To associate a basal insulin dose to the treatment. Expected question on a very important subject: diabetes and its treatment. Patient poorly controlled with metformin and sitagliptin with discrete cardinal symptoms (weight loss, asthenia). The best option is insulin to control cardinal symptoms and decrease HbA1c to < 7%.

A 62-year-old man with type 2 diabetes mellitus of 10 years of evolution is treated with metformin and sitagliptin. He does little physical exercise and follows an adequate diet. In the last 6 months he has lost weight and has more asthenia. Her glycemic controls have deteriorated from baseline blood glucose levels of 110-140 mg/dL to 170-200 mg/dL, as well as her glycosylated hemoglobin which has gone from 7.1 to 8.5%. The most appropriate therapeutic measure to be taken is:

Increase dietary protein and long-chain carbohydrate intake to improve asthenia and weight loss.

Substitute sitagliptin for pioglitazone.

[Therapeutic behavior to follow in the following clinical case: treatment of type 2 diabetes].

A 62-year old woman with obesity, high blood pressure and type 2 diabetes mellitus (DM2) was referred to a Vascular Risk Unit of the Internal Medicine Department due to elevated HbA1C (8.1%) in spite of having taken metformin (850 mg/12h) and glipizide (10 mg/12 h) regularly. She tries to exercise daily (walking 30 min) and has lost weight (from 5 to 12 kg) several times, but always regains what she has lost. Furthermore, she monitors her glucose levels in fasting every two weeks and generally has between 120 and 160 mg/dL. Her high blood pressure is being treated with enalapril/HCTZ and she also takes aspirin 100mg/day and simvastatin 20 mg/day. It is seen in her family background that one brother died suddenly at 50 years of age. Her physical examination shows a BMI of 32.4 Kg/m(2), and she has no edemas in the lower limbs. Her BP is 154/82 mmHg and creatinine 0.9 mg/dL. She has no microalbuminuria and her liver function is normal. What treatment do you think would be the more appropriate? 1 - Add glitazones. 2 - Add incretin mimetics (GLP 1/ DPP-4). 3 - Slow acting insulin.

[Sequential treatment with insulin glargine and metformin, and exenatide in a patient with newly diagnosed type-2 diabetes].

HISTORY AND ADMISSIONS FINDINGS: A 54-year-old man was admitted to hospital for treatment of a newly diagnosed type 2 diabetes. He had polydipsia and polyuria and had lost 11 kg in weight over four weeks. Further diagnoses were visceral obesity and arterial hypertension. Laboratory tests revealed highly elevated blood glucose parameters (HbA1c 14,9 %, fasting glucose 280 mg/dl, maximal postprandial glucose 430 mg/dl and 320 mg/dl before the meal) and triglyceride (2219 mg/dl). The patient was initially treated with a combination of insulin glargine and metformin. After a few days exenatide was added, as the patient wanted to be able to go without insulin. He was given a structured diabetes education and motivated to have five to six hours' of physical activity and a low glycemic diet. After a few days normal glucose levels had been achieved. After one month the insulin treatment was discontinued. The continuing treatment with metformin, 1000 mg twice daily, and exenatide, 5 mg twice daily, prolonged remission of beta-cell dysfunction and maintained normal blood glucose levels for seven months. After reduction of the metformin dosage (500 mg twice daily) and discontinuance of exenatide as well as a reduction of his physical activity (because of joint pain) for six months, the glucose control worsened. When exenatide was administered again, good control of postprandial blood glucose, but not of fasting glucose was achieved. Initial combination treatment with insulin glargine, metformin and exenatide may be beneficial in a subgroup of patients with newly diagnosed type 2 diabetes, markedly elevated blood glucose and free fatty acid levels (glucolipotoxicity). This should be further investigated in randomized controlled trials.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin.

To assess the efficacy and safety of a 24-week treatment with sitagliptin, a highly selective once-daily oral dipeptidyl peptidase-4 (DPP-4) inhibitor, in patients with type 2 diabetes who had inadequate glycaemic control [glycosylated haemoglobin (HbA(1c)) >or=7.5% and <or=10.5%] while on glimepiride alone or in combination with metformin. After a screening, diet/exercise run-in and drug wash-off period, a glimepiride +/- metformin dose titration/stabilization period and a 2-week, single-blind placebo run-in, 441 patients (of ages 18-75 years) were randomized to receive the addition of sitagliptin 100 mg once daily or placebo in a 1 : 1 ratio for 24 weeks. Of these patients, 212 were on glimepiride (>or=4 mg/day) monotherapy and 229 were on glimepiride (>or=4 mg/day) plus metformin (>or=1,500 mg/day) combination therapy. Patients exceeding pre-specified glycaemic thresholds during the double-blind treatment period were provided open-label rescue therapy (pioglitazone) until study end. The primary efficacy analysis evaluated the change in HbA(1c) from baseline to Week 24. Secondary efficacy endpoints included fasting plasma glucose (FPG), 2-h post-meal glucose and lipid measurements. Mean baseline HbA(1c) was 8.34% in the sitagliptin and placebo groups. After 24 weeks, sitagliptin reduced HbA(1c) by 0.74% (p < 0.001) relative to placebo. In the subset of patients on glimepiride plus metformin, sitagliptin reduced HbA(1c) by 0.89% relative to placebo, compared with a reduction of 0.57% in the subset of patients on glimepiride alone. The addition of sitagliptin reduced FPG by 20.1 mg/dl (p < 0.001) and increased homeostasis model assessment-beta, a marker of beta-cell function, by 12% (p < 0.05) relative to placebo. In patients who underwent a meal tolerance test (n = 134), sitagliptin decreased 2-h post-prandial glucose (PPG) by 36.1 mg/dl (p < 0.001) relative to placebo. The addition of sitagliptin was generally well tolerated, although there was a higher incidence of overall (60 vs. 47%) and drug-related adverse experiences (AEs) (15 vs. 7%) in the sitagliptin group than in the placebo group. This was largely because of a higher incidence of hypoglycaemia AEs (12 vs. 2%, respectively) in the sitagliptin group compared with the placebo group. Body weight modestly increased with sitagliptin relative to placebo (+0.8 vs. -0.4 kg; p < 0.001). Sitagliptin 100 mg once daily significantly improved glycaemic control and beta-cell function in patients with type 2 diabetes who had inadequate glycaemic control with glimepiride or glimepiride plus metformin therapy. The addition of sitagliptin was generally well tolerated, with a modest increase in hypoglycaemia and body weight, consistent with glimepiride therapy and the observed degree of glycaemic improvement.

Glycemic control: a combination of lifestyle management and the use of drugs.

