drugs, lactic acidosis during metformin use is very rare and is associated with concurrent comorbidity; moreover, hypoglycemic episodes are substantially less common among patients taking metformin than they are among those taking sulfonylureas. In addition, metformin is the only oral diabetes drug that reliably facilitates modest weight loss. In the UKPDS, it was found to be successful at reducing macrovascular disease endpoints in patients who were obese. The results with concomitant sulfonylureas in a heterogeneous population were conflicting, but overall, this drug probably improves macrovascular risk.
Kooy et al found improvements in body weight, glycemic control, and insulin requirements when metformin was added to insulin in patients with type 2 diabetes mellitus. No improvement of an aggregate of microvascular and macrovascular morbidity and mortality was observed; however, risk reduction of macrovascular disease was evident after a follow-up period of 4.3 years. These sustained beneficial effects indicated that, unless contraindicated, metformin treatment should be continued after the introduction of insulin in patients with type 2 diabetes mellitus.
Alpha-glucosidase inhibitors
Alpha-glucosidase inhibitors prolong the absorption of carbohydrates. Their induction of flatulence greatly limits their use. These agents should be titrated slowly to reduce gastrointestinal intolerance. Their effect on glycemic control is modest, affecting primarily postprandial glycemic excursions.
Thiazolidinediones (glitazones)
Glitazones are a newer class of drugs that reduce insulin resistance in the periphery (i.e., sensitize muscle and fat to the actions of insulin) and perhaps to a small degree in the liver (i.e., insulin sensitizers, antihyperglycemics). They activate peroxisome proliferator–activated receptor (PPAR) gamma, a nuclear transcription factor that is important in fat cell differentiation and fatty acid metabolism. Their major action is probably actually fat redistribution. These drugs may have beta cell preservation properties. Their glycemic efficacy is moderate, between alpha-glucosidase inhibitors and sulfonylureas. They are the most expensive oral agents.
Glitazones require the presence of insulin to work. They generally decrease triglycerides and increase HDL-C, but they increase LDL-C (perhaps large buoyant LDL, which may be less atherogenic). While these drugs have many desirable effects on inflammation and the vasculature, edema and weight gain may be problematic adverse effects in patients taking glitazones, especially when administered with insulin or insulin secretagogues. These effects may induce or worsen congestive heart failure in patients with left ventricular compromise and occasionally in patients with normal left ventricular function. These agents have not been tested in patients with New York Heart Association class III or IV heart failure. A recently recognized possible side effect of these agents is macular edema. Recent animal work suggests that concomitant therapy with the diuretic amiloride may
reduce fluid retention related to glitazone therapy.
The US Food and Drug Administration (FDA) issued an alert on May 21, 2007 to patients and health care professionals of rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths following the online publication of a meta-analysis.
A study indicates that in women with type 2 diabetes, long-term (i.e., 1 y or longer) use of glitazones doubles the risk of fracture. In this investigation, glitazones did not significantly increase fracture risk among men with type 2 diabetes.
Incretin-mimetics
The incretin-mimetic agent exenatide has a novel mechanism of action. Mimicking the endogenous incretin, glucagonlike peptide-1 (GLP-1), it stimulates glucose-dependent insulin release (as opposed to oral insulin secretagogues, which may cause non–glucose-dependent insulin release and hypoglycemia), reduces glucagon, and slows gastric emptying. Studies have used exenatide in addition to metformin and/or a sulfonylurea. Patients may attain modest weight loss. Animal data suggest that this drug prevents beta-cell apoptosis and may in time restore beta-cell mass. This latter property, if proven in humans, would have tremendous therapeutic potential.
Exenatide has greater ease of titration (only 2 possible doses, with most patients progressing to the higher dose) than does insulin. However, exenatide is more expensive than high-dose glitazone therapy and requires twice-daily injections. A long-acting formulation that is given once weekly has been developed and has been found to provide significantly greater improvement in glycemic control than does the twice-daily formulation ; it currently awaits FDA approval.
