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 Table of Contents  
Year : 2022  |  Volume : 1  |  Issue : 2  |  Page : 88-98

Choice of therapy in obese type 2 diabetes

1 Department of Endocrinology, Metabolism and Diabetes, All India Institute of Medical Sciences, New Delhi, India
2 Department of Diabetes and Endocrinology, Chellaram Diabetes Institute, Pune, Maharashtra, India

Date of Submission26-Mar-2022
Date of Decision07-Jun-2022
Date of Acceptance11-Jun-2022
Date of Web Publication16-Jul-2022

Correspondence Address:
Viveka P Jyotsna
Department of Endocrinology, Metabolism and Diabetes, All India Institute of Medical Sciences, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cdrp.cdrp_2_22

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Obesity is a chronic metabolic disease affecting individuals all over the world and is known to be a main risk factor for type 2 diabetes (T2D). In countries like India, T2D occurs with a lower degree of obesity as compared to T2D in western countries. It is important to tackle obesity in T2D because studies have shown that modest weight loss leads to improvements in glycemic levels, thereby reducing the risk of diabetes-related complications and comorbidities. Obesity complicates the management of diabetes, particularly the goal of achieving tight glycemic control as it is associated with insulin resistance. In this article, we are going to discuss choice of therapies in the management of T2D in obese individuals. In patients with T2D and obesity treatment approach should be individualized and it includes intensive lifestyle intervention, pharmacologic therapy, and/or metabolic surgery. Additional attention should be given to concomitant therapies for other comorbidities which may further lead to weight gain. Considering the strong link between obesity and T2D, the first choice of therapy after lifestyle modification should be glucose-lowering agents, which promote weight reduction or are at least weight neutral. Metformin, alpha-glucosidase inhibitor, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, glucagon-like peptide–1 receptor agonist (GLP-1 RA), and amylin mimetic promote weight loss along with additional cardiovascular benefits of GLP-1 RA, SGLT-2 inhibitor, and improved renal outcomes with SGLT-2 inhibitor. Weight neutral therapies include dipeptidyl peptidase-4 inhibitors and fixed ratio insulin/GLP-1 RA combination therapies (insulin degludec/liraglutide, insulin glargine and lixisenatide) can also be considered as they help to limit weight gain. Therapies such as thiazolidinedione, insulin secretagogue (sulfonylurea and meglitinide), and insulin are less suitable for individuals with obesity and T2D as they are associated with weight gain.

Keywords: Glucagon-like peptide–1, metformin, sodium-glucose co-transporter 2

How to cite this article:
Jyotsna VP, Deshmukh S. Choice of therapy in obese type 2 diabetes. Chron Diabetes Res Pract 2022;1:88-98

How to cite this URL:
Jyotsna VP, Deshmukh S. Choice of therapy in obese type 2 diabetes. Chron Diabetes Res Pract [serial online] 2022 [cited 2023 Mar 29];1:88-98. Available from: https://cdrpj.org//text.asp?2022/1/2/88/351234

  Introduction Top

Once considered a hassle in high-income countries, overweight and obesity are now on the rise in low- and middle-income countries, particularly in the urban settings. According to World Obesity Atlas published by the World Obesity Federation, by the year 2030, 1 in 5 women and 1 in 7 men are predicted to live with obesity (body mass index [BMI] >30 kg/m2) which is over 1 billion people will be affected by obesity globally. The percentage is likely to go up with each passing year. Noncommunicable diseases, including cardiovascular (CV) diseases, type 2 diabetes (T2D), musculoskeletal disorders, especially osteoarthritis, and some cancers, are the important consequences of overweight and obesity.[1],[2]

Many fundamental factors contribute to this modern society's epidemic of obesity including increased intake of energy-dense foods, sedentary nature of jobs, changing modes of transportation, poor food processing, expansion of urbanization, and reduced physical activity.[1] More than 95% of people with diabetes have T2D. T2D is largely the result of excess body weight and physical inactivity.[2] Therefore, in this article, we will be addressing the choice of therapies in individuals with obesity and T2D based on the latest evidence.