Some 30% of contemporary cardiology patients have coexisting known diabetes, and another 40% have either undiagnosed diabetes or prediabetes. There is still no final conclusive evidence of cardiovascular benefit by good glycemic control in type 2 diabetes, although studies like the United Kingdom Prospective Diabetes Study (UKPDS) and the Prospective Pioglitazone Clinical Trial in Macrovascular Events, and meta-analyses based on these and other randomized controlled trials of blood glucose-lowering therapies have been encouraging. On the other hand, microvascular disease is clearly reduced by good glycemic control. Structured education has remained a mandatory prerequisite of any successful treatment. Not only is appropriate weight management by diet and exercise able to revert new onset diabetes to normal, but it is also the foundation of any successful pharmacotherapy of diabetes. Aiming at normal fasting plasma glucose concentrations of 5.3 mmol/L or 95 mg/dL appears to be safe since publication of the long-term outcome results of the Outcome Reduction with an Initial Glargine INtervention trial. Individualized target glycosylated hemoglobin levels as near to normal as safely possible (i.e., <7% and avoiding hypoglycaemia) are the goal for glycemic control. Hypoglycemia seems to emerge as a real concern in cardiology patients. Based on the findings of UKPDS, including the "legacy" study, metformin is the most widely recommended first-line drug therapy in type 2 diabetes, also in terms of preventing cardiovascular complications. An alternate first-line option in some parts of the world, especially Asian countries, is the class of alpha-glucosidase inhibitors. In most patients, combination therapies with two or three classes of drugs are warranted. Early combination are the golden strategy as type 2 diabetes is a multi-causal disease; the various classes of drugs have distinct and synergistic modes of action, and the blood glucose-lowering efficacy of these drugs is more or less fully maintained in combination. The recent joint American Diabetes Association/European Association for the Study of Diabetes position statement mentions five options as step two of the treatment algorithm for combination with metformin: sulfonylureas, pioglitazone, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, and basal insulin.

Induction of long-term glycemic control in type 2 diabetic patients using pioglitazone and metformin combination.

To study the effects of pioglitazone and metformin combination in type 2 diabetics in achieving long-term optimal glycemic control. Patients whose duration of type 2 diabetes was less than 24 months were selected for the study. 373 such patients meeting the selection criteria were included in the study and were started on triple drug combination therapy. Three hundred seventy three (183 females and 190 males) patients were initiated on a triple drug combination of gliclazide 80 mg, tid, metformin 500 mg tid and pioglitazone 30 mg od. Once controlled, the doses of gliclazide were reduced if the blood glucose levels decreased. Those patients whose plasma glucose remained in the normal range for more than 6 months without the use of a sulphonylurea were considered to be in pharmacological remission. 48 patients were lost to follow up. At the beginning of the study the pre treatment biochemical parameters in these 325 diabetic patients at the time of enrolment were: average FBG of 209.44+/-73.82 mg/dl, PLBG 294.96+/-107.58 mg/dl, and HbA(1c) 11.21+/-3.85. The post treatment glycemic parameters were: FBG was 124.38+/-40.48 mg/dl (p < 0.0001), and PLBG 162.32+/-54.33 mg/dl (p < 0.001), average glycosylated hemoglobin was 6.45+/-2.17 (p < 0.001). After using the triple drug combination pharmacological remission was achieved in 36.3 percent i.e. 118 (60 males and 58 females) patients. The average time required for achieving remission was 4 (+/-3.3) months in males and 5 (+/-4.02) months in females. 118 patients were maintained remission after 2 years of follow up. The average duration of remission is 27 (+/-2.66) months. There was an average weight gain of 2.56 +/- 1.32 kg in both the groups of patients in remission and those who could not achieve remission. In this study we have found that we could achieve long term glycemic control 'pharmacological remission' in 118 of the 325 patients i.e.36% of type 2 diabetic patients. Insulin sensitizers like pioglitazone along with metformin may induce long-term glycemic control in type 2 diabetic patients.

Managing type 2 diabetes: going beyond glycemic control.

Aggressive management of type 2 diabetes is necessary to achieve glycemic and nonglycemic treatment goals. Attainment of treatment goals is associated with a decreased risk of diabetes-related complications, costs, and health care utilization. To review the advantages and disadvantages of different glucose-lowering agents, with an emphasis on the role of thiazolidinediones (TZDs). Diabetes has become increasingly prevalent, particularly among younger age groups in the United States, accounting for approximately 15% of health care expenditures by managed care organizations. Reducing a patient's glycated hemoglobin (A1C) has been shown to decrease the risk of diabetes-related complications, as well as reduce medical costs and health care utilization. Despite this knowledge, achievement of the American Diabetes Association (ADA) goal A1C of < 7% is suboptimal, and < 1 in 10 patients also reach the ADA targets for cholesterol (low-density lipoprotein < 100 mg per dL) and blood pressure (< 130/80 mm Hg). To ensure that all ADA treatment goals are met, clinicians need to closely monitor patients and adjust therapy as needed, taking into consideration both a drug's glycemic and nonglycemic effects when selecting medication therapy. Four basic defects contribute to type 2 diabetes: insulin resistance, decreased insulin secretion, increased hepatic glucose production, and reduced glucagon-like peptide-1 levels. Unlike metformin, sulfonylureas, and insulin that address only 1 or 2 physiologic defects, TZDs uniquely address 3 of these defects at the adipocyte. Metformin is recommended for initial drug therapy; TZDs, sulfonylureas, and insulin are useful options as add-on therapy for patients whose A1C levels remain >or= 7% despite treatment with metformin and lifestyle interventions. It has been suggested that TZDs, when used either as add-on therapy or when appropriate as monotherapy, may conserve pancreatic beta-cell function over an observed 3- to 5-year period of time and sustain a decrease in A1C ranging from 0.5%-1.5%. Although rarely associated with hypoglycemia, TZDs may cause total body weight gain that is most commonly caused by volume expansion, which may manifest as new or worsened heart failure in susceptible individuals. Pioglitazone and rosiglitazone, the 2 TZDs available in the United States, contain black box label warnings about their potential to cause or exacerbate congestive heart failure; additional data have suggested a link to ischemic cardiac events. Recent data also suggest that TZDs may reduce bone density. Conversely, pioglitazone may have some vasculoprotective effect related to elevation of high-density lipoprotein and lessened progression of carotid intima-media thickness; however, any effect on macrovascular clinical outcomes is unknown. Other drug options are available for the treatment of type 2 diabetes, such as incretin-based therapies. Yet despite their favorable effects on glycemia, they have not been included to date in the ADA treatment algorithm. Proper glycemic control and attainment of other nonglycemic management targets (e.g., blood pressure, lipids, body weight) are essential to the prevention of long-term complications of diabetes and to reduction of overall disease management costs. Therefore, patients with diabetes should be followed closely to ensure that they achieve and maintain both glycemic and nonglycemic treatment goals. Most patients will not sustain an adequate level of control using nondrug or single-drug therapeutic approaches. When choosing among treatment options, consideration should be given to the nonglycemic as well as glycemic effects of various glucose-lowering agents.

Effects of replacing metformin with pioglitazone on glycemic control in japanese patients with poorly controlled type 2 diabetes mellitus: A 12-week, open-label, prospective study.

