A somewhat more complicated question than the previous one. Regarding weight, metformin to a lesser extent, SGLT-2 inhibitors and, above all, GLP-1 agonists have been associated with a significant decrease in weight in patients with DM-2 (answers 1,3 and 4 incorrect). On the other hand, pioglitazone, as reflected in its data sheet, can produce dose-dependent weight gain, mainly due to fat accumulation and added, in some cases, to water retention.

A somewhat more complicated question than the previous one. Regarding weight, metformin to a lesser extent, SGLT-2 inhibitors and, above all, GLP-1 agonists have been associated with a significant decrease in weight in patients with DM-2 ([HIDDEN]). On the other hand, pioglitazone, as reflected in its data sheet, can produce dose-dependent weight gain, mainly due to fat accumulation and added, in some cases, to water retention.

A 66-year-old woman diagnosed with type 2 diabetes mellitus since three months ago. She has a BMI of 31 kg/m2 and presents poor glycemic control despite a program of non-pharmacological measures (healthy diet, exercise). Which of the following hypoglycemic drugs is associated with weight gain and should we avoid in this patient?:

Canagliflozin (sodium-glucose cotransporter 2 inhibitor- iSGLT2).

Role of Metformin, Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors, Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists, and Orlistat based Multidrug Therapy in Glycemic Control, Weight Loss, and Euglycemia in Diabesity: A Real-World Experience.

This study evaluated the real-world weight loss and glycemic outcomes of multidrug therapy (MDT) according to various combinations of metformin, sodium-glucose cotransporter -2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor analogs (GLP1a), and orlistat in diabesity. Data retrospectively captured from medical records of 2 different centers in New Delhi for patients >35 years-age having prediabetes/diabetes and on at least any one of the 4 above medications with >6-months follow-up was analyzed. In total, 5,336 patient records were screened; 2,442 with prediabetes/diabetes were considered; 1,509 patients who fulfilled all criteria were analyzed. Use of metformin, SGLT2i, sulfonylureas, DPP4i, pioglitazone, orlistat, and GLP1a was 85.35%, 74.95%, 68.32%, 60%, 39.16%, 9.08%, and 4.17%, respectively. However, 365, 970, and 104 patients were on one of 4 concerned medications (Group-1; 24.18%), dual MDT (Group-2; 64.28%), and triple/quadruple MDT (Group-3; 6.89%). Metformin with SGLT2i was most commonly used dual MDT (94.12%). Analysis according to weight-loss quartiles from 558 patients showed 6.9 kg weight-loss in the highest quartile. People losing maximum weight were significantly younger; had higher use of metformin, SGLT2i, GLP1, orlistat, and lower pioglitazone use; greatest HbA1c reduction (-1.3 vs. -0.3; quartile-1 vs. quartile -4; <iP</i < 0.001); and significantly higher occurrence of HbA1c<5.7% (16.8% vs. 6.29%; quartile-1 vs. 4; <iP</i < 0.001). Patients in Group-3 had the highest baseline BMI and maximum weight loss with highest number of patients with HbA1c<5.7% (19.44% vs. 10.34%; Group-3 vs. Group-1; <iP</i < 0.001). Greater weight loss with HbA1c reduction along with a greater number of patients attaining HbA1c <5.7% highlights that MDT is the way forward to tackle diabesity in India.

Body Weight Gain and Hyperphagia After Administration of SGLT-2 Inhibitor: A Case Report.

A detailed description is given of a case we encountered in which unexpectedly marked weight gain occurred following a treatment switch from a GLP-1 receptor agonist to an SGLT-2 inhibitor The patient, a 44-year-old man with type 2 diabetes mellitus, had gained about 10 kg in weight in the previous year. Therefore, metformin was replaced with liraglutide to obtain reduction of body weight. Although the patient lost about 8 kg (7%), during the 18-month period on the medication, the weight loss stabilized; therefore, the treatment was again switched to tofogliflozin to obtain further reduction of body weight. However, the patient reported increasing hunger and an exaggerated appetite from week 3 onward after the start of tofogliflozin, and gained about 9 kg in weight within 2 weeks, associated with a tendency towards increased HbA1c; therefore, tofogliflozin was discontinued. Immediate reinstitution of liraglutide resulted in reduction of the increased appetite, weight, and HbA1c level. Caution should be exercised against hyperphagia and weight gain due to hunger that may occur following discontinuation of a GLP-1 receptor agonist and/or initiation of an SGLT-2 inhibitor.