Strong evidence exists that obesity is a major, independent, and modifiable risk factor for T2D mellitus (T2DM). Inadequate amount of insulin production from the β-cells of the pancreas along with insulin resistance, the release of pro-inflammatory cytokines, endothelial dysfunction, deranged fatty acid metabolism, and mitochondrial dysfunction all these factors contribute a major role in the development of obesity and T2D mellitus.[3] The release of nonesterified fatty acids (NEFA) is an important factor affecting insulin insensitivity. Large amount of NEFAs release is observed in T2D, and in obesity, and it is associated with insulin resistance in both conditions.[4] Obesity management helps to improve insulin resistance, thereby delays the progression of prediabetes to T2D. Moreover, even modest weight loss improves glycemic control and reduces the need for glucose-lowering medications. More intensive dietary energy restriction can substantially reduce HbA1c and fasting glucose and promote sustained diabetes remission through at least 2 years.[5],[6],[7] Building positive health behaviors and maintaining psychological well-being are also foundational for achieving diabetes treatment goals and maximizing quality of life.[8],[9],[10]

As per American Diabetes Association (ADA) recommendations adults with overweight/obesity with T2D are best advised to be on an intensive lifestyle program to achieve and maintain a 7% loss of initial body weight and increase moderate-intensity physical activity (such as brisk walking) to at least 150 min/week. A variety of individualized and sustainable eating patterns can be considered to prevent diabetes in individuals with prediabetes.[11]

The Look AHEAD (Action For Health in Diabetes) trial aimed to study an intensive lifestyle intervention focusing on weight loss through decreased caloric intake and increased physical activity at least 175 min of moderate-intensity physical activity (for intervention group) per week compared to control group, the trial demonstrated no reduction in the rate of CV events in overweight or obese adults with T2D but showed that intervention group had significant weight loss compared to the control group which was 8.6% versus 0.7% at 1 year and 6.0% versus 3.5% at the study end. Furthermore, patients in the intervention group had clinical improvements in glycated hemoglobin levels, which were greatest during the 1st year and were partly sustained throughout the follow-up.[12],[13]

For individuals with proliferative diabetic retinopathy or severe nonproliferative diabetic retinopathy, vigorous-intensity aerobic or resistance exercise should be contraindicated because of the high risk of triggering vitreous hemorrhage or retinal detachment. Diabetes is associated with peripheral and autonomic neuropathy, which can increase the risk of sensory loss-related injuries while exercising or can lead to adverse events through decreased cardiac responsiveness to exercise, postural hypotension, impaired thermoregulation, and susceptibility to hypoglycemia.[14]

In obese/overweight individuals at high risk of T2D, care goals should include weight management either through weight loss or minimizing the weight gain, minimizing the progression of hyperglycemia.[15] Diet, physical activity along with behavioral therapy to achieve and maintain 5% weight loss is recommended for most people with T2D and overweight or obesity which further helps in improving glycemic levels and reducing CV risk. Different treatment options according to individual's BMI are mentioned in [Table 1].[16]
Table 1: Treatment options for overweight and obesity in type 2 diabetes

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As per ADA, the therapeutic approach in patients with T2D with overweight/obesity should always consider choosing glucose-lowering medications that promote weight loss or are at least weight neutral.[17] Antihyperglycemic drugs and their effect on weight change is mentioned in [Figure 1]. As far as possible importance should also be given in reducing concomitant medications used for other comorbidities which are associated with weight gain.
Figure 1: Antihyperglycemic drugs and their effect on weight change. DPP-4: Dipeptidyl peptidase-4, SGLT-2: Sodium-glucose co-transporter 2, GLP-1 RA: Glucagon-like peptide–1 receptor agonist, GIP RA: Glucose-dependent insulinotropic polypeptide receptor agonist

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If the patient's response to weight loss medication is effective (typically defined as >5% weight loss after 3 months of use), it is likely that further weight loss will occur with continued use. When the early response is insufficient (typically <5% weight loss after 3 months' use) or if there are significant tolerability or safety issues, discontinuation of medications and use of alternative medications or treatment approaches should be considered.[18]

Further, in this article, we will be discussing in detail individual drug characteristics which are preferred in the treatment of obese T2D patients, their side effects, and their impact on weight and HbA1c reduction.