Insulin resistance is a critical aspect of the pathophysiology of type 2 diabetes mellitus and is also associated with other risk factors for cardiovascular disease (eg, dyslipidemia and hypertension). Accordingly, insulin resistance is a possible target for lowering plasma glucose concentration and preventing diabetic macroangiopathy. Biguanides, such as metformin, and thiazolidinediones (TZDs), such as pioglitazone, improve insulin resistance. The aims of this study were to assess the effects of replacing a biguanide with a TZD on glycemic control in patients with poorly controlled type 2 diabetes mellitus, and also to identify the factors affecting interpatient variation in the effects of treatment change. This was a 12-week, open-label, prospective study in which previously prescribed metformin (500 or 750 mg/d) was replaced with pioglitazone (15 or 30 mg/d) in patients with poorly controlled type 2 diabetes mellitus. Patients with a glycosylated hemoglobin (HbA1c) concentration >7% despite treatment with diet, exercise, and hypoglycemic agents other than TZDs were eligible for the study. Patients who never received TZDs were also eligible for inclusion. Vital signs, metabolic parameters, and arterial stiffness were assessed at baseline and after 12 weeks of treatment with pioglitazone. The primary end point was change in HbA1c concentration after replacing metformin with pioglitazone. Tolerability was assessed by medical history, physical examination, and laboratory tests (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase). Twenty-one Japanese patients (15 women, 6 men; mean [SD] age, 61.8 [8.4] years; body mass index, 25.5 [3.0] kg/m(2)) were included in the study. HbA1c concentration was not significantly changed from baseline after 12 weeks of pioglitazone treatment (8.0% [0.7%] vs 8.2% [0.7%]). Fasting plasma glucose (FPG) concentration also was not significantly changed after the replacement of treatment (156 [27] vs 144 [30] mg/dL). In addition, the resistin concentration did not change significantly from baseline after 12 weeks of pioglitazone treatment (6.6 [3.8] vs 6.4 [3.6] ng/mL). In contrast, significant improvement from baseline was observed in triglyceride (TG) concentrations (157 [109] vs 117 [68] mg/dL; P = 0.003), high-density lipoprotein cholesterol (HDL-C) (55 [12] vs 61 [16] mg/dL; P = 0.016), remnant-like particle cholesterol (6.6 [6.0] vs 5.3 [3.5] mg/dL; P = 0.048), and serum adiponectin (8.8 [4.3] vs 23.3 [11.7] μg/mL; P < 0.001). Pulse wave velocity was also significantly improved (1730 [361] vs 1622 [339] m/sec; P = 0.009). Changes in HbA1c were significantly correlated with serum fasting insulin concentration at baseline in the patients not receiving insulin preparations (r = -0.635, P = 0.013). The percentage change in serum adiponectin concentration was correlated with the percentage changes in HbA1c and FPG concentrations (HbA1c, r = -0.518, P = 0.019; FPG, r = -0.594, P = 0.006). Body weight was significantly increased after treatment (62.6 [11.9] vs 65.5 [12.2] kg; P < 0.001). Mild edema was reported in 5 patients. One patient discontinued treatment due to an increase in serum creatine kinase activity to ~6.6 times the upper limit of normal. Replacement of metformin with pioglitazone did not produce significant differences in HbA1c and FPG concentrations from baseline after 12 weeks of treatment in these patients with poorly controlled type 2 diabetes mellitus. However, the replacement was effective in a subset of patients whose serum insulin concentrations were high or whose serum adiponectin concentrations were sensitive to TZDs. In addition, the replacement was associated with significant improvements in TG, HDL-C, serum adiponectin concentration, pulse wave velocity, and body weight increase from baseline.

Sitagliptin/metformin

Medical uses In the United States, sitagliptin/metformin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. In the European Union, sitagliptin/metformin is indicated as an adjunct to diet and exercise to improve glycemic control in people with type 2 diabetes; in combination with a sulfonylurea as an adjunct to diet and exercise "in people inadequately controlled on their maximal tolerated dose of metformin and a sulfonylurea; as triple combination therapy with a peroxisome proliferator-activated receptor (PPAR) agonist (i.e., a thiazolidinedione) as an adjunct to diet and exercise in people inadequately controlled on their maximal tolerated dose of metformin and a PPAR agonist; and as add on to insulin as an adjunct to diet and exercise to improve glycemic control in people when stable dosage of insulin and metformin alone do not provide adequate glycemic control."

Is insulin the preferred treatment for HbA1c >9%?

The algorithms and guidelines of the American Association of Clinical Endocrinologists and the American Diabetes Association recommend that insulin administration be strongly considered for people with type 2 diabetes (T2D) with HbA1c levels exceeding 9.0% and 10%, respectively. Although the caveat is given in both sets of recommendations that this is particularly appropriate when patients are "symptomatic," referring to urinary frequency with increased thirst and appetite, weight loss, and ketosis, the clinical definition of such presentations may be ill-defined, and it is noteworthy that both documents consider insulin to offer particular benefit under such circumstances. However, with multiple options for glycemic treatment, it is of interest to reconsider this argument for insulin use. It should be recalled that in the UK Prospective Diabetes Study, diet alone was associated with a reduction in HbA1c from 9% to 7%. Drug-naïve people with T2D do often show surprisingly strong reductions in HbA1c with metformin-based dual-agent oral treatment approaches; a recent report showed that even with baseline HbA1c >11%, the combination of metformin with a sulfonylurea, pioglitazone, or sitagliptin was associated with reduction in HbA1c from 11.6% to 6.0%. A 32-week study of the combination of rosiglitazone with metformin in patients with mean baseline HbA1c 8.9% showed a mean HbA1c reduction of 2.3%, and an open-label cohort with baseline HbA1c 11.8% had a reduction in HbA1c to 7.8%. With metformin plus sitagliptin, a mean placebo-adjusted HbA1c reduction of 2.1% from a baseline of 8.8% was reported, with those patients with baseline HbA1c >9% having a 2.6% reduction in HbA1c, and an open-label cohort with baseline HbA1c 11.2% having a 2.9% reduction in HbA1c. Similar 2% HbA1c reductions from baseline levels of 9.1% were seen with metformin in initial combination with the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin. Although such dual oral agent approaches are more effective than monotherapy, with a combination regimen the HbA1c reduction will not be directly additive, because the expected reduction decreases at lower baseline HbA1c levels. As an example of this, administration of canagliflozin 300 mg daily to patients with baseline HbA1c >9% reduced levels from 9.6% by 1.8%, whereas at a baseline HbA1c of 10% either canagliflozin 300 mg or metformin 2 g/day reduced HbA1c by 2%; the addition of both agents led to an HbA1c reduction by somewhat less than 3%, which appears concordant with a reduction by the second agent from approximately 8% (10% to 2%). Similar less-than-additive effects of the addition of exenatide QW to dapagliflozin have been reported, with HbA1c reduction from a baseline of 10.0%-10.1% of 1.9% and 1.6% with the individual agents, respectively, and a reduction of 2.2% with their combination. However, one may consider these approaches inferior to the expected HbA1c reduction with insulin, suggesting that insulin should, indeed, be the preferred treatment for people with T2D and HbA1c >9%. Rather, studies comparing basal insulin directly with glucagon-like peptide-1 (GLP-1) receptor agonists (RA) suggest that the latter agents may offer superior benefit. The Diabetes Therapy Utilization: Researching Changes in HBA1C, Weight, and Other Factors Through Intervention with Exenatide Once Weekly (DURATION)-3 and Liraglutide Effect and Action in Diabetes (LEAD)-5 studies compared exenatide QW and liraglutide, respectively, with insulin glargine. Those study participants in the highest quartile of baseline HbA1c had levels ≥9.0% and ≥8.9%, with the GLP-1RA leading to 0.3% and 0.2% greater reductions in HbA1c, respectively, than insulin glargine. Another study comparing T2D patients receiving oral agents given liraglutide with those given insulin glargine showed that those in the highest baseline HbA1c quartile (mean 10.6%) had an HbA1c reduction of 3.1% with either agent. In the exenatide QW study, the reduction in HbA1c with this agent exceeded that with insulin glargine for those groups of study participants with HbA1c 9.0%-9.4%, 9.5%-9.9%, 10.0%-10.4%, 10.5%-10.9%, and even ≥11.0%. Similar superiority of the HbA1c-lowering effect of exenatide QW compared with that of insulin glargine was reported in a study with baseline HbA1c 8.5%. An individual-patient meta-analysis of six studies of another weekly GLP-1RA, namely dulaglutide, showed that at a baseline HbA1c of 10% the expected HbA1c reduction would be nearly 2.5%, and a study directly comparing dulaglutide with insulin glargine also showed a superior HbA1c-lowering effect of the former. Another advantage of the GLP-1RAs is their association with weight loss, rather than the weight gain associated with insulin treatment. An interesting potential combination is that of a GLP-1RA with a thiazolidinedione. In a study comparing the addition of exenatide QW and pioglitazone with the addition of basal-bolus insulin in 101 people receiving sulfonylureas and metformin with baseline HbA1c >10%, HbA1c fell from >11% by >4% compared with <4%, respectively, and the GLP-1RA plus thiazolidinedione treatment was associated with less weight gain and hypoglycemia. What can we conclude? Should HbA1c 11% be the new "use insulin" point? Insulin is an important part of our armamentarium for T2D, and is certainly needed for many patients, but with current therapeutic approaches including metformin, incretin-based treatments, SGLT2 inhibitors, and, possibly, thiazolidinediones, we can reconsider its use in many instances. Although there is no doubt that insulin is necessary for truly uncontrolled diabetes, we may wish to better define its correct indications.