[Management of hyperglycaemia with non-insulin drugs in adult patients with type 2 diabetes].

Treatment of diabetes mellitus type2 (DM2) includes healthy eating and exercise (150minutes/week) as basic pillars. For pharmacological treatment, metformin is the initial drug except contraindication or intolerance; in case of poor control, 8 therapeutic families are available (6 oral and 2 injectable) as possible combinations. An algorithm and some recommendations for the treatment of DM2 are presented. In secondary cardiovascular prevention, it is recommended to associate an inhibitor of the sodium-glucose cotransporter type 2 (iSGLT2) or a glucagon-like peptide-1 receptor agonist (arGLP1) in patients with obesity. In primary prevention if the patient is obese or overweight metformin should be combined with iSGLT2, arGLP1, or inhibitors of type4 dipeptidylpeptidase (iDPP4). If the patient does not present obesity, iDPP4, iSGLT2 or gliclazide, sulfonylurea, recommended due to its lower tendency to hypoglycaemia, may be used.

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.

Efficacy of SGLT2 Inhibitors as the Fifth Drug in the Management of Type 2 Diabetes Mellitus in Asian Indians not Controlled with at least 4 Oral Antidiabetic Drugs.

To evaluate the efficacy of SGLT2 inhibitors as an add-on therapy along with stricter lifestyle modification in Asian Indian type 2 diabetes mellitus (T2DM) patients with inadequate glycemic control despite receiving an optimum dose of at least 4 oral antidiabetic drugs (OADs). A retrospective analysis of data of 808 T2DM patients being treated with an SGLT2 inhibitor (Dapagliflozin, Empagliflozin or Canagliflozin) as an add-on drug in patients with inadequate glycemic control despite receiving optimum doses of at least any four OADs(metformin, sulphonylureas, pioglitazone, DPP4 Inhibitors, alpha-Glucosidase Inhibitors) and who preferred not to initiate insulin. The average age of the patients included was 51.63 years (SD ± 9.88). 57.7% were males. Average weight was 81.95±16.08 kg. Mean duration of diabetes was 34.08±39.04 months. The mean baseline fasting plasma glucose was 198.21 ± 38.21 mg/dl and mean post prandial plasma glucose was 264.22 ± 45.22 mg/ dl. The baseline HbA1c was 8.92 ± 1.47 %. Total 87.4 % of the cases responded to addition of SGLT2 inhibitors during a mean follow-up period of 6 months. The fasting plasma glucose (FBS) was reduced by -63.65 ± 19.93 mg/dl to a mean FBS of 134.57 ± 33.65 mg/dl (P=0.001). The post prandial plasma glucose (PPBS) was reduced by -79.28 ± 23.57 mg/dl to a mean PPBS of 184.94 ± 38.34 mg/dl (P=0.001). The mean HbA1c reduced significantly by -1.63 ± 0.99 % (P= 0.001). The mean weight reduction at 6 months of therapy was -3.03± 01.84 kg that is 3.8 % decrease from baseline (p=0.001).The response in age group < 55 years was 90.9 %, whereas in ≥55 years, it was 82.2% (p=0.001). The males responded more (91.0%) compared to females (82.5%) (p=0.001). Those with BMI < 23.5 kg/ m2 had marginally higher but insignificant response of 93.0% as compared to 87.1% in patients with high a BMI (≥23.5 kg/m2) (p=0.253). Patients with < 5years duration of diabetes responded better (91.8%) as compared to patients with a ≥ 5 years of diabetes (85.4%). SGLT2 inhibitors are effective in achieving desired glycemic goals even when used as a fifth add-on drug along with strict lifestyle modification in patients with inadequate glycemic control despite receiving an optimum dose of at least 4 oral antidiabetic drugs (OADs). SGLT2 inhibitors can be effectively used at any stage of diabetes.

[Short-term Glucose Lowering Effects of Sodium-glucose Cotransporter 2 Inhibitors Confirmed by Flash Glucose Monitoring in Two Outpatients with Type 1 Diabetes].