[Table 2] gives information about drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with T2D.
Table 2: Factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes

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  Metformin Top

Metformin, a biguanide, is the first-line recommended treatment for T2D, it reduces hyperinsulinemia and promotes modest weight loss, particularly beneficial in patients with T2D and obesity.[19],[20] It has a very low risk of hypoglycemia with only mild gastrointestinal side effects[21] and can be given in doses of 2000–2500 mg/day for a good antihyperglycemic effect.[22] It has been shown to reduce HbA1c levels by & #126;1% compared with placebo.[19] Metformin has been evaluated for its effect on body weight in many clinical studies in diverse patient populations, and in approximately half of these studies, the drug-naive T2D patients treated with metformin demonstrated significant weight loss compared with baseline or comparator drugs and has also shown to mitigate weight gain associated with sulphonylurea-based regimens and insulin.[23] It acts by improving the action of insulin, particularly in the liver, and studies have reported insulin requirements reduced by 25% along with weight changes of +1.5 to −2.9 kg in insulin-naïve patients receiving metformin.[19],[23],[24] The long-term use of metformin may be associated with Vitamin B12 deficiency; hence, it is important to consider periodic measurement and supplementation of Vitamin B12, especially in those with anemia or peripheral neuropathy.[25] Lactic acidosis is a serious, rare complication that usually occurs in patients with renal insufficiency.[20] Metformin should not be used in patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 and total daily dose should be reduced in patients with eGFR between 30 and 45 mL/min/1.73 m2.[22] Metformin seems to be having promising anti-tumor and anti-aging effects along with its anti-diabetic actions.[26],[27]

  Glucagon-Like Peptide-1 Receptor Agonists Top

Glucagon-like peptide-1 (GLP-1)-based therapy improves glycemic control through multiple mechanisms along with the additional benefit of weight loss, reduced blood pressure (BP), and low risk of hypoglycemia events as they have a glucose-dependent mechanism of action. They act by stimulating GLP-1 receptors in the pancreas to enhance glucose-dependent insulin secretion and suppress inappropriately elevated fasting and postprandial glucagon levels. Further GLP-1 receptor agonist (RA) also acts on the central nervous system and gastrointestinal tract to decrease the appetite and enhance satiety through a chain of mechanisms, which includes slow gastric emptying which results in delayed intestinal glucose absorption, thereby reducing postprandial glucose excursions. They are also known to potentially promote β-cell proliferation and have anti-apoptotic effects on these cells, inducing insulin biosynthesis.[28],[29],[30],[31],[32] GLP-1 RA has been shown to reduce A1C ~0.8%–1.9% compared with baseline.[19],[22] Many GLP-1 RA s are developed to get prolonged in vivo actions as native GLP-1 is degraded within ~2–3 min in the circulation. These GLP-1 RA s can be classified according to their duration of action as short-acting (exenatide twice daily and lixisenatide once a day) and long-acting compounds (albiglutide, dulaglutide, semaglutide, liraglutide, and exenatide once weekly). ITCA 650 is a once yearly therapy in development, which provides continuous subcutaneous delivery of exenatide through a sub-dermally embedded miniature pump. The short-acting compounds primarily reduce postprandial blood glucose levels by slowing the gastric emptying, whereas the long-acting GLP-1 RAs have a stronger effect on fasting glucose levels, which is predominantly mediated through their insulinotropic and glucagonostatic actions.[30] Weight loss can vary depending GLP1 drug used and dosage. If actively trying to lose weight through lifestyle changes and one of these medications is added, clinical trial data show that treatment with GLP1 RA s is associated with weight changes ranging from 1.14 to 6.9 kg.[19] Based on the Semaglutide Treatment Effect in People with Obesity (STEP) clinical trial results, the Food and Drug Administration (FDA) approved semaglutide in a 2.4 mg once-weekly injection dose as a treatment option for chronic weight management in individuals with obesity or overweight status plus ≥1 weight-related condition such as T2D mellitus, hypertension, or dyslipidemia. It is available in once weekly injections with 0.25, 0.5, 1.0, 1.7, and 2.4 mg doses (each dose escalation after 4 weeks) for use in adults with obesity. The STEP trial of 68 weeks demonstrated significant weight reduction of −15.3 kg in semaglutide treated group compared to −2.6 kg in the placebo group.[33] Once weekly injection semaglutide is available in 0.5, 1.0, and 2.0 mg doses for the treatment in adults with T2D. In SUSTAIN FORTE trial higher dose of semaglutide injection 2.0 mg versus 1 mg showed superiority in HbA1c reduction, weight loss with similar safety profile which helps in achieving individualized glycemic targets in T2D individuals.[34]