InternalMed_Harrison

follow-up by the health care provider, possibly in the presence of a caregiver. Chlorpropamide has a prolonged half-life, particularly in older adults, and should be avoided because it is associated with a high risk of hypoglycemia. Metformin should be used with caution and only in patients free of severe renal insufficiency. Renal insufficiency should be assessed by a calculated glomerular filtration rate or, in very old patients who have reduced muscle mass, by a direct measure of creatinine clearance from a 24-h urine collection. Lifestyle changes in diet and exercise and a little weight loss can prevent or delay diabetes in high-risk individuals and are substantially more effective than metformin treatment. The risk of type 2 diabetes decreased by 58% in a study of diet and exercise, and this effect was similar at all ages and in all ethnic groups. The risk reduction with standard care plus metformin was 31%.

Hyperglycemia

In diabetes mellitus (by far the most common cause of chronic hyperglycemia), treatment aims at maintaining blood glucose at a level as close to normal as possible, in order to avoid serious long-term complications. This is done by a combination of proper diet, regular exercise, and insulin or other medication such as metformin, etc. Those with hyperglycaemia can be treated using sulphonylureas or metformin or both. These drugs help by improving glycaemic control. Dipeptidyl peptidase 4 inhibitor alone or in combination with basal insulin can be used as a treatment for hyperglycemia with patients still in hospital. Increasing aerobic exercise to at least 30 minutes will make better use of glucose accumulated in the body since glucose is being used for energy by the muscle. Calorie restriction would be one of the main lifestyle changes because it reduces over eating which contributes to hyperglycemia.

A comparison of glycaemic effects of sitagliptin and sulfonylureas in elderly patients with type 2 diabetes mellitus.

In the USA, 45% of patients with type 2 diabetes mellitus (T2DM) are elderly (≥ 65 years old). In general, use of sulfonylurea increases with patient age as does the associated risk for hypoglycaemia, and the consequences of hypoglycaemia can be more pronounced in elderly patients. Sitagliptin, a DPP-4 inhibitor, improves glycaemic control in adult patients of all ages with T2DM, with a low risk of hypoglycaemia when used alone or in combination with other antidiabetic agents that are not generally associated with hypoglycaemia when used independently. In a post hoc analysis, pooled data from elderly patients who participated in one of three double-blind studies comparing the effects of therapy with sitagliptin (100 mg/day) vs. sulfonylurea (in titrated doses) were analysed for changes from baseline in HbA1c, fasting plasma glucose (FPG), and body weight and for the incidence of reported symptomatic hypoglycaemia. In these studies, patients on diet alone or metformin were randomised to sitagliptin or glipizide for 104 weeks (studies 1 and 2) or glimepiride for 30 weeks (study 3). The analysis included 372 elderly patients who completed a trial through 25 or 30 weeks. Both HbA1c and FPG decreased from baseline with each treatment, with no statistically significant differences between treatments. A significantly lower incidence of reported hypoglycaemia was observed with sitagliptin compared with sulfonylurea (6.2% vs. 27.8%; p < 0.001). Body weight decreased significantly with sitagliptin but not with sulfonylurea. Significantly more patients on sitagliptin than on sulfonylureas achieved a composite end-point of >0.5% HbA1c reduction with no reported hypoglycaemia or increase in body weight (44.1% vs. 16.0%; p < 0.001). In this analysis of elderly patients with T2DM, compared with sulfonylurea, sitagliptin provided similar glycaemic efficacy with less hypoglycaemia and with body weight loss.

Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study.

The BLOOM-DM (Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus) study evaluated efficacy and safety of lorcaserin for weight loss in patients with type 2 diabetes. Secondary objectives included evaluations of glycemic control, lipids, blood pressure, and quality of life. This 1-year, randomized, placebo-controlled trial enrolled 604 patients 1:1:1 to placebo, lorcaserin 10 mg once daily (QD) or lorcaserin 10 mg twice daily (BID). Patients were treated with metformin, a sulfonylurea (SFU) or both; had glycated hemoglobin (HbA(1c)) 7-10%; were 18-65 years old; and had BMI 27-45 kg/m(2). Patients received diet and exercise counseling. Safety monitoring included serial echocardiograms. Mean (± SD) age was 52.7 ± 8.7; 54.2% were women; 60.5% were white, 20.9% were African American, and 13.8% were Hispanic. Mean (± SD) weight was 103.6 ± 17.8 kg; BMI was 36.0 ± 4.5 kg/m(2). Most patients (91.7%) took metformin; 50.2% took a SFU. More patients lost ≥5% body weight with lorcaserin BID (37.5%; P < 0.001) or lorcaserin QD (44.7%; P < 0.001) vs. placebo (16.1%; modified intent to treat (MITT)/last observation carried forward (LOCF)). Least square mean (± SEM) weight change was -4.5 ± 0.35% with lorcaserin BID and -5.0 ± 0.5% with lorcaserin QD vs. -1.5 ± 0.36% with placebo (P < 0.001 for each). HbA(1c) decreased 0.9 ± 0.06 with lorcaserin BID, 1.0 ± 0.09 with lorcaserin QD, and 0.4 ± 0.06 with placebo (P < 0.001 for each); fasting glucose decreased 27.4 ± 2.5 mg/dl, -28.4 ± 3.8 mg/dl, and 11.9 ± 2.5 mg/dl, respectively (P < 0.001 for each). Symptomatic hypoglycemia occurred in 7.4% of patients on lorcaserin BID, 10.5% on lorcaserin QD, and 6.3% on placebo. Common adverse events were headache, back pain, nasopharyngitis, and nausea. Lorcaserin was associated with significant weight loss and improvement in glycemic control in patients with type 2 diabetes.