Dipeptidyl peptidase IV inhibitors
The newest addition to available oral hypoglycemic agents is the dipeptidyl peptidase IV (DPP-4) inhibitor, sitagliptin, which gained FDA approval in October 2006. DPP-4 degrades numerous biologically active peptides, including the endogenous incretins GLP-1 and glucose-dependent insulinotropic peptide (GIP). Sitagliptin can be used as a monotherapy or in combination with metformin or a glitazone. It is given once daily and is weight neutral. Another DPP-4 inhibitor, vildagliptin, is currently under review at the FDA.
Insulin
Ultimately, many patients with type 2 diabetes mellitus become markedly insulinopenic. The only therapy that corrects this defect is insulin. Because most patients are insulin resistant, small changes in insulin dosage may make no difference in glycemia in some patients. Furthermore, because insulin resistance is variable from patient to patient, therapy must be individualized in each patient.
A range of insulin preparations, individual and premixed, is currently available. The AHRQ has reviewed the use of premixed insulin analogues in patients with type 2 diabetes mellitus; conclusions for which the strength of evidence was high are as follows:
- For lowering postprandial glucose, premixed insulin analogues are more effective than either long-acting insulin analogues alone or premixed NPH/regular human insulin 70/30.
- For lowering HbA1c, premixed insulin analogues are as effective as premixed NPH/regular human insulin 70/30 and more effective than long-acting insulin analogues.
- The frequency of hypoglycemia reported with premixed insulin analogues is similar to that with premixed human insulin and higher than that with oral antidiabetic agents.
Medication strategy
A great deal of debate exists regarding the best initial oral therapy for patients with type 2 diabetes mellitus. The Agency for Healthcare Research and Quality (AHRQ) reviewed the published evidence (which came from short-term studies but was applicable to long-term use) regarding the comparative effectiveness of oral diabetes medications; the agency found little evidence to support predictions as to whether a particular medication is more likely to be effective in a given patient subgroup or to cause adverse effects in a particular patient.
The AHRQ concluded that when used as a monotherapy, most oral diabetes medications (with the exception of the less-effective nateglinide and alpha-glucosidase inhibitors) produce similar reductions in HbA1c, and that older medications (e.g., metformin, second-generation sulfonylureas) can reasonably be used before newer ones (e.g., glitazones, meglitinides), especially when cost is a factor.
- Based on the results of the UKPDS and safety record, patients who are obese (120% ideal body weight) should be started on metformin initially, titrated to at least 2000 mg/d administered in divided doses (during or after meals to reduce gastrointestinal side effects). Patients who are markedly symptomatic may be treated with an insulin secretagogue initially to rapidly alleviate symptoms and then perhaps switched to other agents. Patients with near-normal weight may be treated with sulfonylureas or metformin initially. Short-acting insulin secretagogues (e.g., repaglinide, nateglinide) can be used in patients unusually predisposed to hypoglycemia.
- Failure of initial therapy usually should result in addition of another class of drug rather than substitution (reserve substitution for intolerance to a drug due to adverse effects). Considerable debate exists regarding second agents added to (or used initially in conjunction with) metformin. The time-honored approach is to add an insulin secretagogue (usually titrated to no more than the half-maximal approved dose to reduce risk for hypoglycemia). However, some experts recommend a glitazone because of the positive effects of these drugs on inflammation and the vasculature. If this strategy is used, a moderate dose of glitazone (as opposed to the highest approved dose) should be used.
Because glitazones not infrequently cause weight gain and edema, the author usually reserves the use of these agents for patients who cannot use metformin, as a result of intolerance or contraindications. Exceptions to this practice might include patients of relatively normal weight who have marked insulin resistance, such as patients of Asian heritage. If an insulin secretagogue is being taken by the patient prior to the addition of a second agent, the patient should be warned about the possibility that hypoglycemia will be induced when another agent is added. In such cases, the dose of the insulin secretagogue, not the newly added agent, should be reduced.
If 2 drugs are unsuccessful, the practitioner may consider adding a third class of oral agents. An alternative would be to add bedtime insulin, usually NPH or glargine, to the initial oral agent or 2-drug combination, or add the new injectable drug exenatide. The expense and side effect profile of glitazones make the oral triple therapy approach less of an option for the author. The new approach of adding exenatide twice daily to 1 or 2 oral agents (e.g., metformin and/or sulfonylureas) is attractive because of its simplicity (i.e., only 2 possible doses of exenatide with easy titration compared with insulin), but its expense may be prohibitive. If insulin is used, the insulin dose is titrated to the fasting sugar concentration, which the patient can measure at home (usually with titration to a maximum bedtime insulin dose of approximately 60 units).
