Pharmacologic therapy for type 2 diabetes mellitus,type 2 diabetes symptoms pdf viewer,how to reduce sore muscles after a workout routine - Reviews


The American Diabetes Association (ADA) released standards of medical care in diabetes for 2014.
Add second oral agent, glucagon-like peptide (GLP)-1 receptor agonist, or insulin if noninsulin monotherapy at maximal tolerated dose does not achieve or maintain A1C target over 3 months. Consider: efficacy, cost, potential side effects, effects on weight, comorbidities, hypoglycemia risk, patient preferences.
Insulin therapy is eventually needed for many patients due to the progressive nature of type 2 diabetes. Osteoporosis is a public health problem affecting 75 million persons in the United States, Europe and Japan, including one third of postmenopausal women and most of the elderly in the United States, Europe and Japan. Milk intake and bone mineral acquisition in adolescent girls: randomised, controlled intervention trial.
The importance of body weight history in the occurrence and recovery of osteoporosis in patients with anorexia nervosa: evaluation by dual x-ray absorptiometry and bone metabolic markers. The initial draft of this commentary was prepared by Ronald Goldenberg MD, FRCPC, FACE, Maureen Clement MD, CCFP, Amir Hanna MB, BCh, FRCPC, FACP, William Harper MD, FRCPC, Andrea Main BScPhm, CDE, Ravi Retnakaran MD, MSc, FRCPC, Diana Sherifali RN, PhD, CDE, Vincent Woo MD, FRCPC, Jean-Francois Yale MD, CSPQ, FRCPC, and Alice Y.Y. The process for the development of the Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada included provisions to update individual chapters prior to the planned published revision in 2018 in the event of significant changes in evidence supporting the recommendations (1).
Since the publication of the 2013 guidelines, several cardiovascular outcome trials have been completed, and they demonstrate the overall cardiovascular safety of 3 dipeptidyl peptidase-4 (DPP-4) inhibitors (alogliptin, saxagliptin, sitagliptin) and 1 glucagon-likeprotein-1 (GLP-1) receptor agonist (lixisenatide) in patients with type 2 diabetes who are at high risk for cardiovascular events (2–5). The results of EMPA-REG OUTCOME are relevant to the management of type 2 diabetes because 40% to 60% of these individuals will die of cardiovascular disease, and the published literature to date shows little evidence that other antihyperglycemic agents provide cardiovascular benefits in patients with clinical CVD (7,8).
Metformin may be used at the time of diagnosis, in conjunction with lifestyle management (Grade D, Consensus). Individuals with symptomatic hyperglycemia and metabolic decompensation should receive an initial antihyperglycemic regimen containing insulin with or without metformin (Grade D, Consensus). Metformin should be the initial drug used in monotherapy (Grade A, Level 1A) (15,16) for overweight patients; Grade D, Consensus for nonoverweight patients).
In people with clinical cardiovascular disease in whom glycemic targets are not met, an SGLT2 inhibitor with demonstrated cardiovascular outcome benefit should be added to antihyperglycemic therapy to reduce the risk for cardiovascular and all-cause mortality (Grade A, Level 1A for empagliflozin) (6).
When basal insulin is added to antihyperglycemic agents, longacting analogues (detemir or glargine) may be used instead of intermediate-acting Neutral Protamine Hagedorn (NPH) to reduce the risk for nocturnal and symptomatic hypoglycemia (Grade A, Level 1A) (17–19). When bolus insulin is added to antihyperglycemic agents, rapidacting analogues may be used instead of regular insulin to improve glycemic control (Grade B, Level 2) (20) and to reduce the risk for hypoglycemia (Grade D, Consensus).
All individuals with type 2 diabetes currently using or starting therapy with insulin or insulin secretagogues should be counselled about the prevention, recognition and treatment of drug-induced hypoglycemia (Grade D, Consensus). Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58) study record detail (updated December 10, 2015). If glycemic targets are not achieved within 2 to 3 months of lifestyle management, antihyperglycemic pharmacotherapy should be initiated.
Unless contraindicated, metformin should be the initial agent of choice, with additional antihyperglycemic agents selected on the basis of clinically relevant issues, such as contraindication to drug, glucose lowering effectiveness, risk of hypoglycemia and effect on body weight. As people with type 2 diabetes form a heterogeneous group, treatment regimens and therapeutic targets should be individualized.