Vildagliptin/metformin

The most common side effects include nausea (feeling sick), vomiting, diarrhea, abdominal (tummy) pain and loss of appetite. Medical uses Vildagliptin/metformin is indicated in the treatment of type-2 diabetes mellitus: it is indicated in the treatment of adults who are unable to achieve sufficient glycaemic control at their maximally tolerated dose of oral metformin alone or who are already treated with the combination of vildagliptin and metformin as separate tablets. it is indicated in combination with a sulphonylurea (i.e. triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled with metformin and a sulphonylurea. it is indicated in triple combination therapy with insulin as an adjunct to diet and exercise to improve glycaemic control in patients when insulin at a stable dose and metformin alone do not provide adequate glycaemic control. References External links

Glycaemic control without weight gain in insulin requiring type 2 diabetes: 1-year results of the GAME regimen.

Weight gain appears to be unavoidable in patients with type 2 diabetes who are switched from oral agents to insulin therapy. Peripheral hyperinsulinism induced by the use of long-acting insulin may be the key to explain this adverse effect. The aim of this study was to investigate whether a regimen free of long-acting insulin can provide long-term glycaemic control without causing weight gain. This is an uncontrolled, 1-year study comprising 58 patients with type 2 diabetes and secondary failure, age 30-75 years, BMI 25-35 kg/m(2), HbA1c > 7.5% and fasting C-peptide level > 0.3 mmol/l. All patients were treated with the GAME regimen, a combination of glimepiride administered at 20:00 hours for nocturnal glycaemic control, insulin aspart three times daily for meal-related glucose control and metformin. Seventy-one per cent of the patients were considered evaluable. HbA1c decreased from 10.0 +/- 0.3 to 7.4 +/- 0.1% (p < 0.001). Fifty-nine per cent reached HbA1c levels <or= 7.5%. Symptomatic nocturnal hypoglycaemia was not reported. Body weight tended to decrease during the first 3 months (-1.0 +/- 0.5 kg, p = 0.06), but then gradually rose to a value 0.8 +/- 0.5 kg higher than at baseline (p = 0.12). This is 4.4 +/- 0.6 kg less than predicted for conventional regimens employing long-acting insulin (p < 0.001). The GAME regimen provides long-term glycaemic control as well as stabilization of body weight in about 60% of type 2 patients presenting with secondary failure.

Sitagliptin: a novel drug for the treatment of type 2 diabetes.

Type 2 diabetes mellitus is a common chronic disease that causes significant morbidity and mortality worldwide. The primary goal of treatment is to target glycemic control by maintaining the glycosylated hemoglobin level near 6-7% without predisposing patients to hypoglycemia. Diabetes results from a combination of increased hepatic glucose production, decreased insulin secretion from beta cells, and insulin resistance in the peripheral tissues. Currently available antidiabetic agents work by different mechanisms to lower blood glucose levels. Unfortunately, each of them has its tolerability and safety concerns that limit its use and dose titration. Sitagliptin is the first antidiabetic agent from the class of dipeptidyl peptidase-4 enzyme inhibitors. It increases the amount of circulating incretins, which stimulate insulin secretion and inhibit glucose production. Sitagliptin was approved by the US Food and Drug Administration (FDA) for use with diet and exercise to improve glycemic control in adult patients with type 2 diabetes. It can be used alone or in combination with metformin or a thiazolidinedione (pioglitazone or rosiglitazone) when treatment with either drug alone provides inadequate glucose control. The usual adult dose is 100 mg once daily. A dose of 25-50 mg once daily is recommended for patients with moderate-to-severe renal impairment. In randomized, placebo-controlled trials that lasted for up to 6 months, sitagliptin lowered glycosylated hemoglobin levels by 0.5-0.8%. In a 52-week clinical trial, sitagliptin was shown to be noninferior to glipizide as an add-on agent in patients inadequately controlled on metformin alone. Sitagliptin was well tolerated with the most common side effects being gastrointestinal complaints (up to 16%), including abdominal pain, nausea and diarrhea; hypoglycemia and body weight gain occurred at similar rates compared with placebo. Overall, sitagliptin provides a treatment option for patients with type 2 diabetes as a monotherapy, or as an adjunct to metformin or a thiazolidinedione when patients achieve inadequate glycemic control while on either of the agents. It is also an alternative therapy for those patients who have contraindications or intolerability to other antidiabetic agents.

[Short-term intensive combined therapy with metformin, sagliptin and dapagliflozin for newly diagnosed type 2 diabetes: efficacy, weight control and safety].

To assess the efficacy and safety of short- term intensive hypoglycemic therapy with a triple regimen consisting of metformin, sagliptin and dapagliflozin in patients with newly diagnosed type 2 diabetes mellitus with hemoglobin Alc (HbA1c) of 9%-12%. We prospectively enrolled 58 patients with newly diagnosed type 2 diabetes, who were treated with metformin combined with sagliptin and dapagliflozin for 12 weeks on the basis of diabetic diet and regular exercise. Blood glucose was monitored during the treatment and the changes in HbA1c, fasting blood glucose (FBG), 2-hour postprandial blood glucose (2 hPBG), fasting insulin (FINS), 2-hour postprandial insulin (2 hPINS), fasting C-peptide (F-CP), 2-hour postprandial C-peptide (2 hP-CP), and body weight after treatment as well as the incidence of hypoglycemia and adverse events associated with the treatment were recorded. Two patients withdrew from the study for intolerance of gastrointestinal reactions, and another 2 withdrew for inconvenience of access to the medicines. Fifty-four of the patients finally completed the study, including 34 male and 20 female patients. After 12 weeks of therapy, all the patients showed significant improvements in FBG, 2 hPBG, HbA1c, HOMA-beta and HOMA-IR (<iP</i < 0.001) with a mean reduction of HbA1c level by (4.19 ± 1.07)%, and the goal of HbA1c control to below 7.0% was achieved in 83.33% of the patients. The reduction of HbA1c was correlated with FBG (<ir</i=0.487, <iP</i=0.000), 2 hPBG (<ir</i=0.310, <iP</i=0.023), and HOMA-β (<ir</i=-0.398, <iP</i=0.003). The patients had a mean body weight loss by 2.47±3.38 kg (<iP</i < 0.001) and a mean decrease of body mass index (BMI) by 0.90± 1.18 kg/m2 (<iP</i < 0.001) after the therapy. The body weight-reducing effect was associated with the patients' baseline body weight (<ir</i=0.678, <iP</i=0.000), BMI (<ir</i=0.818, <iP</i=0.000), F-CP (<ir</i=0.282, <iP</i=0.039) and HOMA-IR (<ir</i=0.297, <iP</i=0.029). During the therapy 8 patients experienced hypoglycemic symptoms (10 times, 14.81%); 3 patients were diagnosed with hypoglycemia (blood glucose ≤3.9 mmol/L, 3 times), and the overall incidence of hypoglycemia was 5.56%. No serious hypoglycemia or infections of the urinary and reproductive systems occurred in these patients. Short-term intensive oral hypoglycemic therapy with metformin combined with sagliptin and dapagliflozin is effective for treatment of patients with newly diagnosed type 2 diabetes with HbA1c of 9%-12% and shows a good weight-reducing effect with a low risk of hypoglycemia. The combined therapy can effectively improve β-cell insulin secretion function, and is suitable for treatment of newly diagnosed type 2 diabetic patients with high blood glucose.