Case 1 was a 41-year-old man with type 1 diabetes. He presented with poor glycemic control [hemoglobin A1c (HbA1c) of 8-9%] despite treatment with more than 20 units/day of insulin and 150 mg of miglitol. Before administration of sodium glucose cotransporter 2 (SGLT2) inhibitor, hyperglycemia was noted mainly at night by Flash Glucose Monitoring (FGM). Administration of ipragliflozin at 50 mg improved the hyperglycemia mainly at night (mean blood glucose, before administration: 205 mg/dl, day 6 of treatment: 119 mg/dl). Two months later, the HbA1c improved to 7.2% without hypoglycemia or ketosis. Case 2 was a 46-year-old woman with type 1 diabetes. She was morbidly obese and presented with poor glycemic control (HbA1c: 9-11%) although she was being treated with more than 50 units/day of insulin and 2,250 mg of metformin. Before administration of SGLT2 inhibitor, hyperglycemia was noted to be mainly nocturnal by FGM. Administration of dapagliflozin at 5 mg improved the hyperglycemia mainly at night on day 2 with improvement in the mean blood glucose level from 188 mg/dl before administration to 128 mg/dl on day 5. Four months later, the HbA1c improved to 8.0% without hypoglycemia and ketosis, and her body weight decreased from 92.1 to 89.8 kg. The hypoglycemic effect of SGLT2 inhibitors is independent of insulin. These agents also have various other effects, including weight loss, improvement of blood pressure and lipid metabolism. Here we report the short-term glucose lowering effects of two SGLT2 inhibitors, as confirmed by FGM, in two outpatients with type 1 diabetes.

Type 2 Diabetes Remission and Substantial Body Weight Reduction Achieved with Metformin and a Sodium-Glucose Cotransporter 2 Inhibitor.

The overall goal in the treatment of type 2 diabetes mellitus (T2DM) is remission. However, the effects of a sodium-glucose cotransporter 2 inhibitor (SGLT2i) on remission of T2DM are unknown. We herein report a case involving an overweight 43-year-old man who completely recovered from T2DM after SGLT2i therapy (dapagliflozin at 5 mg/day). In the pretreatment period, he had a body mass index (BMI) of 26.0 kg/m<sup2</sup, hemoglobin A1c (HbA1c) concentration of 10.3%, advanced insulin resistance, pancreatic β-cell dysfunction, and fatty liver. Eighteen months after comprehensive therapy, including the administration of an SGLT2i and metformin, his BMI had decreased to 21.3 kg/m<sup2</sup and his glycemic control was almost normal (HbA1c of 5.3%) despite discontinuation of all hypoglycemic medications. This report is the first to propose the usefulness of the combination therapy of SGLT2i and metformin for achieving normal body weight and remission of newly diagnosed T2DM in a real-world clinical situation.

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.

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,

Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD).

To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes. This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7-11% (previous oral antidiabetes drug [OAD] monotherapy >or=3 months) or 7-10% (previous OAD combination therapy >or=3 months), and BMI <or=45 kg/m(2). Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean +/- SE -1.5 +/- 0.1% for both 1.2 and 1.8 mg liraglutide and -0.5 +/- 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 +/- 0.3 and 2.0 +/- 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 +/- 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of beta-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient. Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.

Dapagliflozin/saxagliptin/metformin

Medical uses In the United States dapagliflozin/saxagliptin/metformin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. In the European Union it is indicated in adults aged 18 years and older with type 2 diabetes mellitus: to improve glycemic control when metformin with or without sulphonylurea (SU) and either saxagliptin or dapagliflozin does not provide adequate glycemic control. when already being treated with metformin and saxagliptin and dapagliflozin. References External links Anti-diabetic drugs AstraZeneca brands Biguanides Chloroarenes Combination drugs Glucosides Guanidines Phenol ethers SGLT2 inhibitors

Canagliflozin/metformin

Medical uses Canagliflozin/metformin is indicated in adults aged 18 years of age and older with type 2 diabetes as an adjunct to diet and exercise to improve glycemic control. Adverse effects To lessen the risk of developing ketoacidosis (a serious condition in which the body produces high levels of blood acids called ketones) after surgery, the FDA approved changes to the prescribing information for SGLT2 inhibitor diabetes medicines to recommend they be stopped temporarily before scheduled surgery. Canagliflozin, dapagliflozin, and empagliflozin should each be stopped at least three days before, and ertugliflozin should be stopped at least four days before scheduled surgery. Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing. References Further reading External links Anti-diabetic drugs Biguanides Combination drugs Fluoroarenes Glucosides Guanidines SGLT2 inhibitors Thiophenes

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

Therapeutic strategies for type 2 diabetes mellitus in women after menopause.