The initial use of combinations of submaximal doses of antihyperglycemic agents produces more rapid and improved glycemic control and fewer side effects compared to monotherapy at maximal doses (22–25). There is debate over which antihyperglycemic agent (including insulin) should be used initially and which agents should be added subsequently. The recommendation to use metformin as the initial agent in most patients is based on its effectiveness in lowering BG, its relatively mild side effect profile, its long-term safety track record, its negligible risk of hypoglycemia and its lack of causing weight gain. Multiple other agent-specific advantages and disadvantages should be weighed as treatment is individualized to best suit the patient's needs and preferences.
A combination of oral antihyperglycemic agents and insulin often effectively controls glucose levels.
Insulin can be used at diagnosis in individuals with marked hyperglycemia and can also be used temporarily during illness, pregnancy, stress or for a medical procedure or surgery.
As type 2 diabetes progresses, insulin requirements will likely increase, additional doses of basal insulin (intermediate-acting or long-acting analogues) may need to be added and bolus insulin (short-acting or rapid-acting analogues) may also be required. Although not commonly practiced, the use of intensive insulin therapy (basal-bolus regimen or continuous subcutaneous insulin infusion pump), for a transient period of approximately 2 to 3 weeks at the time of diagnosis or early in the disease course, has been shown to induce diabetes remission, subsequently allowing adequate glycemic control with lifestyle management alone (66).
Epidemiological evidence suggesting a possible link between insulin glargine and cancer has not been substantiated in review of clinical trial data for either glargine or detemir (60,68,69). In the United Kingdom Prospective Diabetes Study (UKPDS), the proportion of adults with type 2 diabetes who experienced a severe hypoglycemic episode per year was significantly higher in the intensive group than in the conventional group, particularly for patients using insulin therapy (3). Lower rates of hypoglycemia have been observed in some studies of patients with type 2 diabetes treated with rapid-acting insulin analogues (insulin aspart, insulin lispro, insulin glulisine) compared to those treated with short-acting (regular) insulin (19,73,74). In people with type 2 diabetes, if glycemic targets are not achieved using lifestyle management within 2 to 3 months, antihyperglycemic agent therapy should be initiated [Grade A, Level 1A (3)].
Individuals with symptomatic hyperglycemia and metabolic decompensation should receive an initial antihyperglycemic regimen containing insulin [Grade D, Consensus]. 5.When basal insulin is added to antihyperglycemic agents, long-acting analogues (detemir or glargine) may be used instead of intermediate-acting NPH to reduce the risk of nocturnal and symptomatic hypoglycemia [Grade A, Level 1A (19,78,79)]. 6.When bolus insulin is added to antihyperglycemic agents, rapid-acting analogues may be used instead of regular insulin to improve glycemic control [Grade B, Level 2 (20)] and to reduce the risk of hypoglycemia [Grade D, Consensus)]. 7.All individuals with type 2 diabetes currently using or starting therapy with insulin or insulin secretagogues should be counseled about the prevention, recognition and treatment of drug-induced hypoglycemia [Grade D, Consensus].
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Cheng MD, FRCPC, on behalf of the Steering Committee for the Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada.
In the case of new recommendations or changes to existing recommendations, the process of updating would be the same as the 2013 revision, including the Independent Methodological Review (1). Noninferiority of the primary cardiovascular composite endpoints was achieved, and saxagliptin demonstrated an unexpected increase in hospitalization for heart failure that has yet to be fully explained (2–5). They were randomized to 2 different dosages of empagliflozin (10 mg or 25 mg) or placebo on top of standard care.
Less than 2% of patientswere drug naive, and patients typically had longstanding diabetes and were taking background antihyperglycemic therapies.
Canadian diabetes association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada: Methods. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS); A randomized placebo-controlled trial. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspectivepioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): A multicentre, randomised, openlabel trial.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Effect of intensive bloodglucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Efficacy and safety of insulin analogues for the management of diabetes mellitus: A meta-analysis. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus (review).


Long-acting insulin analogues versus NPH human insulin in type 2 diabetes: A meta-analysis. As type 2 diabetes is characterized by insulin resistance and ongoing decline in beta cell function, glucose levels likely will worsen over time (1), and treatment must be dynamic as therapeutic requirements increase with longer duration of disease. When lifestyle interventions fail to control blood glucose (BG) levels adequately, pharmacological treatment becomes necessary. By and large, the higher the baseline A1C, the greater the A1C reduction seen for each given agent.
Furthermore, many patients on monotherapy with the late addition of another antihyperglycemic agent may not readily attain target BG levels (1). There is also debate over which agents within a given class might be preferred in specific situations.