Liraglutide has half-life of approximately 11–15 h which ensures continuous exposure of the GLP-1 receptors with a once daily dosing. It is currently approved for the treatment of T2DM and its effects are investigated in LEAD study which demonstrated significant reduction in HbA1c (0.8%–1.5%) along with weight-loss properties and also shown CV benefits in Liraglutide Effect and Action in Diabetes: Evaluation of CV Outcome trial.[35],[36] Higher dose of liraglutide is also approved for the treatment of obesity in people who do not have diabetes.[32],[33] Injection liraglutide administration is started with 0.6 mg dose once a day, after a week if well tolerated increase the dose to 1.2 mg and it can further be increased to 1.8 mg for better glycemic control.[37] Lixisenatide which is a shorter acting GLP-1 analog in Evaluation of Lixisenatide in Acute Coronary Syndrome trial did not prove CV benefit in patients with diabetes and a recent acute coronary syndrome.[38] EXSCEL (once-weekly extended-release exenatide) trial also demonstrated CV benefit.[39] Dulaglutide has a half-life of approximately 5 days allowing once a week dosing. The initiation of treatment in T2D adults is done with injection dulaglutide 0.75 mg dose escalated to 1.5 mg once weekly and to 3 and 4.5 mg every 4 weekly if additional glycemic control needed. Dulaglutide achieved noninferiority in head-to-head trial to injection liraglutide (1.8 mg) in AWARD 6 trial. The results of data from all AWARD trials, demonstrated HbA1c reduction of ~0.8%–1.6% with injection dulaglutide 1.5 mg.[37],[40],[41],[42],[43],[44],[45] All GLP1 RA s are currently contraindicated in Stages 4 and 5 chronic kidney disease (CKD) according to American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) Clinical Practice Guidelines. Liraglutide, albiglutide, or dulaglutide can be used in CKD Stages 2 and 3 without dose adjustment, although exenatide should not be used if creatinine clearance is <30 mL/min.[25]

The commonly experienced side effects with these agents are mild-to-moderate, transient gastrointestinal adverse events such as nausea and vomiting. They are used cautiously in patients with a past history of pancreatitis or severe gastroesophageal reflux disease. GLP-1 RAs are an injectable therapy, with frequency of injection ranging from twice daily to once weekly, depending on the compound formulation. The risk of low blood sugar levels is usually low but only increased, if patient is taking another medication known to lower blood sugar at the same time, such as sulfonylureas or insulin. According to the AACE and ACE Clinical Practice Guidelines, the GLP-1 class of drugs are not recommended if there is personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome Type 2. Laboratory studies have linked these drugs with thyroid tumors in rats, but until more long-term studies are completed, the risk to humans is not known.[22]

  Oral Semaglutide Top

In addition to the once weekly subcutaneous form of semaglutide, tablet formulation of semaglutide is developed which has simplified and made it convenient early use of GLP-1RA in T2D patients who are overweight or obese considering its significant additional benefit of weight reduction. It is a first oral GLP-1 RA which is coformulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate.[46] Oral semaglutide has a different absorption profile as compared to subcutaneous semaglutide, but once the drug gets absorbed, the effects of semaglutide and pharmacokinetic properties are similar, regardless of the route of administration.[46] In Phase II of PIONEER-6 trial, oral semaglutide (doses ranging from 2.5 to 40 mg once daily) showed greater reduction in HbA1c levels compared with placebo in a dose-dependent manner (−0.7% to −1.9% compared with −0.3% with placebo). Furthermore, in the same trial, oral semaglutide demonstrated significant dose-dependent weight reduction (−2.1 to −6.9 kg vs. −1.2 kg with placebo).[47] In PIONEER-6 trial, oral semaglutide has demonstrated similar CV safety profile to that of once weekly subcutaneous semaglutide form as demonstrated in SUSTAIN-6 TRIAL.[48]