As type 2 diabetes mellitus (T2DM) is affected by both chronological and ovarian ageing, it is common in postmenopausal women. This review analyses and critically appraises the literature regarding the optimal therapeutic strategies for T2DM in women after menopause. Lifestyle interventions, including changes in dietary habits and physical exercise in everyday life targeting a modest weight loss (5%), represent the cornerstone of management. Limited intake of alcohol and sodium, as well as smoking cessation, are additional lifestyle changes for both endothelial and bone health. Regarding medications, postmenopausal women should be initially treated with metformin, concurrently with lifestyle intervention. If glycosylated haemoglobin (HbA<sub1c</sub) remains over the target level (usually ≥7%), dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1RA) should be preferred. Thiazolidinediones (TZDs) and canagliflozin should be avoided in postmenopausal women with increased fracture risk. Insulin should be used with caution to avoid hypoglycaemia. Bariatric surgery is a well established and effective therapeutic option for both weight loss and glycaemic control in very obese patients with T2DM; however, metabolic benefits should be balanced against nutritional deficiencies that often present after surgery. Proper control of hypertension, with avoidance of hypotension, is of great importance as a measure against falls. Annual tests for retinopathy and neuropathy are crucial for the same reason. Menopausal hormone therapy (MHT) has a beneficial effect on glucose homeostasis, reduces the risk of new-onset T2DM and improves glucose control in women with T2DM. T2DM has been considered a cardiovascular disease equivalent, which meant that postmenopausal women with the disease could not take MHT but current evidence supports an individualised approach to this issue. Therapeutic strategies for women with T2DM after menopause should aim to maximise benefits for metabolic, cardiovascular and bone health with the minimum of adverse effects, bearing in mind that most women will spend more than one-third of their life being of postmenopausal status.

Liraglutide

Liraglutide was approved for medical use in the European Union in 2009, and in the United States in 2010. In 2019, it was the 142nd most commonly prescribed medication in the United States, with more than 4million prescriptions. Medical uses Liraglutide is a medication used for the treatment of type 2 diabetes or obesity. Type 2 diabetes Liraglutide improves control of blood glucose. As of 2017 it is unclear if incretin mimetics like liraglutide affect a person's risk of death. In diabetes it is a less preferred agent. It may be used in those in who metformin and another antidiabetic medication such as a sulfonylurea are not sufficient. Obesity Liraglutide may also be used together with diet and exercise for chronic weight management in adult patients. The body mass index (BMI) needs to be greater than 30 kg/m2, or greater than 27 kg/m2 together with high blood pressure, type 2 diabetes mellitus, or dyslipidemia.

A cardiologic approach to non-insulin antidiabetic pharmacotherapy in patients with heart disease.

Classical non-insulin antihyperglycemic drugs currently approved for the treatment of type 2 diabetes mellitus (T2DM) comprise five groups: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. Novel compounds are represented by the incretin mimetic drugs like glucagon like peptide-1 (GLP-1), the dipeptidyl peptidase 4 (DPP-4) inhibitors, dual peroxisome proliferator-activated receptors (PPAR) agonists (glitazars) and amylin mimetic drugs. We review the cardiovascular effects of these drugs in an attempt to improve knowledge regarding their potential risks when treating T2DM in cardiac patients. Metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as recent myocardial infarction, heart or renal failure. Sulfonylureas exert their effect by closing the ATP-dependent potassium channels. This prevents the opening of these channels during myocardial ischemia, impeding the necessary hyperpolarization that protects the cell. The combined sulfonylurea/metformin therapy reveals additive effects on mortality in patients with coronary artery disease (CAD). Meglitinides effects are similar to those of sulfonylureas, due to their almost analogous mechanism of action. Glitazones lower leptin levels, leading to weight gain and are unsafe in NYHA class III or IV. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates is yet unknown. The incretin GLP-1 is associated with reductions in body weight and appears to present positive inotropic effects. DPP-4 inhibitors influences on the cardiovascular system seem to be neutral and patients do not gain weight. The future of glitazars is presently uncertain following concerns about their safety. The amylin mimetic drug paramlintide, while a satisfactory adjuvant medication in insulin-dependent diabetes, is unlikely to play a major role in the management of T2DM. Summarizing the present information it can be stated that 1. Four out the five classical oral antidiabetic drug groups present proven or potential cardiac hazards; 2. These hazards are not mere 'side effects', but biochemical phenomena which are deeply rooted in the drugs' mechanism of action; 3. Current data indicate that the combined glibenclamide/metformin therapy seems to present special risk and should be avoided in the long-term management of T2DM with proven CAD; 4. Glitazones should be avoided in patients with overt heart failure; 5, The novel incretin mimetic drugs and DPP-4 inhibitors--while usually inadequate as monotherapy--appear to be satisfactory adjuvant drugs due to the lack of known undesirable cardiovascular effects; 6. Customized antihyperglycemic pharmacological approaches should be implemented for the achievement of optimal treatment of T2DM patients with heart disease. In this context, it should be carefully taken into consideration whether the leading clinical status is CAD or heart failure.