The demonstrated cardiovascular benefit in overweight patients is also cited as a reason to select metformin as first-line treatment (26), but more recent evidence has been equivocal on this matter (27). In deciding upon which agent to add after metformin, there must be consideration of multiple factors. In particular, attention should be paid to the agent's effects on body weight as this is a clinically relevant issue for many people with type 2 diabetes, and some agents cause significant weight gain while others can help to promote significant weight loss.
When insulin is added to oral antihyperglycemic agent(s), a single injection of intermediate-acting (NPH) (49) or a long-acting insulin analogue (insulin glargine or insulin detemir) (50) may be added. There is no evidence that exogenous insulin accelerates the risk of macrovascular complications of diabetes, and its appropriate use should be encouraged (59,60). Generally, once bolus insulin is introduced into a treatment regimen, either as a separate meal time bolus or as part of a premixed containing regimen, insulin secretagogues, such as sulfonylureas and meglitinides, are usually discontinued. This normoglycemic state is often transient, however, and such interventions have been tested only in patients early in the course of disease where the degree of residual beta cell function is relatively preserved (67).
Physicians should refer to the most recent edition of the Compendium of Pharmaceuticals and Specialties (Canadian Pharmacists Association, Ottawa, Ontario, Canada) for product monographs and detailed prescribing information.
It is estimated that hypoglycemia of any severity occurs annually in up to approximately 20% of patients taking insulin secretagogues (70). Although the risk of hypoglycemia was less than that seen in the patients with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT), each year approximately 3% of patients treated with insulin in the UKPDS experienced a severe hypoglycemic episode, and 40% had a hypoglycemic episode of any severity (3). Use of long-acting basal insulin analogues (insulin detemir, insulin glargine) reduces the risk of nocturnal hypoglycemia compared to treatment with NPH insulin (19,50,75–79). To break this cycle, a dually focused treatment that includes both pharmacologic and nonpharmacologic therapies is recommended.PowerPoint slides for teachingDownloading may take up to 30 seconds.
Because osteoporosis is usually asymptomatic until a fracture occurs, family physicians must identify the appropriate timing and methods for screening those at risk. Therefore, early menopause or premenopausal estrogen deficiency states may hasten the development of primary osteoporosis. However, they are important in screening for secondary forms of osteoporosis and directing the evaluation. Working with patients to prevent, treat and manage osteoporosis: a curriculum guide for health professions. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP.
More recently, the first cardiovascular outcome trial of the sodium glucose linked transporter 2 (SGLT2) inhibitor classwas published, and it demonstrated cardiovascular superiority, thereby qualifying as a practice-changing study (6). More than 98% of the patients were receiving antihyperglycemic agents prior to randomization, and approximately 75% were taking metformin. The lag period before adding other antihyperglycemic agent(s) should be kept to a minimum, taking into account the characteristics of the different medications.
When combining antihyperglycemic agents with or without insulin, classes of agents that have different mechanisms of action should be used. Symptomatic patients with high BG and A1C levels require agents that lower BG levels substantially and quickly (e.g.
While monotherapy with the thiazolidinedione (TZD) rosiglitazone produces more long-lasting glycemic control compared to metformin or glyburide therapy (28), the edema, weight gain, risk of congestive heart failure (CHF), increased risk of fractures (29,30) and inconsistent data regarding myocardial infarction (MI) risk (31–33) significantly limit the clinical utility of this drug class. GLP-1 receptor agonists are particularly effective at promoting concomitant glycemic control and weight reduction (45–48), but long-term efficacy and safety data are currently lacking for this class. This approach may result in better glycemic control with a smaller dose of insulin (51), and may induce less weight gain and less hypoglycemia than that seen when oral agents are stopped and insulin is used alone (52). Concomitant metformin therapy, unless contraindicated, should be continued with regimens containing bolus insulin, including intensive basal-bolus regimen, to allow for improved glycemic control with less risk of weight gain and hypoglycemia (65). Although these hypoglycemic episodes are rarely fatal, they can be associated with serious clinical sequelae. Prevention is the most important step, and women of all ages should be encouraged to take 1,000 to 1,500 mg of supplemental calcium daily, participate in regular weight-bearing exercise, avoid medications known to compromise bone density, institute hormone replacement therapy at menopause unless contraindicated and avoid tobacco and excessive alcohol intake.