  Dual Glucose-Dependent Insulinotropic Polypeptide/Glucagon-Like Peptide–1 Receptor Agonist Top

The US FDA approved tirzepatide injection on May 13, 2022, it is a new once-weekly dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) RA which can be used as an adjunct to diet and exercise to improve glycemic control in adults with T2D and is likely to be available in US Soon. The SURPASS clinical trial program, a development program for tirzepatide demonstrated average A1c reductions between 1.8% and 2.1% for tirzepatide 5 mg dose and between 1.7% and 2.4% for both 10 mg and 15 mg doses. A key secondary endpoint in all SURPASS studies was significant mean change in body weight which was around 12 lb with 5 mg and 25 lb and with 15 mg on an average without increased risk of hypoglycemia. All doses of tirzepatide showed significant beneficial effects on HbA1c and weight. The phase 3 SURPASS clinical trial demonstrated superiority of tirzepatide in A1C reduction as compared to injectable semaglutide 1 mg, insulin glargine, and insulin degludec. Tirzepatide will be available in six doses 2.5, 5, 7.5, 10, 12.5, and 15 mg which will come in Lilly's auto-injector pen with a preattached, hidden needle.[49],[50],[51],[52],[53],[54],[55] It is not indicated in Type 1 diabetes patients and is not being studied in patients with a past history of pancreatitis.[49] Tirazepatide can cause gastrointestinal side effects such as nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain. It is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome Type 2. The safety profile was consistent with GLP-1 RA s, indicating a potential monotherapy use of tirzepatide for T2D treatment.[50],[51],[52],[53]

  Sodium-Glucose Co-Transporter 2 Inhibitors Top

Sodium glucose cotransporter 2 (SGLT2) proteins are expressed in the proximal convoluted tubule of the kidneys. These transporters are an ideal target for the treatment of diabetes because they are responsible for 90% of filtered glucose reabsorption. They have glucosuric effect that results in decreased HbA1c, weight, and systolic BP.[56] In a recent study, it was found that empagliflozin improves insulin sensitivity of the hypothalamus in humans with prediabetes.[57] A large meta-analysis demonstrated that SGLT2 inhibitors were associated with reduction of weight in a range of −2.0–−2.3 kg compared with placebo with the largest weight reduction associated with canagliflozin.[58] In patients with T2D not willing to start insulin, SGLT2 inhibitors are an option. Patients at risk of hypoglycemia may benefit from the combination of SGLT2 inhibitors and metformin because with SGLT2 inhibitors risk of hypoglycemia is less compared to insulin and sulphonylureas. One of the most significant trials was the EMPA-REG OUTCOME study.[59] The randomized double-blind, placebo-controlled study included 7020 participants with established CV disease and demonstrated a 38% relative risk reduction in death from CV causes in the empagliflozin group versus the placebo group. Whether these results were due to improved glycemic control or the secondary benefits of SGLT2 inhibitors can only be speculated at this point and requires further investigation. In Canagliflozin Cardiovascular Assessment Study, canagliflozin demonstrated CV benefit[60] and reduced hospitalization for heart failure but was associated with increased the risk of amputation. People taking these drugs have seen improvements in their BP and cholesterol levels, although it is not clear whether these benefits are from the medication or the weight loss. SGLT2 inhibitors are associated with increased risk of mycotic genital infections and also slightly increased low density lipoprotein cholesterol levels, dehydration due to increased diuresis, diabetic ketoacidosis and because of their mechanism of action, they have limited efficacy in patients with an eGFR <45 ml/min/1.73 m2 AACE/ACE Scientific and Clinical Review expert consensus group recommended stopping SGLT2 inhibitors 24 h prior to scheduled surgeries and anticipated metabolically stressful activities (e.g., extreme sports) and that patients taking SGLT2 inhibitors with insulin should avoid very low carbohydrate meal plans and excess alcohol intake.[22],[61]