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."

Semaglutide

Medical uses Semaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. In the United States, semaglutide is also indicated as an adjunct to diet and exercise for long-term weight management in adults with obesity (initial body mass index (BMI) ≥ 30 kg/m2) or overweight (initial BMI ≥ 27 kg/m2) with at least one weight-related comorbidity. Semaglutide was found to be inferior to tirzepatide, in a study of tirzepatide (LY3298176) vs semaglutide once weekly as add-on therapy to metformin in participants with type 2 diabetes (SURPASS-2), in both endpoints of reduction in A1C and body weight, with a roughly similar safety profile.

Albiglutide

Albiglutide (trade names Eperzan in Europe and Tanzeum in the US) is a glucagon-like peptide-1 agonist (GLP-1 agonist) drug marketed by GlaxoSmithKline (GSK) for treatment of type 2 diabetes. As of 2017 it is unclear if it affects a person's risk of death. GSK has announced that it intends to withdraw the drug from the worldwide market by July 2018 for economic reasons. Medical uses Albiglutide is used for the treatment of type 2 diabetes in adults. It can be used alone (if metformin therapy is ineffective or not tolerated) or in combination with other antidiabetic drugs, including insulins. According to a 2015 analysis, albiglutide is less effective than other GLP-1 agonists for lowering glycated hemoglobin (HbA1c, an indicator for long-term blood glucose control) and weight loss. It also seems to have fewer side effects than most other drugs of this class, except for reactions at the injection site which are more common under albiglutide than, for example, under liraglutide.

Canagliflozin/metformin

Canagliflozin/metformin, sold under the brand name Vokanamet among others, is a fixed-dose combination anti-diabetic medication used for the treatment of type 2 diabetes. It is used in combination with diet and exercise. It is taken by mouth. The most common side effects include hypoglycemia (low blood glucose levels) when used in combination with insulin or a sulphonylurea and vulvovaginal candidiasis (thrush, a fungal infection of the female genital area caused by Candida). Canagliflozin/metformin was approved for medical use in the European Union in April 2014, and for use in the United States in August 2014. Medical uses Canagliflozin/metformin is indicated in adults aged 18 years of age and older with type 2 diabetes as an adjunct to diet and exercise to improve glycemic control. Adverse effects

Type 2 Diabetes -- Treatment / Management

If adequate glycemia cannot be achieved, metformin is the first-line therapy. Following metformin, many other therapies such as oral sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors. Glucagon-like peptide-1 (GLP-I) receptor agonists, Sodium-glucose co-transporter-2 (SGLT2) inhibitors, pioglitazone, especially if the patient has fatty liver disease, alpha-glucosidase inhibitors, and insulin, are available. Recent studies have shown that the SGLT2 inhibitor, empagliflozin (EMPA), and the GLP-1 receptor agonist, liraglutide, reduce significant cardiovascular (CV) events and mortality. Hence, in patients with CV disease, these drugs should be considered next. For patients with T1DM, a regime of basal-bolus insulin is the mainstay of therapy. Also, insulin pump therapy is a reasonable choice. Since hypoglycemia portends increased mortality, preference should be given to therapies that do not induce hypoglycemia, for example, DPP-4 Inhibitors, SGLT-2 inhibitors, GLP-I receptor agonists, and pioglitazone with metformin. The other advantages of SGLT-2 inhibitors and GLP-I receptor agonists are a reduction in body weight, blood pressure (BP), and albuminuria.