Prolonged periods of inadequate calcium intake, sedentary lifestyle and tobacco and alcohol abuse also contribute to this condition.Secondary osteoporosis results from chronic conditions that contribute significantly to accelerated bone loss. However, osteoporosis in men is now recognized as an important health problem, particularly in the aged.9 Many clinical decisions involving men must be based on extrapolations from what is known about osteoporosis in women. A medical history provides valuable clues to the presence of chronic conditions, behaviors, physical fitness and the long-term use of medications that could influence bone density.Those already affected by complications of osteoporosis may complain of upper- or midthoracic back pain associated with activity, aggravated by long periods of sitting or standing, and easily relieved by rest in the recumbent position. Baseline glycated hemoglobin (A1C) levels were in the 7% to 10% range, with a mean A1C level of 8.1%, and 82% had had diabetes for more than 5 years (6). Therefore, empagliflozin should be utilized in patients with type 2 diabetes and clinical CVD who are already taking antihyperglycemic therapy. Lifestyle modification, including nutritional therapy and physical activity, should continue to be emphasized while pharmacotherapy is being used as many agent classes can cause weight gain as a side effect. Several classes of antihyperglycemic agents have greater efficacy at lowering postprandial BG levels (7–20), although adopting an approach of specifically targeting postprandial BG control has not been shown to be effective at reducing macrovascular diabetes complications (21).
Although meta-analyses of smaller, underpowered studies suggested possible risk of MI with rosiglitazone (31,32), this has not been demonstrated in a larger randomized clinical trial (33,34). The addition of bedtime insulin to metformin therapy leads to less weight gain than insulin plus a sulfonylurea or twice-daily NPH insulin (53). There was a neutral effect on cardiovascular outcomes and cancer, a reduction in new-onset diabetes and a slight increase in hypoglycemia and weight. Therefore, it is important to prevent, recognize and treat hypoglycemic episodes secondary to the use of insulin secretagogues. Hunt The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. Arora Improved postprandial glycemic control during treatment with Humalog Mix25, a novel protamine-based insulin lispro formulation.
Nikkila Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus.
Nuttall Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM). All postmenopausal women who present with fractures as well as younger women who have risk factors should be evaluated for the disease. These chronic conditions include endogenous and exogenous thyroxine excess, hyperparathyroidism, malignancies, gastrointestinal diseases, medications, renal failure and connective tissue diseases.7A  Osteoporosis is a common complication of long-term glucocorticoid therapy and is responsive to bisphosphonates in this setting. Approximately 80% were taking renin-angiotensin-aldosterone system inhibitors, statins and acetylsalicylic acid (6).


EMPA-REG OUTCOME is the first completed cardiovascular outcome trial to include an SGLT2 inhibitor, so it is currently unknown whether the other members of this class provide the same CV benefits. However, the issue of how to reach glycemic targets may be less important than the need to achieve that target.
Conversely, the evidence for pioglitazone suggests a possible reduced risk of cardiovascular events, although heart failure and increased fractures are still concerning side effects (35,36).
While combining insulin with a TZD is not an approved indication in Canada, the addition of such agents to insulin in carefully selected patients improves glycemic control and reduces insulin requirements (54). Indeed, use of insulin earlier in the course of type 2 diabetes can be an effective strategy over oral antihyperglycemic agents (60,61).
Few large, randomized clinical trials have compared the rates of hypoglycemia between these agents.
Physicians should recommend bone mineral density testing to younger women at risk and postmenopausal women younger than 65 years who have risk factors for osteoporosis other than being postmenopausal. Secondary forms of osteoporosis are listed in Table 1.8 If secondary osteoporosis is suspected, appropriate diagnostic work-up could identify a different management course. Osteoporosis-related fracture in older men is associated with lower femoral neck bone mineral density, quadriceps weakness, higher body sway, lower body weight and decreased stature.10Osteoporosis is much more common in older persons and in the ethnic groups previously mentioned.
Low bone density, a propensity to fall, greater height and prior fractures are indications of increased fracture risk.The physical examination should be thorough for the same reasons. The primary outcome was a composite cardiovascular endpoint of death from cardiovascular causes, nonfatal MI or nonfatal stroke and occurred less commonly in the group taking empagliflozin (both doses combined) compared to recipients of placebo (10.5% vs. Table 1 identifies the mechanism of action for all classes of antihyperglycemic agents to aid the reader in avoiding the selection of agents with overlapping mechanisms.
Improved BG and A1C levels are associated with better outcomes, even if recommended glycemic targets cannot be reached (3). Such combinations can result in increased weight, fluid retention and, in few patients, CHF. When insulin is used in type 2 diabetes, the insulin regimen should be tailored to achieve good metabolic control while trying to avoid excessive hypoglycemia. Bone mineral density testing should be recommended to all women 65 years and older regardless of additional risk factors. Osteoporotic fractures are more common in whites and Asians than in blacks and Hispanics, and are more common in women than in men.