  Pramlintide Top

Amylin is a peptide co-secreted with insulin by pancreatic beta-cells. Pramlintide, which is a synthetic amylin agonist acts by slowing gastric emptying, suppresses inappropriately elevated postprandial glucagon secretion, and reduce food intake, which collectively limits postprandial glucose fluctuations and improve overall glycemic control. In individuals treated with pramlintide, improvements in glycemic control occur in the context of weight reduction, allowing it to be an additional therapeutic choice for many insulin-using patients with Type 1 diabetes or T2D.[62]

  α-Glucosidase Inhibitors Top

α-Glucosidase inhibitors delay the end stage of carbohydrate absorption at the brush border of the intestinal epithelium as a result slows the spike in postprandial glucose. The agents currently available include acarbose, Voglibose, and miglitol. Their use is limited by a number of factors, including the need to administer the medication at the start of each meal, only modest reductions in blood glucose levels and flatulence as a main common side effect. These factors should be balanced against their ability to lower postprandial glucose without increasing weight or hypoglycemic risk.[63] There is also evidence suggesting that acarbose improves CV outcomes better than most antihyperglycemic agents. To effectively get the maximum potential and tolerance of these agents, the starting dose should be low, only once a day (e.g., one-fourth of maximum dose), with slow titration in dosage and frequency of administration over a period of weeks or months. α–Glucosidase inhibitors are particularly useful in individuals whose meals consist of high carbohydrate content. They are associated with a weight change in ranges from −0.43 to −1.80 kg and HbA1c reduction of ~1.0%. α–Glucosidase inhibitors should be used with caution in patients with CKD.[19],[64]

  Dipeptidyl Peptidase-4 Inhibitors Top

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a category of oral drugs for T2D that inhibit the breakdown of GLP-1 and enhance the release of insulin in response to a carbohydrate intake. In clinical practice, they are weight neutral, with a very low incidence of hypoglycemia. Studies associated with sitagliptin treatment showed variability between 1.5 kg of weight loss in 52 weeks of therapy to 1.8 kg of weight gain in 24 weeks of therapy.[65] Side effects of DPP-4 inhibitors include flu-like symptoms, runny nose, headache, sore throat, gastrointestinal problems including nausea, stomach pain, and diarrhea. Skin reactions are in a form of painful red or purple rash. DPP-4 inhibitors have been associated with an increased risk of pancreatitis.

  Fixed–Ration Combination Therapy Top

Fixed-ratio combinations can be used to intensify basal-supported oral therapy to achieve individualized targeted HbA1c levels. Till date two regimens are available: insulin glargine and lixisenatide (iGlarLixi) and insulin degludec and liraglutide (IDegLira). The use of once-daily injection of GLP-1 RA/basal insulin titratable fixed-ratio combination has reduced complexity of therapeutic regimen compared to the daily burden of basal bolus multiple injection therapy and also is cost-effective by reducing total daily dose thereby increasing patient adherence to treatment. Clinical trial data from patients receiving fixed-ratio combination therapies showed a weight change of −0.3–−0.7 kg for iGlarLixi and −2.7–+2.0 for IDegLira compared to using insulin glargine and degludec alone, respectively.[19]

The use of GLP1 RA either liraglutide or lixisenatide in the combination with basal insulin has mitigated these differences in weight along with reduced hypoglycemia risks and gastrointestinal side effects. Fixed ratio combination therapy has shown and better safety profile in intensifying basal insulin therapy with a higher likelihood of achieving A1c <7.0% and produce greater A1c reductions (~0.72%) compared with using individual basal insulin alone. According to the Delphi consensus, the fixed-ratio combination IDegLira was considered preferable to the fixed-ratio combination iGlarLixi in the control of glycemia, body weight, and CV risk.[66]

  Metabolic Surgery Top

As per the ADA guidelines, metabolic/bariatric surgery should be recommended for T2D patients with BMI >40 kg/m2 (BMI 37.5 kg/m2 in Asian Americans) and in adults with BMI 35.0–39.9 kg/m2 (32.5–37.4 kg/m2 in Asian Americans) who do not achieve durable weight loss and improvement in comorbidities irrespective of extent of glycemic control with nonsurgical methods.[17]