Some patients need reduction of their insulin secretagogue to prevent daytime hypoglycemia as the bedtime insulin is initiated or increased and the fasting glucose concentration is decreased. If exenatide is used, the author monitors fasting and postprandial sugars, expecting a marked flattening of the postprandial rise in glucose concentrations.
Measurement of glucose patterns in patients with type 2 diabetes, particularly those who have central obesity and hepatic steatosis, often reveals that the highest preprandial glucose level of the day is before breakfast (because of disordered hepatic glucose production overnight), with a "stair-step" decrease during the day (after the usual postmeal rise). These higher-than-desired morning glucose values do not necessarily dictate abandonment of the current therapeutic regimen, provided that the HbA1c level is at target. For patients who primarily have fasting hyperglycemia, bedtime insulin is the easiest way to correct this abnormality.
When the previous approaches are unsuccessful, the patient should be switched to conventional twice-daily or multiple daily dose insulin with or without an insulin sensitizer. The author prefers metformin in this scenario if there are no problems with tolerability or contraindications. If a glitazone is used, a moderate dose should be administered to minimize fluid retention and weight gain.
A necessary condition for twice-daily insulin to succeed is a regimented lifestyle, with mealtimes regularly spaced and insulin injections taken at essentially the same time every day, including weekends and holidays. Lack of regularity in the schedule is self-defeating for this approach to therapy. The author limits the use of premixed insulin to patients who might have trouble mixing their insulins. The author also prefers premixes containing regular insulin if the premix is administered to maintain better midday coverage. Premixes with rapid-acting medications can be used if the midday meal is small. All insulin injections should be administered in the abdomen.
A systematic review found that glycemic control with premixed insulin analogues (i.e., mixtures of rapid-acting and intermediate-acting insulin analogues) is similar to that of premixed human insulin.
Conventional multiple daily dosing of insulin gives the patient the greatest flexibility. In this approach, insulin glargine or twice-daily insulin detemir is generally given as the basal insulin, and rapid-acting insulin (e.g., aspart, glulisine, lispro) are administered just before each meal. The basal component can be administered any time of day as long as it is given at the same time each day. Interpreting glucose patterns is probably easiest if the basal insulin is administered at or near bedtime. The basal insulin can then be titrated to the morning sugar, and the bolus premeal insulin can be titrated to the next premeal sugar and, in some cases, a postprandial (2 h) value.
For patients trying to achieve near euglycemia, premeal glucose values of 80-120 mg/dL are the goal, with the patient going to sleep at night with a value at least 100 mg/dL. In patients with less stringent glycemic goals (e.g., because of advanced age, advanced complications, severe concomitant disease), preprandial glucose values of 100-140 mg/dL are desired. Because of the limitations of therapies, essentially no patient is able to achieve these goals all the time if, in fact, insulin is needed to treat their disease.
Unlike in long-standing type 1 diabetes mellitus, patients with type 2 diabetes mellitus usually maintain adequate warning symptoms and signs of hypoglycemia. This situation greatly facilitates hypoglycemic therapy (i.e., insulin secretagogues, insulin) in patients with type 2 diabetes.
Glycemic control is a function of not only of fasting and preprandial glucose values but also of postprandial glycemic excursions. Emphasis on postprandial glucose measurements has been fueled to some degree by the availability of short-acting insulin secretagogues, very – short-acting insulin, and alpha-glucosidase inhibitors, all of which target postprandial glycemia. While postprandial glucose levels are a better predictor of macrovascular disease risk early in the course of loss of glucose tolerance, it remains to be seen whether targeting after-meal glucose excursions has more of an effect on the risk of complications than do more conventional strategies.
Intuitively, one would assume that therapies that normalize preprandial and postprandial glycemia (or that come close to normalizing them) would be optimal. Whether such a strategy can be achieved without untoward adverse effects and with further reductions in microvascular and macrovascular disease risk (compared to regimens used in the UKPDS) with newly available therapies is open to question. Practically speaking, most patients are fully occupied trying to do conventional glucose monitoring and insulin dose adjustment.