InternalMed_Harrison

lost 5–7% of their body weight during the 3 years of the study. Studies in Finnish and Chinese populations noted similar efficacy of diet and exercise in preventing or delaying type 2 DM. A number of agents, including α-glucosidase inhibitors, metformin, thiazolidinediones, GLP-1 receptor pathway modifiers, and orlistat, prevent or delay type 2 DM but are not approved for this purpose. Individuals with a strong family history of type 2 DM and individuals with IFG or IGT should be strongly encouraged to maintain a normal BMI and engage in regular physical activity. Pharmacologic therapy for individuals with prediabetes is currently controversial because its cost-effectiveness and safety profile are not known. The ADA has suggested that metformin be considered in individuals with both IFG and IGT who are at very high risk for progression to diabetes (age <60 years, BMI ≥35 kg/m2, family history of diabetes in first-degree relative, and women with a history of GDM). Individuals with IFG,

Long-term glycaemic efficacy and weight changes associated with thiazolidinediones when added at an advanced stage of type 2 diabetes.

To describe the outcome of 35 patients with type 2 diabetes prospectively followed for 6 years after the addition of a thiazolidinedione (TZD) to a failing regimen of a sulphonylurea and metformin -- triple oral therapy. Study patients were assessed for the need for the addition of insulin to their regimen, and follow-up clinical and laboratory findings were analysed. At a mean follow-up of 72 +/- 1.5 months (range 53-80), 18 (51%) of patients remained well controlled on triple oral therapy with a mean glycosylated haemoglobin (HbA1c) value of 6.9 +/- 0.2% (upper limit of normal 6.2%). In 17 other patients, triple oral therapy failed and the use of insulin was necessary after a mean duration of 38 (range 18-68) months. The mean HbA1c in these patients was 8.0 +/- 0.3%. The group that was maintained on triple oral therapy gained 15.2 +/- 1.9 lbs over the 6-year study which was significantly higher than the baseline weight. Alternatively, the group that failed and had insulin added to their therapy gained 20.2 +/- 4.5 lbs over the same period which was also significantly different from baseline but not from the triple oral therapy group. Although after 3 years a trend towards weight loss occurred in the triple oral therapy group, the insulin-added group continued to gain weight. Stimulated C-peptide levels increased significantly in the triple therapy group from 3.6 +/- 0.9 to 4.3 +/- 1.2 ng/ml and had not increased or decreased non-significantly from 3.7 +/- 0.8 to 3.2 +/- 0.6 ng/ml at the time of insulin initiation in the insulin-requiring group. When used late in the course of type 2 diabetes, TZDs result in improved and prolonged glycaemic control which persisted for a median time of 6 years. Weight gain with TZDs peaks and then plateaus (and even trends downwards) at 3 years, although the addition of insulin to a failing oral therapy regimen results in a further and continuing weight gain in spite of inferior glycaemic control. Continuing glycaemic control with triple oral therapy is dependent on preservation or augmentation of endogenous insulin production.

Gemigliptin

Glycemic variability and chronic sustained hyperglycemia are the main components of dysglycemia in diabetes. The previous studies suggested that different pharmacodynamic profiles between DPP-4 inhibitors have been associated with the different effects on glycemic variability. In this study, a multicenter, randomized, active-controlled, parallel group, open-label, exploratory study was designed to evaluate the efficacy on glycemic variability and safety of initial combination therapy of gemigliptin 50 mg qd versus sitagliptin 100 mg qd, or glimepiride 2 mg qd with metformin in patients with T2DM (study identifier: LG-DPCL012, STABLE study; ClinicalTrials.gov registration number: NCT01890629). The mean amplitude of glycemic excursions (MAGE) and SD of glucose were used for assessing glucose fluctuations from the baseline after 12 weeks of treatment. At 12 weeks, MAGE was significantly lower in the DPP-4 inhibitor groups (gemigliptin and sitagliptin) than in the glimepiride group

Diabetes management

"Perfect glycemic control" would mean that glucose levels were always normal (70–130 mg/dl, or 3.9–7.2 mmol/L) and indistinguishable from a person without diabetes. In reality, because of the imperfections of treatment measures, even "good glycemic control" describes blood glucose levels that average somewhat higher than normal much of the time. In addition, one survey of type 2 diabetics found that they rated the harm to their quality of life from intensive interventions to control their blood sugar to be just as severe as the harm resulting from intermediate levels of diabetic complications. In the 1990s the American Diabetes Association conducted a publicity campaign to persuade patients and physicians to strive for average glucose and hemoglobin A1c values below 200 mg/dl (11 mmol/l) and 8%. Currently, many patients and physicians attempt to do better than that.

Pioglitazone/glimepiride

Medical uses In the United States pioglitazone/glimepiride is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and sulfonylurea or who have inadequate glycemic control on a thiazolidinedione alone or a sulfonylurea alone. In the European Union pioglitazone/glimepiride is indicated for the treatment of people with type 2 diabetes mellitus who show intolerance to metformin or for whom metformin is contraindicated and who are already treated with a combination of pioglitazone and glimepiride. References External links Anti-diabetic drugs

[Starting insulin or not? And if so, which basal insulin?]

A 55-year-old patient with a BMI of 30 kg/m2 is referred for uncontrolled type 2 diabetes mellitus. His HbA1c-concentration is 71 mmol/mol, despite an initial 8% weight loss and treatment with metformin and glimepiride. The general practitioner proposes to start with insulin, but the patient refuses. We discuss whether there is a good alternative for insulin such as more weight loss and the addition of more drugs. Our patient then changes his mind and agrees to start insulin treatment. Basal insulin is usually recommended in cases like this.Since there are no significant differences between different types of available basal insulin, it seems reasonable to take price into account. Our patient achieved reasonable glucose control without weight gain using a combination of basal insulin and a GLP-1 receptor agonist.

First_Aid_Step2

The goal of treatment is tight glucose control—i.e., blood glucose levels ranging from 80 to 120 mg/dL and HbA1c levels < 7. Treatment measures include the following: Diet, weight loss, and exercise. Oral agents (monotherapy or combination if uncontrolled): Sulfonylureas (glipizide, glyburide, and glimepiride): Insulin secretagogues. Hypoglycemia and weight gain are side effects. Meglitinides (repaglinide and nateglinide): Short-acting agents whose mechanism of action is similar to that of sulfonylureas. Metformin: Inhibits hepatic gluconeogenesis; ↑ peripheral sensitivity to insulin. Side effects include weight loss, GI upset, and, rarely, lactic acidosis. Contraindicated in the elderly (those > 80 years of age) and in patients with renal disease. Thiazolidinediones (the “glitazones”): ↑ insulin sensitivity. Side effects include weight gain, edema, and potential hepatotoxicity.

Combination exenatide-sitagliptin therapy used with glipizide in a patient with type 2 diabetes mellitus.