Type 2 diabetes

, there is insufficient data to recommend nonnutritive sweeteners, which may help reduce caloric intake. Medications Blood sugar control There are several classes of anti-diabetic medications available. Metformin is generally recommended as a first line treatment as there is some evidence that it decreases mortality; however, this conclusion is questioned. Metformin should not be used in those with severe kidney or liver problems. A second oral agent of another class or insulin may be added if metformin is not sufficient after three months. Other classes of medications include: sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and glucagon-like peptide-1 analogs. As of 2015 there was no significant difference between these agents. A 2018 review found that SGLT2 inhibitors and GLP-1 agonists, but not DPP-4 inhibitors, were associated with lower mortality than placebo or no treatment.

Pioglitazone/metformin

Pioglitazone/metformin, sold under the brand name Actoplus Met among others, is a fixed-dose combination anti-diabetic medication used to improve glycemic control in adults with type 2 diabetes. It contains pioglitazone, a thiazolidinedione, and metformin, a biguanide. Mechanisms Pioglitazone is a member of the thiazolidinedione class, it decreases insulin resistance in the periphery and in the liver resulting in increased insulin dependent glucose disposal and decreased hepatic glucose output. Metformin is a member of the biguanide class, improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

[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.

[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.

Diabetes medication

Multiple retrospective studies have resulted in a concern about rosiglitazone's safety, although it is established that the group, as a whole, has beneficial effects on diabetes. The greatest concern is an increase in the number of severe cardiac events in patients taking it. The ADOPT study showed that initial therapy with drugs of this type may prevent the progression of disease, as did the DREAM trial. The American Association of Clinical Endocrinologists (AACE), which provides clinical practice guidelines for management of diabetes, retains thiazolidinediones as recommended first, second, or third line agents for type 2 diabetes mellitus, as of their 2019 executive summary, over sulfonylureas and α-glucosidase inhibitors. However, they are less preferred than GLP-1 agonists or SGLT2 inhibitors, especially in patients with cardiovascular disease (which liraglutide, empagliflozin, and canagliflozin are all FDA approved to treat).

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.

Diabetes medication

SGLT-2 inhibitors block the re-uptake of glucose in the renal tubules, promoting loss of glucose in the urine. This causes both mild weight loss, and a mild reduction in blood sugar levels with little risk of hypoglycemia. Oral preparations may be available alone or in combination with other agents. Along with GLP-1 agonists, they are considered preferred second or third agents for type 2 diabetics sub-optimally controlled with metformin alone, according to most recent clinical practice guidelines. Because they are taken by mouth, rather than injected (like GLP-1 agonists), patients who are injection-averse may prefer these agents over the former. They may be considered first line in diabetic patients with cardiovascular disease, especially heart failure, as these medications have been shown to reduce the risk of hospitalization in patients with such comorbidities. Because they are not available as generic medications, however, cost may limit their feasibility for many patients.

Efficacy and safety of antihyperglycaemic drug regimens added to metformin and sulphonylurea therapy in Type 2 diabetes: a network meta-analysis.