For example, if a pituitary tumor is identified, surgical removal could prevent ongoing accelerated bone loss. For example, lid lag, and enlargement or nodularity of the thyroid suggest hyperthyroidism.
The management of hyperglycemia in type 2 diabetes is summarized in Figure 1, which integrates the findings of EMPA-REG OUTCOME by prioritizing the presence of clinical cardiovascular disease when adding an antihyperglycemic and choosing an SGLT2 inhibitor with demonstrated CV benefits in this patient population. Unfortunately, the majority of evidence remains equivocal in this regard as most clinical trials compared varying levels of glycemic lowering as opposed to direct comparison between agents used to achieve such glycemic control (38–40).
DPP-4 inhibitors and GLP-1 receptor agonists have been shown to be effective at further lowering glucose levels when combined with insulin therapy (55–58). With intensive glycemic control, there is an increased risk of hypoglycemia, but this risk is lower in people with type 2 diabetes than in those with type 1 diabetes.
Bone mineral density screening should be used as an adjunct to clinical judgment only if the results would influence the choice of therapy or convince the patient to take appropriate preventive measures. One possible reason is that blacks and men achieve higher peak bone densities than whites and women. One example of genetically determined osteoporosis is seen in patients with Turner's syndrome (45XO gonadal dysgenesis). Figure 2 illustrates the basis on which agent selection is influenced by renal function as dictated by product monograph precautions. More recent studies looking at the benefits seen with select agents are of such short duration that their results are still preliminary with respect to proving clinical event reduction (41–44) and confirmation awaits the results of more definitive long-term studies. The number of insulin injections (1 to 4 per day) and the timing of injections may vary, depending on each individual's situation (62).
With respect to women, age-related bone loss accelerates during menopause as estrogen levels decrease.5Primary vs.
Only data fromprospective randomized controlled trials of CV outcomes with a specific antihyperglycemic agent were included in this column. The reduction in A1C achieved with insulin therapy depends on the dose and number of injections per day (63). Therewere modestmetabolic benefits and, overall, empagliflozin was well tolerated, although genital infections occurred at a higher rate in patients treated with empagliflozin (6). Therefore, in addition to the data fromrecent trials of incretin and an SGLT2 inhibitor, the new column includes the CV neutrality of insulin glargine (11) and thiazolidinediones (12,13) in CV outcome trials. Insulin regimens based on basal or bolus insulin appear to be equally effective (21,64) and superior with respect to glycemic lowering compared to biphasic insulin-based regimens (63).
Unquestionably, adolescents must maintain a dietary balance among calcium, protein, other calorie sources and phosphorus. As future cardiovascular outcome trials of antihyperglycemic agents are published, the guidelines committee will continue to assess new evidence and update as appropriate. For example, phosphorus is a substantial component of carbonated drinks, and high phosphorus intake compromises calcium uptake by bone, thereby promoting decreased bone mass.Eating disorders also affect bone mineral density. The presence of a dowager's hump (spinal curvature) in elderly patients indicates multiple vertebral fractures and decreased bone volume.LABORATORY TESTSBasic chemical analysis of serum is indicated when the history suggests other clinical conditions influencing the bone density.
The tests presented in Tables 3 7 and 45 are appropriate for excluding secondary causes of osteoporosis.7 These tests provide specific clues to serious illnesses that may otherwise have gone undetected and which, if treated, could result in resolution or modification of the bone loss. Specific biochemical markers (human osteocalcin, bone alkaline phosphatase, immunoassays for pyrinoline cross-links and type 1 collagen-related peptides in urine) that reflect the overall rate of bone formation and bone resorption are now available. Excessive alcohol consumption has been shown to depress osteoblast function and, thus, to decrease bone formation. These include DXA scans of the distal forearm and the middle phalanx of the nondominant hand, and a variety of devices for obtaining quantitative ultrasound measurements on bone. The predictive value of these peripheral measures in assessing fracture risk at the hip or vertebrae is not clear. If follow-up measurements are needed to monitor therapy, the peripheral scans can be compared with the original measurements.
Follow-up measures must be obtained using the same instruments to ensure reliability of data.Bone densitometry reports provide a T score (the number of standard deviations above or below the mean bone mineral density for sex and race matched to young controls) or a Z score (comparing the patient with a population adjusted for age, sex and race). The bone mineral density result enables the classification of patients into three categories: normal, osteopenic and osteoporotic.
Bone densitometry can assist in the decision-making process if the patient's age confers risk, there are no manifestations of disease and the decision point is prevention versus treatment.



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