The case of a patient with type 2 diabetes mellitus who received combination exenatide-sitagliptin with glipizide is reported. A 55-year-old, 204-lb Caucasian woman arrived at a clinic with polydipsia. Her blood glucose concentration was 450 mg/dL and her glycosylated hemoglobin (HbA(1c)) value was 13.4%. She was diagnosed with type 2 diabetes mellitus and started on metformin hydrochloride 500 mg orally twice daily. Metformin was later discontinued due to elevated liver function test values. Sitagliptin 100 mg daily was substituted, and glipizide was later added and its dosage adjusted over the next several months. After six months, her HbA(1c) value had decreased to 9.3% and she had gained 14 lb. Exenatide was then added to her regimen, and the dosage was adjusted to 10 μg subcutaneously twice daily. Two months after the initiation of sitagliptin, glipizide, and exenatide, the patient had lost 10 lb, reported significant improvements in self-monitored blood glucose readings, and required a reduction in glipizide dosage despite no reported therapeutic lifestyle changes. Seven months after the initiation of exenatide, sitagliptin, and glipizide, her HbA(1c) value was 7.4%. Triple therapy resulted in a total HbA(1c) value reduction of 1.9%, a weight loss of 11 lb, and normalized liver function test values. The patient's high blood pressure was treated with losartan and remained at goal throughout the duration of this report. In a patient with type 2 diabetes mellitus, the addition of the incretin mimetic exenatide and the dipeptidyl peptidase-4 inhibitor sitagliptin to glipizide therapy appeared effective and safe.

Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes.

Metformin is the recommended initial drug therapy for patients with type 2 diabetes mellitus (DM). However, the optimal second-line drug when metformin monotherapy fails is unclear. To determine the comparative efficacy, risk of weight gain, and hypoglycemia associated with noninsulin antidiabetic drugs in patients with type 2 DM not controlled by metformin alone. A literature search via MEDLINE (beginning in January 1950) and Cochrane CENTRAL through January 2010 and a manual search of references for additional relevant studies. Randomized controlled trials (RCTs) with at least 3 months' duration, evaluating noninsulin antidiabetic drugs added to metformin in patients experiencing an inadequate response to maximized and stable (> or = 4 weeks at > or = 1500 mg or maximally tolerated dose) metformin therapy. Inclusion/exclusion criteria; duration of patient follow-up; drug, dose, and schedule used; use of concurrent lifestyle modification; and baseline characteristics (age, sex, anthropometrics, glycated hemoglobin A(1c) [HbA(1c)], duration of DM, and metformin dose). End points collected included mean change in HbA(1c), proportion of patients achieving HbA(1c) goal of less than 7%, change in weight, and incidence of hypoglycemia. Mixed-treatment comparison meta-analysis was used to calculate the weighted mean difference for changes from baseline in HbA(1c) and body weight and relative risk (RR) of HbA(1c) goal attainment and hypoglycemia, with associated 95% credible intervals. Overall, 27 RCTs (n = 11 198) were included. Mean (range) trial duration was 32 (12-52) weeks. The different classes of drugs were associated with similar HbA(1c) reductions (range, 0.64%-0.97%) compared with placebo. Although use of thiazolidinediones, sulfonylureas, and glinides were associated with weight gain (range, 1.77-2.08 kg), glucagon-like peptide-1 analogs, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were associated with weight loss or no weight change. Sulfonylureas and glinides were associated with higher rates of hypoglycemia than with placebo (RR range, 4.57-7.50). When added to maximal metformin therapy, all noninsulin antidiabetic drugs were associated with similar HbA(1c) reductions but differed in their associations with weight gain and risk of hypoglycemia.

Real-World Clinical Effectiveness and Tolerability of Hydroxychloroquine 400 Mg in Uncontrolled Type 2 Diabetes Subjects who are not Willing to Initiate Insulin Therapy (HYQ-Real-World Study).

The epidemic of T2DM is rising across the globe. Systemic inflammation plays a pivotal role in the pathogenesis and complications of T2DM. Combination of two or more oral hypoglycemic agents (OHA) is widely prescribed in patients with T2DM, however many patients have poor glycemic control despite receiving combination therapy. The new antidiabetic drugs are relatively costly or many patients have anxiety over the use of injectable insulin. The objective of this observational study was to investigate the effectiveness and tolerability of hydroxychloroquine (HCQ) in T2DM patients uncontrolled on multiple OHA and despite high sugar level not willing to initiate insulin therapy in a real-world clinical setting. A prospective, investigator-initiated, observational, single-centred study was conducted where 250 patients (18-65 years) with T2DM for more than 5 years, with uncontrolled glycemia despite on a combination of multiple OHA, HbA1c between ≥7% and <10.5%, FPG >130 mg/dL or PPG >180 mg/dL and BMI between >25 and <39 kg/m2, were prescribed hydroxychloroquine sulphate 400 mg once daily for 48 weeks. Percentage of drugs used at the baseline were as follows: metformin 2000 mg (100%), glimepiride 4 mg (100%), pioglitazone 30 mg (100%), sitagliptin 100 mg (100%), canagliflozin 300 mg (52.4%), empagliflozin 25 mg (22.8%), dapagliflozin 10 mg (17.6%) and voglibose 0.3 mg (62%). Mean change in HbA1c, blood glucose and hs-CRP at baseline, week 12, 24 and 48 were assessed using the paired t-test. After 48 weeks of add-on treatment with HCQ, almost all SGLT-2 inhibitors were withdrawn; metformin dose was reduced to 1000 mg, glimepiride reduced to 1 mg and sitagliptin reduced to 50 mg OD. Patients continued to have good glycemic control. HbA1c was reduced from 8.83% to 6.44%. Reduction in FPG was 40.78% (baseline 177.30 mg/dL) and PPG was reduced by 58.95% (baseline 329.86 mg/dL). Change in mean body weight was -4.66 Kg. The reduction in glycemic parameters and mean body weight was significant (p < 0.0001). Hs-CRP was significantly reduced from 2.70±1.98 mg/L to 0.71±0.30 mg/L 9 (p < 0.0001). More reduction in glycemic parameters and body weight was observed among the patients with higher hs-CRP (> 3 mg/L) as compared to patients with baseline hs- CRP ≤ 3 mg/L. Most common adverse events reported with the drug therapy were GI irritation (3.6%) and hypoglycemia (2%). None of the patients required medical assistance for hypoglycemia. Add-on treatment of HCQ effectively improved glycemic control in T2DM patients uncontrolled on multiple antidiabetic drugs. By virtue of its antidiabetic and anti-inflammatory properties, it may emerge as a valuable therapeutic intervention for the patients with T2DM.

InternalMed_Harrison

As with any therapy, the benefits of efforts directed toward glycemic control must be balanced against the risks of treatment (Table 418-5). Side effects of intensive treatment include an increased frequency of serious hypoglycemia, weight gain, increased economic costs, and greater demands on the patient. In the DCCT, quality of life was very similar in 2417 the intensive and standard therapy groups. The most serious complication of therapy for DM is hypoglycemia, and its treatment with oral glucose or glucagon injection is discussed in Chap. 420. Severe, recurrent hypoglycemia warrants examination of treatment regimen and glycemic goal for the individual patient. Weight gain occurs with most (insulin, insulin secretagogues, thiazolidinediones) but not all (metformin, α-glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors) therapies. The weight gain is partially due to the anabolic effects of insulin and the reduction in glucosuria. As a result of recent controversies

Diabetes mellitus in the young: Gliptins or sulfonylurea after metformin?