To assess the efficacy and safety of third-line adjuvant antihyperglycaemic agents in people with Type 2 diabetes mellitus failing metformin and sulphonylurea combination therapy. We searched MEDLINE, CENTRAL, clinicaltrials.gov and regulatory websites, and conducted a manual search of references in the identified studies. Randomized trials evaluating antihyperglycaemic agents in adults with Type 2 diabetes experiencing poor glycaemic control despite optimized metformin and sulphonylurea therapy (≥ 1500 mg metformin or maximum tolerated dose; ≥ 50% of maximum sulphonylurea dose for ≥ 3 weeks) were included. Data extraction included: study characteristics; change in HbA1c concentration; weight; systolic blood pressure; and relative risk of hypoglycaemia, urinary tract infections; and genital tract infections. A network meta-analysis was performed. A total of 20 trials evaluating 13 antihyperglycaemic agents were included. Compared with placebo/control, all antihyperglycaemic agents reduced HbA1c levels, albeit by differing magnitudes [range 7 mmol/mol (0.6%) for acarbose to 13 mmol/mol (1.20%) for liraglutide]. Sodium glucose cotransporter-2 inhibitors reduced weight (1.43-2.07 kg) whereas thiazolidinediones, glargine and sitagliptin caused weight gain (1.48-3.62 kg) compared with placebo/control. Sodium glucose cotransporter-2 inhibitors, rosiglitazone and liraglutide decreased systolic blood pressure compared with placebo/control, pioglitazone, glargine and sitagliptin (2.41-8.88 mm Hg). Glargine, thiazolidinediones, liraglutide, sitagliptin and canagliflozin increased hypoglycaemia risk compared with placebo/control (relative risk 1.92-7.47), while glargine and rosiglitazone increased hypoglycaemia compared with most antihyperglycaemic agents (relative risk 2.81-7.47). No antihyperglycaemic agent increased the risk of urinary tract infection, but canagliflozin increased the risk of genital tract infection by 3.9-fold compared with placebo/control. When added to metformin and a sulphonylurea, antihyperglycaemic agents had varying effects on efficacy and safety endpoints. These conclusions should be considered when clinicians choose between possible adjunctive agents.

Case Study: Weight loss in a patient with type 2 diabetes: Challenges of diabetes management.

This patient with BMI 36 kg/m² and T2DM on insulin glargine and glyburide as well as atenolol for HTN was able to lose 10% of his initial body weight with a low-carbohydrate diet and exercise and adjustment of medications in approximately a 36-week time frame. Insulin glargine and glyburide were reduced gradually with blood glucose monitoring and replaced by an increase in metformin, start of liraglutide, and eventually phentermine/topiramate and canagliflozin (Figure). Therefore, medications that can exacerbate weight gain were discontinued in place of medications which promote weight loss.

Discovery and development of gliflozins

Activity of SGLT-2 inhibitors in glycemic control Michael Nauck recounts that meta-analyses of studies about the activity of SGLT-2 inhibitors in glycemic control in type 2 diabetes mellitus patients shows improvement in the control of glucose, when compared with placebos, metformin, sulfonylurea, thiazolidinediones, insulin and more. The HbA1c was examined after SGLT-2 inhibitors were given alone (as monotherapy) and as an add-on therapy to the other diabetes medicines. The SGLT-2 inhibitors that were used were dapagliflozin and canagliflozin and others in the same drug class. The meta-analysis was taken together from studies ranging from period of few weeks up to more than 100 weeks.

Liraglutide and obesity in elderly: efficacy in fat loss and safety in order to prevent sarcopenia. A perspective case series study.

For the growing numbers of obese elderly with diabetes, the glucagon-like peptide-1 (GLP-1) receptor analogue (liraglutide) appears a safe way to promote and maintain substantial weight loss. Given this background, the aim of this study was to assess the effect of the liraglutide treatment, at doses up to 3.0 mg per day, on the body composition, focusing on sarcopenia, in overweight and obese elderly with type 2 diabetes mellitus (T2DM). A perspective study was carried out in overweight and obese T2DM patients with HbA1c equal to 7.0 % (53 mmol/mol) ~10.0 % (86), under 3-month treatment (at least) of maximal dose of metformin at stable regime, and additional liraglutide at doses up to 3.0 mg per day. Body composition markers such as skeletal muscle index (SMI), android and gynoid fat mass, and arms and legs fat free mass, was measured by dual-energy X-ray densitometry (DXA) at baseline and after 24 weeks of liraglutide treatment. Glucose control was also carried out by glucose and HbA1c. Nine subjects (male/female 6/3, mean age 68.22 ± 3.86 years, BMI 32.34 ± 4.89 kg/m<sup2</sup) were evaluated. We noted a median decrease in BMI (-0.78 kg/m<sup2</sup), weight (-2000 g), fat mass (-1498 g) and android fat (-0.9 %), and a increase in SMI (+0.03 kg/m<sup2</sup) from baseline. Glycemic control also improved, with a median change HbA1c of -0.80 %. Twenty-four weeks of liraglutide treatment was associated with reductions in fat mass and android fat. In addition, in order to prevent sarcopenia, it preserved the muscular tropism.