Metabolic surgery can be considered as treatment option in T2D adults with BMI 30.0–34.9 kg/m2 (27.5–32.4 kg/m2 in Asian Americans) who are unable to achieve durable weight loss despite of intense lifestyle intervention and optimal pharmacotherapy. People who undergo metabolic surgery should undergo routine monitoring of micronutrient, nutritional, and metabolic status and should receive careful, long-term medical and behavioral support.[17] Studies have shown that the clinical and laboratory manifestations of T2D are resolved or improved in majority of patients after bariatric surgery and these responses are more dominantly noticed with procedures that resulted in a greater percentage of excess body weight loss and this postbariatric surgery weight loss maintained for 2 years or more. A large meta-analysis of 621studies showed significant weight loss of 38.5 kg or 55.9% excess body weight loss. Overall, 78.1% of individuals with T2D had complete resolution, and diabetes was improved or resolved in 86.6% of patients. Weight loss and resolution of diabetes were the greatest for patients undergoing biliopancreatic diversion/duodenal switch, followed by gastric bypass and lowest for banding procedures.[67]

  Future Pharmacological Agents for Management of Type 2 Diabetes and Obesity Top

CagriSema studied in a randomized, double-blind, placebo-controlled 20 weeks' phase 1b study which was done to investigate the use of cagrilintide (0.16, 0.30, 0.60, 1.2, 2.4, and 4.5 mg) in combination with semaglutide 2·4 mg for weight management. The study results showed the use of cagrilintide which is a long-acting acylated amylin analog in combination with semaglutide 2·4 mg had acceptable safety profile and was well tolerated in participants with overweight and obesity with and that this treatment combination can promote clinically significant dose-dependent weight loss up to 17·1% bodyweight, without lifestyle interventions.[68] The elimination half-life of cagrilintide was 7–8 days, with maximum exposure after administration 24–25 h, making it suitable for once-weekly dosing and its concomitant administration did not affect exposure or elimination of semaglutide further supporting the combination clinical trial. Although the study was of short duration, study data support the further clinical development of CagriSema which is a combination of cagrilintide and semaglutide 2·4 mg as a potential novel and effective therapy for weight management.[69] Another novel drug IcoSema, taken once a week, which is a combination of insulin icodec and semaglutide is being studied in COMBINE 2 and COMBINE 3 primarily to investigate its efficacy in HbA1c reduction along with its potential effect on weight reduction. Many unimolecular multiagonist peptides are in preclinical and clinical trials which are being developed as novel therapeutic approaches for obesity-diabetes to achieve the combinatorial metabolic efficacy by concurrent activation of multiple gut hormone receptors. One such example is GLP-1/Glucagon/GIP triple agonist peptides, namely DPP IV resistant Y (1)-dA (2)-I (12)-N (17)-V (18)-I (27)-G (28, 29)-glucagon (termed YAG-glucagon), [DAla2] GIP/oxyntomodulin, and [DAla2] GLP-1/glucagon hybrids all were reported to activate GLP-1, GIP, and glucagon-signaling pathways and are going to offer breakthrough nonsurgical options for obesity and T2D management. However, chronic safety and sustainability of these novel agents needs to be carefully evaluated.[70],[71],[72],[73] Dual-agonist peptides GLP-1/Glucagon Receptor, GLP-1/cholecystokinin, GLP-1/gastrin, and GLP-1/xenin GLP-1/amylin agonists are also being evaluated in clinical trials and will require cautious interpretation of preclinical studies to ensure bench-to-bedside translation.[70]

  Conclusion Top

Intensive lifestyle modification with diet and exercise is an essential part of management of T2D in individuals with obesity. Pharmacological agents which improve glycemia, insulin resistance, and limit weight gain are preferred. Metformin is the most time tested and incurs less cost. Drugs from class of SGLT2 inhibitors, GLP-1 RA provide additional CV benefits, and better renal outcomes along with considerable weight loss. If insulin is used to reach targeted HbA1c levels prefer combination therapy with a GLP 1 RA is recommended for greater efficacy and durability of treatment effect. Novel drugs such as oral semaglutide and tirzepatide have made it feasible to get significant weight loss in T2D obese patients when used with diet and intensive life intervention. In future, unimolecular multiagonist peptides (triple agonist and dual peptide agonist) will further improve the therapeutic approach of obesity and T2D management.

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