Diagnosis and initial management of diabetes mellitus (DM) in the young are clinical dilemma. Gliptins may be a safer and more effective option than sulfonylureas. Few Indian studies have addressed this issue of clinical relevance. To compare the use of sitagliptin and glimepiride as early add-on drugs along with metformin in young patients with DM to achieve optimum glycemic targets. This was a prospective, open-label, cohort study set in a tertiary care hospital in North India. Newly diagnosed patients of DM ≤35 year of age were initially treated to pre-defined glycemic goals (Fasting plasma glucose (FPG) 70-130, post prandial glucose (PPG) < 180 mg/dl) with insulin and metformin 1 g for 8 weeks. Insulin was discontinued and metformin increased to 2 g daily for next 4 weeks. Thereafter, glimepiride 1 mg or sitagliptin 100 mg was randomly added to those who were not maintaining the set glucose targets. Dose of glimepiride was uptitrated every 4 weeks upto a maximum of 4 mg. Three groups (Gp A: Metfromin 2 g/d, Gp B: Metformin 2 g + Glimepiride 1-4 mg/d, and Gp C: Metformin 2 g + sitagliptin 100 mg/d) were followed up over next 24 weeks. They were compared for glycemic control and weight change. Those failing therapy on these drugs (FPG > 180, PPG > 250 mg/dl with/without catabolic symptoms/ketosis) were withdrawn. Sitagliptin with metfromin and metfromin alone group fared better than the glimepiride group for glycemic control, lesser treatment failures, and less weight gain. In this limited study, we found that sitagliptin is a safer and more effective option in young, newly diagnosed patients with DM. Findings of this study are relevant for clinical practice in Indian setting.

Insulin glargine provides greater improvements in glycaemic control vs. intensifying lifestyle management for people with type 2 diabetes treated with OADs and 7-8% A1c levels. The TULIP study.

To determine whether earlier administration of insulin glargine (glargine) vs. the intensification of lifestyle management (LM) improves glycaemic control in type 2 diabetes patients with A1c 7-8% treated with oral therapy. TULIP [Testing the Usefulness of gLargine when Initiated Promptly in type 2 diabetes mellitus (T2DM)] was a 9-month, 12-visit, open-label, multinational, multicentre, randomized study to evaluate starting glargine or intensifying LM in T2DM patients aged 40-75 years, body mass index (BMI) 24-35 kg/m2 and A1c 7-8%, treated with maximum doses of metformin and sulphonylurea for > or = 2 years. Glargine was injected once daily (evening) and titrated to fasting blood glucose 0.7-1.0 g/l. In the LM arm, dietary and physical activity counselling recommended stable weight for people with BMI < 27 kg/m2 or weight loss of 3 kg for patients with BMI > or = 27 kg/m2. A total of 215 patients were randomized to glargine (n = 106) or LM (n = 109). The primary objective was patients achieving A1c < 7% at endpoint. Secondary endpoints included changes in A1c, in fasting plasma glucose (FPG), body weight and hypoglycaemia incidence. Two hundred and eleven (52.6% male) patients were randomized and treated; mean (+/- s.d.) age 60.7 +/- 7.9 years, weight 84.5 +/- 13.1 kg, BMI 29.9 +/- 3.5 kg/m2 and A1c 7.6 +/- 0.4%. More patients reached A1c < 7% (66 vs. 38%; p < 0.0001) or < 6.5% (34 vs. 11%; p = 0.0001) with glargine vs. LM. The change in FPG from baseline to study endpoint was significantly greater in the glargine vs. the LM arm (-0.50 +/- 0.47 vs. -0.05 +/- 0.39 g/l respectively; p < 0.0001). Compared with the glargine group, the LM group showed a decrease in weight (+0.9 +/- 2.9 vs. -2.5 +/- 3.2 kg; p < 0.0001), as well as the expected lower symptomatic hypoglycaemia (55.3 vs. 25.0%; p < 0.0001) and nocturnal hypoglycaemia (20.4 vs. 5.6%; p = 0.0016). No significant changes were observed from baseline to study endpoint in any of the lipid parameters tested. In patients with T2DM with A1c 7-8%, who were previously treated by conventional LM and OAD therapy, adding glargine resulted in greater improvements in glycaemic control vs. intensifying LM.

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.

Treatment with diet alone, insulin, sulfonylurea, or metformin is known to improve glycemia in patients with type 2 diabetes mellitus, but which treatment most frequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A1c (HbA1c) below 7% is unknown. To assess how often each therapy can achieve the glycemic control target levels set by the American Diabetes Association. Randomized controlled trial conducted between 1977 and 1997. Patients were recruited between 1977 and 1991 and were followed up every 3 months for 3, 6, and 9 years after enrollment. Outpatient diabetes clinics in 15 UK hospitals. A total of 4075 patients newly diagnosed as having type 2 diabetes ranged in age between 25 and 65 years and had a median (interquartile range) FPG concentration of 11.5 (9.0-14.4) mmol/L [207 (162-259) mg/dL], HbA1c levels of 9.1% (7.5%-10.7%), and a mean (SD) body mass index of 29 (6) kg/m2. After 3 months on a low-fat, high-carbohydrate, high-fiber diet, patients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin. Fasting plasma glucose and HbA1c levels, and the proportion of patients who achieved target levels below 7% HbA1c or less than 7.8 mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis. The proportion of patients who maintained target glycemic levels declined markedly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA1c levels below 7%. In obese patients randomized to metformin, 18% attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA1c levels below 7%. Patients less likely to achieve target levels were younger, more obese, or more hyperglycemic than other patients. Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA1c below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years approximately 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need multiple therapies to attain these glycemic target levels in the longer term.

Effects on Diabetes Medications, Weight and Glycated Hemoglobin Among Adult Patients With Obesity and Type 2 Diabetes: 6-Month Observations From a Full Meal Replacement, Low-Calorie Diet Weight Management Program.

A 6-month weight-management program with full meal replacement, low-calorie diet (full MR-LCD) (900 kcal/day for 6 to 12 weeks) follows a protocol for patients with diabetes for decreasing or discontinuing weight-gaining diabetes medications first (Group WG) and then titrating weight-neutral medications (Group WN). This is a retrospective cohort study (1992 to 2009) of weight, glycemic control and diabetes medications changes in 317 patients with obesity and type 2 diabetes who were taking medications. Group WG and Group WN were similar at baseline, except that glycated hemoglobin (A1C) levels were significantly lower in Group WN (7.5% vs. 6.6%; p<0.001). At 6 months, both groups had lost 16% of their weight, and the decreases or discontinuations of medications were 92.1% sulfonureas, 86.5% insulins, 78.8% thiazolidinediones, 77.8% alpha-glucosidase inhibitors, 50% meglitinides, 33.3% dipeptidyl peptidase-4 (DPP-4) inhibitors and 32.8% metformin. At 6 months, compared with baseline, A1C levels improved in Group WG and Group WN (6-month A1C levels 6.7% and 5.8%, respectively; p<0.0001), and Group WN had significantly better A1C levels than Group WG. At 6 months, 30% of patients were no longer taking diabetes medications and had significantly better percentages of weight loss compared with those taking medications (18.6% vs. 16%; p=0.002); both groups had improved glycemic control at 6 months (A1C 6.0% vs. A1C 6.6%; NS). In patients with obesity and type 2 diabetes taking medications, a full MR-LCD program appears to be safe and includes improvement in A1C levels. At 6 months, the percentage of weight loss can be significantly better in patients who no longer require diabetes medications, and A1C levels are best controlled in patients who are on WN medications.